Document 5kxkQx1qwQ82ppkNpxank6d1z

Summary Tables on the Health Effects Data for Hazardous Air Pollutants (HAPs) - Group 1 Prepared By: Michael W. Neal, Nancy Goddard, and Heather Printup Environmental Science Center Syracuse Research Corporation Merrill Lane Syracuse, NY 13210 August 1995 DO 1 7 9 6 8 7 g o nftdfnt ia i DO 1 2 9 6 8 8 OONFTOFNTT Table of Contents by Chemical Name Chemical Name CAS Number l,l'-Biphenyl Carbonyl Sulfide Chlorine Chlorobenzene Chloroprene Cresols Diethanolamine Ethylbenzene Ethylene dichloride Ethylene glycol Hydrochloric acid Hydrogen fluoride Maleic anhydride Methyl isobutyl ketone Methyl methacrylate Naphthalene Phenol Phthalic anhydride l ,2,4-Trichlorobenzene 1,1,2-Trich loroethane Vinylidene chloride 92-52-4 463-58-1 ..................... 7782-50-5 .. 108-90-7 126-99-8 ... 1319-77-3 .. 111-42-2 .. . 100-41-4 . . 107-06-2 ... 107-21-1 ... 7647-01-0 .. 7664-39-3 .. 108-31-6 ... 108-10-t ... 80-62-6 ___ 91-20-3 108-95-2 ... 85-44-9 ___ 120-82-1 . 79-00-5 .... 75-35-4 .... II X> Page .. 56 . 144 ., 173 .. 102 .. 126 . 147 .. 115 .. 60 . 69 ...80 .. 162 .. 167 ... 96 ... 90 .. 30 .. 49 . 108 .. 45 .. 120 ... 18 .... I Table of Contents by CAS Registry Number CAS Number Chemical Name Page 75-35-4 79-00-5 80-62-6 85-44-9 91-20-3 92-52-4 100-41-4 107-06-2 107-21-1 108-10-1 108-31-6 108-90-7 108-95-2 111-42-2 120-82-1 126-99-8 463-58-1 1319-77-3 7647-01-0 7664-39-3 7782-50-5 Vinylidene chloride............................................................................ .......... .. ] 1,1,2-Tricbloroethane ............................... .................................. J* Methyl methacrylate......................................................... .............................. 30 Pbthalic anhydride............................................................. ... .................... 45 Naphthalene........................................................................................ ___ ... . 49 t,t'-Biphenyi....................................................................... 56 Ethylbenzene..................... ......................................... ........................................ . 60 Ethylene dichloride ,, ............................................. ....................................................................... 69 Ethyleneglycol ........................................................................................ ...............................................................................80 Methyl isobutyl ketone ..................................................... ......................................... ... 90 Maleic anhydride.................................................................................. ............................................................................... 96 Chlorobenzene ........................................................................ Phenol ............................................................................... ........................................ , .. JO* Diethanolamine..................................................................... . , .............................................................................115 1^,4-Trichlorobenzene....................................................... Chloroprene ............................................................................ ............................................................................. 120 ... 126 Carbonyl sulfide ............................................................... ...................... ................................................................... M4 Cresols.................................................................................................... ........ .................... .. |47 Hydrochloric acid ............................................................. 162 Hydrogen fluoride.................................................................................... ................................................................. 167 Chlorine .................................................................................. ............................................................................. 173 DO 1 7 9 6 8 9 CO NFIDFNT 1Al in TECHNICAL APPROACH FOR DEVELOPING HEALTH EFFECTS PROFILES FOR HAPS Scope of this document: The information contained in this document is not intended to be an exhaustive review of the scientific health effects literature on these chemicals, but to provide a summary of the relevant literature needed to make a decision as to whether additional testing is needed to understand the toxicity of these compounds following inhalation exposure. To fulfill this goal, the following criteria were used for the inclusion of studies, and the final summaries were reviewed by EPA Acute, Subchronic, and Chronic Systemic Noncancer Toxicity - Since the main concern of this review is inhalation nsk, only inhalation studies were reviewed. Although oral studies can provide important information on target organ toxicity and should be considered in the design of any testing protocol, these studies usually provide no information on the effects of a compound on the respiratory tract. In addition, the systemic dose of many compounds are affected by "first pass" effects at the portal of entry into the body making extrapolation between oral and inhalation exposure problematic unless extensive pharmacokinetic data are available. An exception to this is dibutyl phthalate, which, because of its low vapor pressure, is being considered for oral testing. For this chemical, oral acute, subchronic, and chronic toxicity studies were reviewed and summarized. Reproductive Toxicity, Developmental Toxicity, Neurotoxicity and Carcinogenicity - These endpoints were considered to be very important in evaluating the potential health effects of the chemicals and for these endpoints, studies were reviewed regardless of the route of administration. In the evaluation of these endpoints, studies that were considered to provide no useful information because of inadequate study design or poor reporting of experimental procedures were not included in the tables. > Pharmacokinetics - For pharmacokinetics, only a summary statement was provided on the availability of pharmacokinetics data. The source of information on pharmacokinetics data was obtained from secondary sources initially consulted for evaluation of the HAPs. The purpose of this pharmacokinetics summary statement was to indicate whether there was potentially sufficient information on the pharmacokinetics from the oral and inhalation routes to allow route-to-route extrapolation of toxicological studies. Genotoxiclty - This toxicological endpoint was not included in this document, but summarized separately in Waters, 1990 which is available in the docket for the Test Rule. Adequacy of Data - in the tables, adequacy is used to indicate if the conduct and design of the study are sufficient to meet the requirements of OPPTs Test Guidelines. It should be noted that a study does not have to specifically meet the TSCA testing guideline, but it must have such qualities as sufficient numbers of test animals so that adequate statistics can be performed and sufficient doses tested to define a dose-response relationship. When a study is indicated as inadequate, it is not implied that the study was necessarily poorly conducted or does not provide useful and accurate test data, but only that the study does not meet OPPT's test guidelines and that it would not provide the best basis for a risk assessment using current EPA methodology. Identification of relevant scientific literature: Under EPA's direction, SRC performed searches of the literature in a step-wise manner to save both time and expense. The first step was to identify and review secondary source health effect documents. EPA realizes that using secondary sources of information is not idea), since the secondary source can miss important information or incorrectly interpret a study. If information appeared to be missing or the interpretation was unclear, SRC obtained the original article for clarification. The second step was to conduct up-date searches of the scientific literature, identify studies, obtain the original articles, and review these studies for inclusion in this document. The following details the strategy that was utilized' For this group of HAPs, EPA, IARC, or ATSDR health effects documents were identified and relevant data were extracted from these secondary sources and placed in the tables. If essential information was missing from the review documents, then foe original article was consulted iv ro> v z-n o o't Z (T -I *0 r--I O T>  To obtain unpublished studies submitted to EPA under TSCA, the TSCATS data base was searched by CAS Registry number, the documents were retrieved, and the study information was entered into the table. A current (1993) printout of the NTP Results Report (generated from NTP's CHEMTRACK data base) was reviewed to determine if there were completed studies conducted by NTT* and obtain the status of studies tn progress or planned. The National Toxicology Program Review of Current DHHS, DOE, and EPA Research Re/afed to Toxicology Fiscal year 1993 was reviewed to determine the status of on-going toxicity studies on these HAPs If few studies were identified, then searches were conducted on CAS ONLINE The EPA IRIS data sheets were reviewed to ascertain if additional data had been identified by the working group, and if studies were found, they were retrieved and added to the table. An up-date search of the open literature was conducted on TOXLINE from 3 years prior to the date of the review document used to initially obtain toxicity information. These searches were reviewed, hard copies of relevant articles were retrieved, and the data from these articles were entered into the tables. The literature searches were conducted in the latter part of 1992 and earfy in 1993, however, additional studies have been added through the middle of 1994 as these studies were identified during the review process by EPA and SRC. In general, translations of foreign articles were not available and few such articles are included in this document. Exceptions occurred when the translation was readily available in SRC's achives or through EPA. The tables were reviewed by a committee in EPA Representatives from NIOSH, OSHA, FDA, and Nl EHS were consulted to determine if these organizations had any information on completed or on-going studies that might not be included on any readily available database. Representative trade organizations of the chemical industry were contacted to determine if they were aware of any on-going testing. Other related documents: Two additional documents were prepared for the evaluation of die testing needs for these HAPs. One was a support document on physical chemical properties, environmental transport and persistence, and exposure (occupational, consumer, environmental, and general population) entitled Exposure Profile for HAPs - Group 1 prepared by SRC (May 25, 1994) The second was an evaluation of the genotoxic potential of these HAPs entitled Genefrc Activity Profiles of 110 Hazardous Air Pollutants Listed Under Title III of the Clean Air Act prepared by Waters at EPA. Both of these documents are included in the docket for this Test Rule. V Table of Toxicity Data for HAPs Chemical Name Vim !i dene chloride [ Vinylidene chloride Vm>lrdene chloride Vinyl idene chloride Vinylidene chloride Vinyl idene chloride n oD zo M t- o \) m so Z O' -f sO -< \> I> CAS Number Study Type 75-35-4 Epidemiology (Cohort study) Species Route of Administration Type of Exposure Duration Humans Occupational Inhalation Less than 12 to over 120 months 75-35-4 75-35-4 Epidemiology - Summary Acute toxicity Rats and Inhalation mice Vapor 6 hours 75-35-4 7505-4 75-35-4 Acute toxicity Rats Inhalation Vapor 4 hours Acute toxicity - Summary Subchronic toxicity Rats Inhalation Not reported 90 days; continuous exposure Exposure levels Less than 500, 500-999, 1,0001,999. to over 2,000 ppm months 0. 10. and 50 ppm Not reported 0,20,61, 101, and 189 mg/m' (0. 5 04, 15.39, 25.47, and 47.67 ppm) I Number studied/ exposure level Response Study Adequacy Comments Reference 28 to 32 in the three higher exposure groups and 50 in the lowest exposure group There was no increase in lung cancers tn exposed workers Inadequate because study cohort was small and there was no allowance for a latency period There was exposure to other chemicals including vinyl chloride. Ott ctal 1976 No adequate epidemiological studies were located; however, some information regarding occupational exposure is available (ATSDR, 1992). Males Tissue damage and increased DNA replication were noted in kidneys of exposed mice Inadequate because of loo few concentration levels tested and the use of only one sex. The authors suggested that tumors in mice arose primarily through effects of the chemical on oongenelic components of the cells Reitz et al, 1980 6/exposure group LCW= 32,000 ppm Adequacy could not be determined. This is a brief description of sludy results. Carpenter el al., 1949 No adequate acute inhalati cm toxicity studies are available ISAreatment group, 304 control rats; sex not reported Reduced weight gam and elevated liver alkaline phosphatase and serum glutanicpyruvic transaminase activities were observed in high-exposure animals. Microscopic liver and kidney lesions were also observed only in high-dose animals This is a marginally adequate subchronic toxicity sludy because of the number of animals in the treated groups LOAEL = 189 mg/m' (NOAEL* 101 mg/m') for subchronic inhalation toxicity. Prendergast et al. 1967 Table of Toxicity Data for MAPs (continued) Chcmfcul Name______ CAS NumberStudy TypeSpecies Route of Number studied/ Administration Type of exposureDurationexposure levelsexposure level________ _____Rcsprmr _____ ____^ludy Adequacy 1 Vinylidene chloride 75-35-4 Subchronic loxifMy Guinea P'gs Inhalation Not reported 90 days; continuous exposure Vinylidene chloride 75-35-4 Subchroaic toxicity - Summary ft. 20, 61, 101, and 189 mg/m1 1 5/treatmenl group, 314 control gurnca pigs; sex nol reported Reduced weight gain and elevated liver alkaline phosphatase and serum glutamicpyruvic transaminase activities were observed in high-exposure animals No gross or histopalhological changes were observed This is a marginally adequate subchronic toxicity study because of the number of animals in the treated groups These data suggest a LOEL of 189 mg/m' (NOEL * 101 mg/m') for subchronic inhalation toxicity. Prendergast el at., 1967 Available data suggest a potential for subchronic inhalation toxicity, with liver and kidney as possible target organs {HEEP. 1986). 1 1 O bd 2"T-* O 5--f --i O V, '"f7 ^0 2: ^ \0 x> 2 Table of Toxicity Data for HAPs (continued) Chemical Name Vmylidcne chloride CAS Number Study Type 75*35-4 Chronic toxicity O ib ^ zo Tl rj \> -n *o X O' -t _t r> 9 Vinylidene chlornJc 75-35-4 Chronic toxicity Species Route of Admin istratton Type or Exposure Duration Exposure levels Number studied/ exposure level Response Study Adequacy Comments Rais Inhalation Mice Inhalation Vapor Whole-body 6 hours/day. 5 days/week, for \ 8 months 4 hours/day. 4-5 days/week for 12 months Nominal vapor concentrations of 0, 10. and 40 ppm (during first month), 0,25, and 75 ppm (during remaining 17 months) Interim sacrifices occurred after 1. 6, and 12 months of exposure A 6month observation period followed the exposure period 0 10 of 25 ppm (maximum loleralcd exposure) 85-86/sex/group No treatment-related changes were observed with respect to appearance and demeanor, hematology, clinical chemistry, or urinalysis. Statistically significant increases in absolute liver (males) and kidney (females) weights were observed in the treated groups at 12 months Organ weights returned to control level by 24 months Increased cumulative incidences (all sacrifices) were observed in mtdzonal hepatK fatty changes (females, 75 ppm), chronic or acute tracheitis (males and females; 25 and 75 ppm), and chronic murine pneumonia (males and females, 25 and 75 ppm) Both hepatic and pulmonary effects were diminished after cessation of exposure. This is an inadequate chronic toxicity study; a NOAEL was not identified 30 to 120/sex/ group Decreased body weight and kidney lesions occurred in high-dose animals, no effects were noted on survival An inadequate duration oftreatment was utilized, but was sufficient to identify effects. A free-standing LOAELof 25 ppm for respiratory effects in males and females during exposure is supported by these data. NOAEC = 10 ppm; LOAEC = 25 ppm Reference Rampyei al., 1977. 1978. McKenna et al., 1982. Quasi et a)., 1986 Maltoni et al. 1985 3 Table of Toxicily Rata for IIAPs (continued) Chemical Name 1 Vinrlidcnc cblondc CA.S Number Study Type 75-3S-4 Chrome toxicity Species Route of Administration Type of Exposure Duration Exposure levels Mice Inhalation Not reported 6 hours/day. 5 days/week for t2 months 0 or 55 ppm Number studied/ exposure level 16/sex/e vposnre VinyEidcne chloride 75-35-4 Chronic toxicity Mice inhalation Not reported 6 hours/day, 5 days/week for 6 months Gor 55 ppm 12/sex/exposure Vinylidene chloride 75-35-4 Chronic toxicily Rats inhalalion Not reported 6 hours/day, 5 days/week for If) months 0 or 55 ppm 15 or 16/sex/group 1 Vinylidene chloride 75-35-4 Chronic toxicity - Summary Response Study Adequacy Comments Reference Two males died and had acute toxic hepattlis and tubular necrosis of the renal cortex Decreased body weight and hepatocellular changes were noted in treated mice of both sexes, along with hepatic lesions including focal degeneration and necrosis, microfoci of mononuclear cells, and other Inadequate because of (he use of only one exposure level and a low number of tcsl anim afs for a short exposure period Additional groups of 4 mice/sex were sacrificed after 1.2,3, 6, and 9 months of treatment with similar results Lee et al, I977h 1978 Eleven died or were killed when moribund during the 18-month observation period Inadequate, because only one exposure level was used in a low number of lest animals for a short exposure period Cause of death was not reported, but tumor incidence did not differ significantly between treated and untreated animals Hong elal., L981 20/30 died or were killed when moribund during the observation period, as compared to 13/32 deaths among controls Inadequate because of the short exposure duration and use of too few test animals and treatment levels Cause of death was not reported, hut tumor incidence did not differ significantly between treated and untreated animats. Honget al, 1981 Available data indicate hepatic and pulmonary toxicity (Quasi et al, 1986, KEEP. 1986). O O Z> zo Z! \) "H *0 z Cf --I i--t C/t > 4 Table of Toxicity Data for HAPs (continued) Chemical Name______ CAS NumberStudy TypeSpecies Route of Administration Type or ExposureDmattooExposure levels Number studied/ exposure levelResponseStudy AdequacyCommentsReference Vinyl idene chloride 75-35-4 Vinyl idetie chloride 75*35-4 Carcinogenicity Rats Oral Carcinogenicity Rats Inhalation Drinking water Vapor 2 years 6 hours/day, 5 days/week, for IS months Nominal drinking water concentrations of 0. 50. 100, and 200 ppm (calculated TWA doses of: 0, 7, 10, and 20 mg/kg/day for males; 0, 9. 14, and 30 mg/kg/day for females) Nominal vapor concentrations of 0, 10. and 40 ppm (during first month), and 0, 25. and 75 ppm (during remaining 17 months) Interim sacrifices occurred after 1, 6, and 12 months ofexposurc A 6-monlh observation period followed the exposure period 48 rals/scx/group for treated groups; SO rats/sex for control group 85-86/scx/group No significant treatment-related carcinogenic effect was observed No treatment-related significant increases in tumors were observed in males or females. This is an adequate assay This is an adequate carcinogenicity assay Exposure duration was as in testing guidelines, however, animals were observed for lifetime Systemic toxicity was indicated by hepatocellular changes at 9 mg/kg/day in females and at 20 mg/kg/day in males Quasi et al.. 1983; Rampy el al., 1977; 1978, Humtston el al. 1978 A free-standing LOAELor25 ppm for respiralory effects in males and females during exposure is supported by these data Quastcl aJ., 1986. Table of Toxicity Data for liAPs (continued) Chemical Name I VinyEtdcne chlondc CAS Number Study Type Species Route of Administration Type of Exposure Duration 75-35-4 Carcinogenicity Mice Inhalatron Vapor 4 hours/day, 4-5 days/week., for S2 weeks Kxposure levels Number sludicdT exposure level 0, 10, and 25 ppm (acute toxic effects in 50. 100, and 200 ppm groups necessitated discontinuing treatment at these exposure concentrations) 30-120 males and fcmalcs/group Vinyl idene chloride 75-35-4 Carcinogenicity Mice Inhalation Vapor 6 hours/day, 5 days/week for 12 months 0 or 55 ppm 16/sex/exposure Vinylidene chloride 75-35-4 Carcinogenicity Mice Inhalation Vapor 6 hours/day, 5 days/week for 1, 3. or 6 months 0 or 55 ppm 8 or 12/sex/ exposure Response Study Adequacy Comments Reference Significant increases in the incidence of renal adenocarcinomas (doserelated) and mammary carcinomas (not doserelated) were observed in males (25 ppm) and females (10 and 25 ppm), respectively. Pulmonary adenomas (not dose-related) were increased in males and females of both treated groups Increased incidence of hepatic hemangiosarcomas and lung, skin, and liver cell turnon was noted, but the increases were not significantly different from that of controls. No significant increase in incidence of turnon was noted This is an inadequate carcinogenicity study on the basis of exposure duration, however, it is adequate to qualitatively determine carcinogenicity since the results were positive This study indicates a potential for carcinogenicity after prolonged inhalation exposure Inadequate because of the use of only one exposure level, and a low number of test animals for a short exposure period Additional groups of 4 mice/sex were sacrificed after 1,2,3, 6, and 9 months of treatment with similar results. Inadequate, because only one exposure level was used in a low number of test animals for a short period of time Negative results were obtained. Mallom cl al, 1985 Lee el at., 1977; 1978 S Hong el tl, 1981 O oo ZO n m -> Z 7--t X' Nj 3> 6 Table of Toxicity Data for HAPs (continued) Chemical Name______ CAS Number Study Type Species Route of Administration Type of Exposure Duration Exposure levels Number studied1 exposure levelResponse Study AdequacyComments Reference Vimfidcnc chloride 75*35-4 Vinvlidene chloride 75-35-4 Vmyhdene chloride 75-35-4 Vinytidene chloride 75-35-4 r> oo 2o 3 i--t M OT| \) -a 2 O' H M V0 3 3 Carcinogenicity Rats Inhalation Vapor Carcinogenicity Rats Inhalation Not reported Carcinogenicity Rats Inhalation Vapor Carcinogenicity Rats Inhalation Not reported 4 hours/day, 4-5 days/wcik for 52 weeks 0, 10.25, 50, or 100 ppm 30/sex/exposure 4 hours/day, 4-5 days/week for 52 weeks 0, 10,25, 50, or 100 ppm 30/sex/ex posure 6 hours/day, 5 days/week for 18 months 0, 10, and 40 ppm for first 42 days, then 25 and 75 ppm for remainder 8 5 -86/sex/e xposure 4 hours/day, S days/week for a total of 12 months 0 and 200 ppm for 5 months, followed by 100 ppm for 7 months 30-51 /sex/group Increased total number of rats with mammary tumors in 10 and 100 ppm groups and in total number of rats with fibromas and fibroadenomas in all groups, but a clear dose-response was not seen. Mammary carcinoma incidence in treated groups was not significantly different from that of controls. Life-time observations indicated incidences of brain tumors (gliomas, meningiomas, or ependymomas) were not significantly increased over control values Increased incidence of mammary noted at 25 ppm, but not at 75 ppm. Inadequate due to the low number of lest animals and short exposure duration. Inadequate due to the low number of test animals and shod exposure duralion. Inadequate due to the short duration of exposure A significant increase in tumor incidence was not seen Inadequate because of the short exposure duration and use of loo few treatment levels A clear dose-response was not observed Mallom et al, 1985 No evidence of carcinogenicity was seen. Mallonitl at, 1982 An exposure-related response was not seen, so the mammary tumor incidence was not considered trealment-retated This is a limited report, and the extent of histological examination was nol specified. Rampy et al., 1977, 1978; McKenna et al. 1982. Quasi el al, 1986 Viola and Caputo, 1977 7 1 able ofTosicity Data for HAI's (continued) Chemical Name Vmylidenc chloride CAS Number Study Type Species 75-35-4 Carcinogenicity Rats Route of Administration Type of hxpcvsurc Duration Inhalation Not reported fi hours/day. 5 days/week for 1 2 months exposure levels 0 or 55 ppm Number studied/ exposure level 1 fi/sex/group Vinylidene chloride 75-35-4 Carcinogenicity Rats Inhalation Not reported f> hours/day, 5 days/week for 10 months Oor 55 ppm 16/sex/group i Vinyl (dene chloride 75-35*4 Carcinogenicity Rais Oral Gavage 5 days/week for 104 weeks 0, 1, or 5 mg/kg/day in com oil 50/sex/group Response Study Adequacy A increased incidence of hepatic hemangiosarcomas was noted, but was not srgnificantly different from controls A significant increase in tumor incidence was not seen. Inadequate because of the short exposure duralion and use of too few test animals and treatment levels Inadequate because of the shod exposure duration and use of too few test animals and treatment levels No significant increase was noted in incidence of tumors with Bonferroni correction and Itfe table analysts; a significantly increased incidence of lymphomas was seen in female mice without the statistical corrections Inadequate because an MTD was not achieved Comments Reference Additional groups of 4 rats/sex were sacrificed after t, 2, 3, 6, and 9 months of treatment with similar results. Additional groups of 4 (o 8 tats/sex woe sacrificed after 1,3, and 6 months of treatment and 12 months observation with similar results. Use of a maximum tolerated dose was not demonstrated. Leeetal, 1977, 1978 Honget al 1981 NTP, 1982 I O oo zo T( Z> *0 vD Z O' --t --t xO I> 8 Oo Z3 ~n v Table of To'cicity Data for HAPs (continued) Chemical Name Vmylidene chloride CAS Number Study Type Species Route of Administration Type of Exposure Duration 75-35-4 Carcinogenicity Mice Oral Gavagc 5 days/week for 104 weeks Vinyl idene chloride 75-35-4 Carcinogenicity Rats Oral Drinking water 2 years I Virylidcoe chloride 85-35-4 Carcinogenicity Rais Oral Cravage 52 weeks Exposure levels 0,2, and 30 mg/kg/day in com oil Number studied/ exposure level 50/sex/day 0.7, 10. or 20 mg/kg/day (males), 0,9, M. or 30 (females) 48/sex/group; 80/sex in controls 0,5. 10, or 20 mg/Vg/day in olive oil 50/sex/group, 100/sex/group in controls Response Study Adequacy No significant increase wasnoled in incidence of tumors with Bonferroni correction and life table analysis, without these statistical corrections, there were increased incidences of adrenal pheochromocytomas, pancreatic islet-cell adenomas and carcinomas, testes interstitial cell tumors, and subcutaneous fibromas in males and piluitavy adenomas in females. Increased incidence of mammary gland fibroadenomas/ adenofibromas in low dose, but no doseresponse was noted. A high incidence of these tumors was seen in controls. Mammary carcinomas were not increased; increased incidence of total tumors was seen in males. No significanl increase m incidence of tumors was observed Inadequate because an MID was not ach ieved This is an adequate carcinogenicity study. The study is inadequate because the minimum acceptable dural ion is not used Comments Reference Use of a maximum tolerated dose was not shown NTP, 1982 Clear evidence of carcinogenicity was not demonstrated. Rampy et al, 1977. 1978, Humiston el al., 1978, Quasi et at., 1983 A longer exposure duration did not yield positive results in other oral studies. Malloniel al., 1985 0 Table of roxicily Data for HAPs (continued) Chemical Nar-Vinylidene chloride CA.S Number 75-35-4 Study Type Carcinogenicity Species Rats Route of Administration Type of Exposure Oral Gavagc Duration 52 weeks | Vinylidene chtoride 75-35-4 Carcinogenicity Rats Oral 1 Vinylidene chloride 75-35-4 Carcinogenicity Rats Oral Not reported, but appears to be gavage 52 to 59 weeks Gavagc 1 day/week for 120 weeks Vinylidene chloride 75-35-4 Carcinogenicity Mice Dermal Topical application 3 applications/ week for life i Vinylidene chloride 75-35-4 Carcinogenicity- Summary 1-xposure levels 0 or 0 5 mp/kg/day in olive oil Number studied/ exposure level 50/sex/group, 77 to 82/sex/group in controls 0,0 5, 5, 10 or 20 mg/kg/day in olive oil 50/sex/group, 175/sex/group tn controls 0 or 150 mg/kg on day 17 of gestation, from weaning, 0 or 50 mg/kg in olive oil 64 to 90 males and females 0, 40, or 121 mg/application in acetone 30 females/group Response No significant increase in incidence of tumors was observed. Incidence of brain tumors (gliomas, meningiomas, or ependymomas) were not significantly increased over controls Exposure in utero followed by weekly treatment from weaning did not lead to a significant increase in incidence of tumors An increased prevalence of hyperplastic nodules was seen in the liver. No local paptl tarnas or carcinomas, nor significant increase in incidence of distant tumors Study Adequacy Comments The study was inadequate since only one exposure group was used and the exposure duration was loo short Inadequate because of short exposure duration Data from other oral studies indicate that this dose was well below the MTD. Negative findings agree with other oral findings Reference Maltoni cl at. 1985 | Malloni <t a!., I9S2 Inadequate study Animate were treated once/week, which is not a standard TSCA guidelines regimen. Treatment has no effect on Utter size or pre-weaning deaths. Ponomartov and Tomatis, 1980 Inadequate study Animals were not treated the minimum recommended 6 hours/d ay. Van Duuren el il. 1979 j Available data suggest a potential for carcinogenicity fHEEP, 1986). E Table of Toxicity Data for HAPs (continued) Chemical Name J Vinyl idene chloride CAS Number 75-35-4 Vinylrdcne chloride 75*35-4 Vinylidene chloride 75-35-4 o OO 2O 1------ -q* ---1 O \> "n v0 2 \J HO --t V Sludy Type Developmental Neurotoxicity Species Route of Admin islratkm Type of Exposure Duration Rats Inhalation Not reported 23 hours/day. days 6-16 of gestation, and sacrificed on gestation day 20 Neurotoxicity - Summary Developmenial toxicity Rats -Fnhalaiion Not reported 7 hours/day, gestation days 615 Exposure levels 0.57, and 283 ppm (0, 230. and 1,142 mg/m'! 0, 20,80. and 160 ppm (0,80. 320. and 630 mg/m') 11 Number studied/ exposure level Response 13 to 18 treated and 1 7 control litlers. with tests conducted on 2/H Iter/e xposure group, one male and one female Tests were conducted from postnatal day I lo 12 or 14. No effects were observed in the following behavior tests: surface righting, pivoting, auditory startle, bar holding, righting in air, visual placing, swimming, physical maturation or activity tests 30-44 presumed* pregnant females in treated groups, 2047 in concurrent controls for each treated group Maternal effects were decreased food consumption and decreased body weight gain (days 6-9) m the 2 highest exposure groups, and increased liver weight in the high* exposure group. Significant <p < 0.05) changes in the incidence of delayed skull and cervical vertebra ossification and wavy ribs were observed in the 80 and 160 ppm exposure groups. Study Adequacy This is an adequate developmental behavioral sludy Comments A feed restricted control group was included because all treated dams ale less and had lower body weights lhan controls Reference Stan a ,.1,77* 1 Some information is available that indicates neurological effects (signs of inebriation) in humans and animals after acute inhalation exposure to high concentrations of vinyl idene chloride (ATSDR, 1992) A developmental behavioral study showed no effects of treatment This is an adequate developmental toxicity study A LOAEL of 80 ppm (NOAEL = 20 ppm) for aflerations in skeletal development and maternal toxicity was determined. Murray et al, 1979 Tabic ofToxicily Dala for IMPs (continued) Chemical Name jj Vmvlidcnc chloride CA.S Number Study T ype 75-35-4 Developmental toxicity Species Rabbits Roule of Administration Type of Exposure Duration Inhalation Not reported 7 hours/d ay, gestation days 6t5 Fxposurc levels 0. 80, and 160 ppm (0, 320, and 630 mg/m') Number studied/ exposure level Response Study Adequacy 18-22 presumedpregnant rabbits in treated groups. 16 in control group Maternal effects were a significant decrease m body weight gain in the 160 ppm group, and increased Iivct weight at 80 ppm (statistically significant) and 160 ppm (not statistically significant) groups There was an increased incidence of resorptions and skeletal alterations at 160 ppm This is a marginally adequate developmental toxicity study Only 2 exposure levels were tested. Comments Reference Maternal and developmental toxicity was seen at 160 ppm and maternal toxicity at 80 ppm Murray el al * 1979 D oa zo -n i--1 "* o \> T> -0 Z Nl HO --; 3> 12 Table of Toxicity Data for HAPs (continued) Chemical Name I Vinylidcne chloride CAS Number Study Type 75-35-4 Developmental loxicity Species Route of Administration Type of Exposure Duration Rats Inhalation Nol reported 23 hours/day. days 6-16 of gestation, and sacrificed on gestation day 20 Exposure levels Number studied/' exposure level 0, 15, 57.300. and 449 ppm (0. 59, 230, X190, and ITBOrrg/m1) Approximately 20/ exposure group. 60 in the control group Response Study Adequacy Maternal toxicily was noted at all test levels (decreased body weight gain and food consumption); 25% malemaf deaths occurred at 300 ppm and higher. There was an increased incidence of resorptions al 57 and 449 ppm, a decrease m number of fetuses/dm at 300 ppm, and a decrease in fetal weight al 57,300. and 449 ppm. The incidence of lateral ventricle hydrocephalus increased al 15 and 57 ppm (statistically significant) amt also at 300 ppm (not statistically significant). Also, a significant increase in incomplete stemebrae ossification was observed in the 15, 57, and 300 ppm groups This is a marginally adequate developmental toxicity study. A NOAEC was not identified for maternal and developmental toxicity. Comments Reference No effects were observed in behavioral tests of the pups Short el al, 1977a n o z 3? 3) n H --> D \) T1 Z \! HO --4 13 1 able of Toxicity Dala for I!Al's (continued) Chemical Name Vtnyhdcne chloride Vinylidene chloride 9 Vinylidene chloride CAS Number Study Type Species Route of Number studied/ Administration TypeofTaposurelluralronf.xpnsurc levelsexposure levelResponseStudy Adequacy CommentsReference 75-35-4 75-35-4 75-35-4 Development toxicity Mice Inhalation Developmental toxicity Mice Inhalation Developmental Itrcicity Sun mary Not reported Not reported 23 hours/d ay, days 6-16 of gestation, and sacrificed on gestation day 17 0. 15, 10. 57, 144, and 300 ppm HO 59. 120 230, 571,and 1190 mg/m1) 56 and 2R3 ppm (gd 8-2(1) 23 hours/day gestation days (g d) 6-15. 8-15. 10-15. 12-15 69,9-12, 12-15, and 15-17 54 ppm (g d 615), 41, 54, and 74 ppm (g d 815). 41 ppm (g d 10-15). 54 ppm (gd 10-15 and 12-15), 56 81. and 112 ppm (g d. 6-9, 9-12. 12-15. and 1517) Approximately 20/ exposure group. 60 m the control group Not reported Maternal mortality was 100% at 144 and 300 ppm, and decreased food consumption with decreased weight gain occurred tn groups exposed to a 30 ppm. There were no viable fetuses at 30 ppm or higher. Also, a significant increase in incomplete stemebrae ossification was observed in (he 15 ppm group. This is an inadequate developmental toxicity study because of severe maternal toxicity A NOAEC was nol identified for fetal effects Short et al, 1977a Maternal toxicity (decreased weight gain) was evidence at these shorter exposure periods, but incidences of resorption were decreased Developmental toxicity (increased incidences of cleft palate) was seen at 54 ppm levels, after treatment cm gestation days 10-15 and 12-15 Delayed ossification, immature skin, and hematomas were also noted in various groups (not specified). Inadequate study. Maternal toxicity occurred at nearly all concentrations The authors were attempting to eliminate the severe maternal toxicity observed in other studies by treatment for shorter times during gestation, along with identifying the sensitive times during gestation Short el al , 1977a Adequate or marginally adequate data are available for maternal and developmental effects in two species D DO 23 T C 'd T| vO 2 Nf -> o --i 3 I> 14 Table of Toxicity Data for HAPs (continued) | Vinyl idenc chlondc Vinylidene chloride Vinylidenc chloride Vinyl idene chloride CAS Number Study Type Species Route of Administration Type of Exposure Number stud ied/ DurationExposure levelsexposure levelResponseStudy AdequacyCommentsReference 75-35-4 75-35-4 75-35-4 75-35-4 Reproductive toxic rly Rats Inhalation Reproductive toxicity Rats Oral Reproductive toxicity - Summary Pharmacokinetics - Summary Not reported Drinking water 6 hours/day. 5 days/week, 11 weeks premating 55 ppm, control group not reported 3-generalion study Parental animals were exposed for 100 days before mating (after raising one litter, they were mated again for a second litter) and Flk rats were exposed after weaning. Exposure continued with the F} and FT animals Drinking water concentrations were 0.50, MX), or 200 ppm 12 males mated with 1 or 2 females Parental: ID males, 20 females in treated groups, 15 males, 30 females in the control group. Number of animals thal were bred in subsequent generations ranged from 20 to 24 tn the treated group Male fertility and the incidence of pie- aid post-implantation losses in females were not affected by treatment; however, there was a significant decrease in number of pregnancies. No clear dose-related reproductive effects were observed in any generation. This is an adequate dominant lethal lest, but does not fully evaluate the reproductive effects. These concentrations caused mild dose related lesions in the liver There were 20 maied females in the treated and 24 in the control group A free-standing NOEL of 200 ppm for reproductive effects after oral exposure is indicated by these data. Short el al., 1977b Nitschke et al. 1983 Available information sugj tests low reproductive toxfcJty potential, although adequate inhalation studies were not located (HEEP, 986; ATSDR, 1992) Data are available regarding the pharmacokinetics of inhaled or mgesled vinylidenc chloride. Absorption appears to be rapid and complete, pulmonary absorption appears to be brphasic with a rapid first-order phase. Distribution is primarily to the liver and kidneys, and significant accumulation does not seem to occur, up to 70-80% of absorbed oral and inhalation doses are excreted within 24 hours (KEEP, 1986) REFERENCES ATSDR (Agency for Toxic Substances and Disease Registry) "Toxicological Profile on 1,1-Dichlorncihene." (1992) Table of Icviciiy Data for I TAPs (continued) t'arpcnicr. C I* Smylh, It I*. and Pozzam, D C. "The assay of acute vapor toxicity, and the grading and interpretation of results on nincly-six chemical compounds " Journal of Industrial Ihgtcne and Toxicology 31(6)343-346 (1949). IIITP "lleaflh and Environmental Effects Profile Tor Dichlorocthcnes " US Environmental Protection Agency (1986) I long CM. Winston l M Thornburg, I, P , txe.CC., and Woods, J S "Follow-up study on the carcinogenicity of vmy I chlorulc and vtnylidene chloride in rats and mice tumor incidence and mortality subsequent to exposure N Journal of Toxicology and Environmental Health 7(6):909-924 (1981) T lumiston, C G-. Quasi, J F Wade. C F, Ballard, J , Beyer. J F . and Lisowe, R W "Results of a two-year toxicity and oncogenicity study with virtylidcne chloride incorporated in the drinking water of rats " MCA Report No. VCD 1 3-Tox-Orl-Dow. Toxicology Research Laboratory Health and Tnv ironmental Research, Dow Chemical USA. Midland, MI (1978) 1 cc, C C , Bhandvi. J C , Winston. I M , House, Wr.B . Peters, PL, Dixon, R L * and Woods, J S "Inhalation toxicity of vinyl chloride and vinyl idene chloride " Environmental Health Perspectives 21 25-32 (1977} Lee, C C , Rhandari J C . Winston. J M . House, W B . Dixon. R L, and Woods. J S "Carcinogenicity of vinyl chloride and vinyhdcnc chloride "Journal of Toxicology and Environmental Health 4(1) 15-30 (1978) Mallont. C . Ciliberti A . and Canetti. D "Experimental contributions in identifying brain potential carcinogens tn the pelrochemical industry " Annals of the Hew York Academy of Science 381 216-249 (1982) MaJtoni. C. Lefemme, G, Chteco, P., Com, G., and Patella. V "Experimental research on vinylidene chloride carcinogenesis" In Archives ofResearch on Industrial Carcinogenesis Volume 3 Mai ton i, C, and Mehlman, M.A , eds Princeton. NJ: Princeton Scientific Publishers pp 16-25 Bid 41-48(1985) McKenna. M J . Quast, F, Ballmer. M.F., and Rampy, L.W. "Vinylidene chloride' A chronic tnhalalicn toxicity and oncogenicity study in rats " Chemical Manufacturers Association Report No VDC l 3 September 8.1982. Murray, F J Nitschke. K D . Rampy. L, and Schweiz, B "Embryotoxicity and fetotoxicity of inhaled or ingesled vinytidene chloride in rals Bid rabbits " Toxicology and Applied Pharmacology 49:189-202 (1979) Nitschke. K P,, Smith, F A , Quasi. J F , Norris. J M , and Schwetz, B A "A three-generation rat reproductive toxicity study of vinylidene chloride in the drinking water" Fundamental and Applied Toxicology 3 75-79(1983). NTP. National Toxicology Program "Carcinogenesis bioassay of vinylidene chloride in F344/N rats and B6C3F1/N mice (gavage study) " NTP Technical Report No 228 (1982) Oil. M G , Fishbeck, W A , Townsend, J C.. and Shncider, E.J. 1976 "A health study of employees exposed lo vinylidene chloride * Journal ofOccupational Medicine 18(11) 735-738 Ponomarkov. V . and Tomalis, L "Long-term testing of vinylidene chloride and chloroprene in rats " Oncology 37(3) 136-141 (1980) Prendergast, J A. Jones, R A . Jenkins, LJ. Jr, Bid Siegel. J "Effects on experimental anrmafs of iong-term inhalation of trichloroethylene, carbon tetrachloride. 1,1,1 -trichloroelhane, dichlorodilluoromelhane. Bid 1,1-dichloroelhylene.' Toxicology and Applied Pharmacology I Q(2):270-289 (1967) Quasi, J F., Humislon, C G., Wade, C E , et al "A chronic toxicity and oncogenicity study in rats and subchronic loxicity study in dogs on ingested vinylidene chloride " Fundamental and Applied Toxicology 3(1) 55-62 (1983). Quast, J F., McKenna, M J , Rampy, L.W , and Norris, J.M "Chronic toxicity and oncogenicity study on inhaled vinylidene chloride in rals " Fundamental and Applied Toxicology 6.105-144 (1986) Rampy, L W . Quast, J F . Ifumtston, C G., Balmet. M F, and Schwetz, B A. "Interim results of two-year toxicological studies in rats of vinylidene chloride incorporated in the drinking water or administered by repeated inhalation " Eirviroomen/o/ Health Perspectives 21:33-43 (1977). Rampy, L W Quast, J F . Humtston, C G., Balmet, M F., and Schwetz, B.A "Results of 2-year toxtcological studies in rats of vtnylidene chloride incorporated in the drinking water or administered by repealed inhalation." Toxicology and Applied Pharmacology. 45(1) 244-245 (1978) Reitz, R H , Watanabe. P G . McKenna, MJ . Quast, J F., Bid Gehring. P J "Effects of vinylidene chloride on DNA synthesis and DNA repair in the rat and mouse: A comparative study with dimethylnitrosaminc * Toxicology and Applied Pharmacology 52 357-370(1980) 16 So zo -n O n J) Z-4 o -4 'J T> Table of Toxicity Data for H A Ps {continued} Shari. R D. Jr. Minor. J L.T Winston, J M , Eertuson. 8 , and Unger, T "Toxicity sludies of selected chemicals Task II. The developmental toxicity ofvinyhdene chloride inhaled by rats and mice during gestation Prepared by Midwest Research Institute. Kansas City, MO for the US EPA, Washington. DC t'PA-560/6-77-022 (19?7a> Short. R D Jr . Minor. J1.. Wirrston J M .and Lee. C.-C "A dominant lethal study in male rats afler repeated exposures to vinyl chloride or vinyl iderte chloride * Journal of Toxicology and Environmental Heailh 3 965-968 (1977b) Siegel. J . Jones. R A . Coon. R A , and Lyon. J P "Effects on experimental animals of acute, repeated and continuous inhalation exposures to dichloroacetylenc mixtures " Toxicology and Applied Pharmacology 18{l). 168*174 (1971). Viola P I. and Caputo, A "Carcmogcnicily studies on vinylidene chloride " Environmental Health Perspectives 21 45-47 (1977) n o z? zo m ~H --* O \j "n vO 2 vj -1 O -> o:< i> 17 Chemical Name t .1,2-Trichloroclhanc 1.1.2-Trichlorocthane 1.1,2-Trichloroethane 1,1,2-Trichlorocthane Table of Toxicity Data for MAPs (continued) CAS Number 79-00-1' Study Type epidemiology (Cohort study) Species Humans Route of Administration Type of Exposure Occupational Not reported Duration Not reported 79-00-5 Epidemiology (Cohort study) Humans Occupational Not reported >! year 79-00-5 79-00-5 Epidemiology Summary Acute loxtcity Rats Inhalation Not specified 6 hours Exposure levels Number studied/ exposure level Response Study Adequacy Comments Reference Not reported Not reported Not reported 58 solvenls/EDC plant workers (55 males and 3 females) and 38 contractors (sex not reported) 270 men(28 known deceased); comparison groups were all white males in United Slates during 1944-1982 (28 deaths compared to 29 15 expected deaths), and all white males in Texas during 1965-1982 (24 deaths compared to 19 37 expected deaths). Males; number not specified No effed of occupational exposure to 1,1,2Uichloroethane (among at least 15 other solvents) on serum chemistry including SGPT and cholesterol was reported, as compared to an unspecified range of reference values (the source of the range was not reported). Total deaths and cancer deaths were not related to occupational exposure to ], 1 ,2-tnchlorocthane (among 15 other chemicals) in 270 workers at a Texas manufacturing plant during 1944-1982. LCW = 1654 ppm. This study was inadequate because of the lack of exposure information This document was a sanitized summary report of a review of internal health records at Dow Chemical Co. submitted under TSCAto OPPT/EPA Dow Chemical Company, 1991 This study was inadequate because of the lack of exposuie informal ton. The study had 80% power to detect a i 5-, 1.8, and 24fold risk m all deaths, circulatory deaths, and cancer deaths, respectively. Dow Chemical Company, 1989 No adequate epidemi Dlogical studies on 1,1,2-tricbloroethanc were located [ATSDR, J98 9. CHEMTRACK, 7/93, US. CPA, 1984a (HEA, Final Draft), l S EPA, 1984b (EPA 540/1-86-045), 1ARC, 1991; TSCATS, 9/93 This study inadequately reported methods and results. This was a brief summary of an acute toxicity study, exposure was whote-body. Bonnet et at, 1980 18 n oo z~n o --< --> o <> z XJ HO '--f I> Chemical Name f 1 2-Trichloroethsne 1.1.2-Trichfnrneihant 1.1 2-Trichloroethane LI ,2-Trichloroe thane n oa OV T v6 2 \l Table of Toxicity Data for HAPs (continued) CAS Number 79-00-5 Study Type Acule loxicily Species Rais Route of Administralion Type of Exposure Duration Inhalation Vapor 4 hours 79-00-5 Acute toxicity Rats Inhalation Vapor S hours 79-00-5 Acute toxicity Mice Inhalation Not reported 6 hours 79-00-5 Acule loxicily Mice Inhatalion Not reported 3 hours Exposure levels Number studied/ exposure level 500 ppm, coni ml group nol reported 6/group; sex nol reported 1000, 2000 ppm; control group not reported 6/group. sex not reported Exposure levels not specified Number and sex not specified 800 ppm (control not reported) Number and sex nol specified Response 1/6 rals died. Study Adequacy This study inadequately reported methods and results Mortality was 3/6 in rats exposed to 1000 ppm, and 6/6 in rats exposed to 2000 ppm; all rats apparently died within the 8-hour exposure period This study inadequately reported methods and results. LCv, = 4J6 ppm Insufficient information is available for evaluation Transient decreases in plasma triglycerides and ATP and an increase in fiver triglycerides were observed SGPT was also increased, and remained elevated through 20 hours post dosing Insufficient information was available for evaluation Comments Reference This was a brief summary of a comparison between chemicals with respect to mortality due to inhalation; no LC*, or NOAEL was indicated Union Carbide Corporation, 1987 a This was a brief summary of a comparison between chemicals with respect to mortality due to inhalation, no LC* or NOAEL was indicated Union Carbide Corporation. I987d; Union Carbide Corporation, 1961 This was a brief summary of an acule toxicity study, a NOAEL was not indicated. Grediski et al, 1978 This was a brief summwy of an acute toxicity study, no NOAEL was suggested from these data, and it is not clew that all exposure levels were reported Takahara, 1986 19 Table of Toxicity Data for MAPs (continued) Chemical NameCAS Number 1 t.2-I'nchloroclhane 7*00-5 1,1,2-Tnchloroethane 79-00-5 1.1.2 -Tnchlnroethane 79-00-5 1 1.1.2-Trichlcwoethane 79-00-5 Rnulc of Sludy TypeSpecies_____ Administration type of exposureIXirationHxposure levels Number studied/ exposure level Acute toxicity Rats Inhalation Not reported 7 hours 100, 250, or 500 ppm (control group not reported) Females, number not specified Acute toxicity Rats Inhalation Not reported U 2. or 4 hours 250 ppm (control group not reported) Females, number not specified Acute toxicity Rats Inhalation Vapor 8 hours Not specified 6 females/group Acute toxicity Rats Inhalation Vapor 2 hours Oor 890 ppm 5 males/group Response Study Adequacy Comments Reference Mortality in over 50% of rats in the 250 and 500 ppm groups was reported; necropsy of survivors revealed "marked" kidney and liver damage. At 100 ppm, all survived but were not microscopically examined Liver and kidney necrosis were observed after a 4-hour exposure, but "apparently" not after 1 - or 2-hour exposures. 8-hour LCjo = 5 45 mg/L (1,000 ppm) (calculated by the moving average method). No treatment-related effects were observed with respect to relative liver weight, serum gtucose-6-phosphalasc, SGPT, or SGOT Adequacy could not be evaluated, methods and results were inadequately reported Adequacy could not be evaluated, methods and results were inadequately reported. This study was limited by a failure to report exposure levels, and insufficient endpoints examined. This study was limited by an insufficient number of exposure levels used and endpoints examined. This ts a summary of unpublished data, no NOAE1. was suggested from these data, since no histopalhology was conducted on the lowest exposure group This is a summary of unpublished data; aNOAEL was not suggested from the data and only a single dose level and a limited number of endpoints were reported. A NOAEL could not be determined This study indicates a free-standing NOEL of 890 ppm for hepatotoxicity. Torkelson and Rowe, 1981 Torkelson and Rowe, 1981 Pozzam el al, 1959 Carlson, 1973 r> oz zo "n n vD ZM --I -> T> 20 Chemical Name 1 1,1,2-Trichloroclhnnc 1,1 ,2-Trichloroethane o o o zo --nt o T1 v0 zH V--/1 i--i *'0 3> Table of Toxicity Data for HAPs (continued) CAS Number 79-00*5 79-00-5 Study Type Species Acute tonicity Summary Subchronic toxicity Rats Route of Administration Type of Exposure Inhalation Vapor Duration 7 hours/day. 5 days/week, 6 months Exposure levels Nuntbei studied/ exposure level 0 or 84 ppm 12 males and 12 femafes/group (5 replacement rats were used because of deaths in the first month) Response Study Adequacy Comments Reference The mortality Tate among exposed rats was 62% (18/29), although severe lung infection among some treated rats confounded the interpretation. "Major" damage occurred in liver, kidney, and lung m 55%, 52%, and 59% of exposed rats, compared to respective incidences of 46%, 25%, and 29% in controls. No notable differences with the control group were observed with respect to body length, liver and kidney weights, icterus index, liver fat and blood cvtoloev No adequate acute inhalation toxicity studies were located [ATSDR, 1989; CHEMTRACK, 7/93; U.S EPA, 1984a (HEA, Final Draft); U.S EPA, 1984b (EPA 541V1-86-045); LARC, 1991, TSCATS. 9/93], however, available data indicate that acute renal and hepatic toxicity and death result from single exposures of a250 ppm for *4 hours. This is an inadequate study due to the lung infection problem and the deficiency in number of exposure levels The replacement rats weTe exposed for 45 periods Union Carbide Corporation, 1987b 2 Chemical Name 1.1.2-7 ncMorocihanc 1,1,2-Tnchloroelhane l.t 2-Trichtomelhane 1.1,2 -Trichloroethsne T able of I oxicity Data for MAP's {continued) CAS Number 79-00-5 79-00-5 79-00-5 79-00-5 Study Type Subchrnmc toxicity Route of Species_____ Administration type ofT yposurc_______ Duration_____ I xposurc levels ITogs Inbafalion Vapor 7 hours/day 5 days/wcek. 6 months 0 or 84 ppm Subchronic toxicity Rats Inhalation Vapor Subchronic toxicity Mice Oral Gavage Subchromc toxicity/ Immunotoxicity Mice Oral Gavage 6 months, frequency not reported 0 or 100 ppm 14 days 0, 7 8, and 38 mg/kg 14 days 0.3 8, and 38 mg/kg Number studied/ exposure level 1 malc/group 4 males. 7 females in the treated group. 5 males. 6 females in the control group 8-12/sex/exposure group 8-12/sex/exposure group Response_________ Study AdequacyCommentsReference No notable changes from pre-exposure values were observed with resped to bromsulfalcm retention, scrum phosphatase level, blood urea nitrogen, and blood cytology A'light cloudy swelling" of the liver and "light" congestion ofthe lungs were noted at necropsy, while liver and kidney weights were not remarkable Mean liver and kidney weights as a percent of the controls were 93.0% and 94.1%, respectively. No other endpoints were reported. Brain, thymic, and testicular weights were significantly increased in males at 38 mg/kg. No alterations were noted in humoral or cellmediated immune status. This is an inadequate study due to deficiency in number of exposure levels and number of dogs exposed per level Methods and results were inadequately reported, only one concentration and too few animals were tesied This appears to be an adequate study. This appears to be an adequate study. Clinical values were determined monthly except for the Iasi month where they were determined weekly Umon Carbide Corporation, 1987b This report consisted of excerpts of tables from a large report Union Carbide Corporation, 1987c LDW is 378 mg/kg for males and 491 mg/kg for females. Doses tested were L/10 and 1/100 of LDW White et al., 1985a, White et al., 1985b Doses tested were 1/10 and 1/100 of ________ Sanders et al, 1985; White eta!., 1985b 1 Table of Toxicity Data for HAPs (continued) Chemical Name I 1.1,2-Trich lorocthane 1. \ .2-Trichloroeihane 1,1.2-Trichtofoclhanc 1 1.2-Trichforoclhane O zo oV sD Z N! -i --i x> CAS Number 79-00-5 79-00-5 79-00-5 79-00-5 Study Type Subchromc lox icily Species Mice Route of Administration Type of Exposure Oral Drinking water Duration 90 days Subchronic loxicity/ fmmunotoxicity Mfcc Oral Drinking water 90 days Subchronic loxicity Rats, guinea pigs, and rabbits Inhalation Not reported 7 hours/day, 5 days/wcek, 6 months Subrhronir to*icily - Summary Exposure levels Number studied/ exposure level Response Study Adequacy Comments Reference 0, 4 6. 46, and 305 mg/kg for males, 0.3 9,44, and 384 mg/kg for females 0. 4 6. 46, and 305 mg/kg for males. 0.3 9,44. and 384 mg/kg for females 15 ppm (control group not reported) 8-12/sex/exposure group 8-1Vsex/exposure group Males and females, number not specified There was a concentration dependant reduction in weight gain in males and alterations in hepalic microsomal enzyme activities and scrum enzyme levels in both sexes. A significant decrease in hematocrit aid hemoglobin levels in females was noted. Cell-mediated immunity was unaltered in both sexes and humoral immune status was depressed in both sexes Spleen lymphocyte responsiveness EPS <B cell mitogen) was significantly decreased in females. Macrophage function was depressed in males. No treatment-related effects were observed with respect to growth, mortality, organ weights, hematology, clinical chemistry, and hislopalhology, This appears to be an adequale study The liver was a target of loxicity in both sexes While et al, 1985a; While et al., 1985b This appears to be an adequale study There are sex differences in the ability of I.MirichloToethane to alter immune function. Sanders etd., I98S; White et al., 1985b Inadequate because only one concentration and loo few animals were tested This is a summary of tinpubl ished data. Tortelson md Rowe, 1981 No adequate subchronic inhalation toxicity studies were located (ATSDR, J989, CMEMTRACK, 7/93, U S EPA, 1984a (HEA, Final Draff). US. EPA, !984b(EPA 540/1-86-045), (ARC, 1991, TSCATS. 9/93) 23 t'hem ic al Name \ 1.1.2- rnchlorocllum: 1 |. 1.2-Tnchtorocthanc 1 U.2-Tnchiofoclhane I 'able of I n\icity Dala for HAPs (continued) CA S NumberStudy TypeSpecies 79-00-5 Chronic toiicity - Suinniiry 79-0A-5 Carcinogenicity Mice 79-00*5 Carcinogenicity Rats Rome of Administration Oral Oral Number slurficdf lyre uflApouiteDurationexposure levelsexposure levelResponseStudy Adequacy (ravage Oavage 5 days/week. 78 weeks; 13wcek posttreatment observation period 5 days/week, 78 weeks, 35week posttreatment observation period 0, 150. or 300 mg/kg/day in com oil for 8 weeks, then 0. 200, and 400 mg/kg/day for the remaining 70 weeks (TWA 0,195, and 390 mg/kg/day, calculated for 7 days/wcek); both vehicle and untreated control groups were used. 0, 35,and 70 mg/kg/day in com oil for 20 weeks, then 0. 50. and 100 mg/kg/day for the remaining 58 weeks (TWA: 0,46, and 92 mg/kg/day calculated for 7 days/week); both vehicle and untreated control groups were used. 50/sex 50/sex No chronic inhalation toxicity studies on 1,1,* trichloroethane were located {ATSDR, 1989, CHEMTRACK, 7/93; US EPA, 1984a (HEA, Final Draft), U S EPA, 1984b (EPA 540/1-86-045); IARC. 1991, TSCATS, 9/931 !j Hepatocellular carcinomas were increased in all treated groups (p<0.0l), adrenal pheochrocnocytomas were present in 8/48 and 12/43 high-dose males and females, respectively, but in no other group 50% mortality was achieved in each treated group during the period 58-90 weeks after initiation of dosing. This assay is limited by the alteration of dose levels in midtreatment and the brevity of the treatment period. However, the remaining methods and results appear adequate as a qualitative indicator of carcinogenicity A single technical grade batch of the lest substance was used; results of purity testing ranged between 9199% over 1 year; impurities were not specified. NCI. 1978 No significant increase in tumor incidence was found in males or females 50% mortality was achieved in each dose group during the penod 96 to >105 weeks after initiation of dosing. This assay is limited by the alteration of dose levels m midtreatment and an abbreviated treatment period. However, the remaining methods and results appear adequate. A single technical grade batch ofthe test substance was used, results of purity testing ranged between 91 99% over 1 year, impurities were not specified NCI, 1978 24 r> ov z- TI -r 'S'S> TabTe of Toxicity Data for HAPs (continued) Chemical Name 1.1.2-rrichforoclhane CAS Number 79-00-5 Study Type Species Carcinogenicity - Summary Route of Administration Type of Exposure Duration 1 I J,2-Trichlorncthane 79-00-5 Neurotoxicity Mice Oral Gavage (in water/com oil) Once I 1,1,2-Trichlorocthant 79-00-5 Neurotoxicity Mice Inhalalion Vapor 4 hours 1. t, 2-Trichloroethane 79-00-5 r> oo ------------ 2 ----------------1 Neurotoxicity - Summary Number studied/1 Exposure levelsexposure levelResponseStudy AdequacyCommentsReference 100 mg/kg; other dose levels not specified Not reported Male and female mice, number/group not reported 10 males/group 128 mg/kg caused reversible "motor impairment" m 50% of treated mice (although neither this dose level nor higher dose levels were reported in the methods) The peak effect apparently occurred 5 minutes after dosing Results of necropsy were not reported- Taste aversion" (not elaborated in study report) occurred in the 100 mg/kg dose group. 41B ppm of 1,14trichloroelhane was required for a 50% elevation in the clonic seizure threshold dose of penletrazole Carcinogenicity was demonstrated in mice but not in Tats (NCI. 197$), although the exposure levels in the ral assay are significantly lower than in the mouse assay and neither study strictly followed TSCA guidelines A review of other sources (ATSDR, 19S9, CHEMTRACK 7/93.1ARC. 199); TSCATS. 9/93) revealed no further carcinogenicity data This study is limited by insufficient reporting of methods and results These data do not support a NOAEL, since the dose levels were not clear. Borzclleca, 1983 This study is limited by failure to report the exposure levels tested, and by the failure to examine sufficient endpoints. This is a translation of a French study; these data do not support a NOAEL. since the dose levels were not clear De Ceaurrizel al. 1981 No adequate inhalalici or oral neurotoxicity s tudies on ) J4trkhloroethane were ocated J ATSDR. I99: <:HEMTRACK, 7/93. US EPA. l9Wa(HEA, Final Draft); U S. EP V 19Mb (EPA 540/186-045). 1ARC. 1991 TSCATS, 9/93). ailhou `h available data are suaeesiive of neurolo Steal effects Table of J oxietty Data for 11A Ps (continued) Chemical Name 1.1.2-1 richloroethane 1. 1.2 -Trichloroethane 1. 1,2-Tnchloroethanc LI 2-lnchfnroethane CAS Number 79-00-5 79-00-5 Study Type Chemofff Kavlock postnatal mouse screening lest Species Mice Route of Administration Type ofExposure Oral Gavapc [Juration Oncc/day. gestation days 8-12 Exposure levels Number studied/ exposure level 0 or 350 mgAg/day in com oil 30 timed-pregnant mice Developmental toxicity - Summary Reproductive toxicity - Summary Pharmacokinetics - Summsn Response Study Adequacy Comments Reference No treatment-related effects were observed with respect maternal toxicity, number of litlers bom, number of 1 itlers resorbed, number live pups/liTter, number dead pups/lilter, pup survival, live pup weight, and pup weight gam This is an adequate screening lest, but is not adequale to evaluate developmental toxicity since malformations were not studied. The major purpose of this study was to test the utility and accuracy of a developmental toxicity screen with numerous chemicals, including 1,1,2trichloroethane Scidcnberg el al, 1986, Scidenberg and Becker, 1987 No adequate Inhalation or oral developmental toxicity studies on M,2'trichloroelhanc were located (ATSDR, 1989.CHEMTRACK, 7/93. U.S EPA, 1984a (HEA. Final Draft); U S. EPA, 1984b (EPA 540/1-86-045); IARC, 1991; TSCATS, 9/931-_____________________ No inhalation or oral reproductive toxicity studies on 1,1,2tndiloroethane were localed [ATSDR, 1989; CHEMTRACK, 7/93; U.S. EPA. 1984a (HEA, Final Draft); U S EPA, 1984b (EPA 540/186-045)1ARC 1991; TSCATS, 9/93]____________________________ The blood/gas partit ion coe fficienl of 1.1,2-trichloroethane in rats and humans is suggestive of rapid absorption after inhalation exposure (IARC, 1991); data concerning respiratory and urinary elimination of radioactive label in humans after single-breath inhalation exposure to '*CI-labelled 1,1,2-TCE are available (ATSDR, 1989 JARC, 1991). Other data are available concerning distribution, metabolism, and excretion of L1,2-ICE after inhalation exposure, and after exposure by other routes (ATSDR, 1989, [ARC, 1991)__________________________________ REFERENCES ATSDR. (Agency for Toxic Substances and Disease Registry). "Toxicological Profile on Trichloroethylenes" (1989). Bonnet, P. Francin, J M . Gradi ski, D., Raoult, G., and Zissu, D." Determ in at ion of the LC w of the pri ncipal chlorinated al i phatic hydrocarbons i n the rat" A rch Mai Prof 41 317-321 (1980) fkwYclIcca. J F "A review of volatile organic contaminant data." Proceedings of the American Water Works Association Water Quality Technical Conference pp 225-244 (1983) t arlson G P "Effect of pbenobarbital and 3-methylcholarthrene pretreatment on the hepatotoxicily of l.bl-lrichloroelhane and 1.1.2-lrichloroeihanc " Life Sciences 13 67-73 (1973) 26 O oo zo T1 V 'J ti 41 Z "j --4 r-* ''J 1> J--"l 0 z -<x T| ^ z^ > Table of Toxicity Data for HAPs (continued) CKEMTRACK National Toxicology Program Results Report "Results, status and publication informaiion on all NfP chemicals produced from NTPCHFMTRACK. system " July (1993). De Ceauniz. J C , Micilfino. J . Bonnet P , and Gtiemer. J P "Sensory imutton caused by various industrial airborne chemicals " Toxicology Letters 9:137-143 (198!) Dow Chemical Company "Mortaltly among Dow Chemical employees of a Texas operations per-let manufacturing plant v. ith cover letter dated 050389 " TSCA 8D submission 86-890000215, microfiche number OTS0516752 Washington, DC OPPT, US EPA (1989) Dow Chemical Company, "letter from Dow Chemical Company to USEPA submitting studies on health effects of multiple chemicals on workers at several planl sites " TSCA 8D submission 86*910000955S, microfiche Number OTS0530632 Washington, DC: OPPT, US EPA (1991). Gradiski, D, flonnel. P. Raoult, G . Magadur. J L . and Francm. J M 'Compared acute pulmonary toxicity oT the main chlorinated aliphatic solvents " Arch Mai Prof MedTrav SecurSoc. 39 249-257 (1978). I ARC (International Agency for Research on Cancer) Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Ifumans 'Chlorinated drinking-water, chlorination by-products; some other haJogenaled compounds, cobalt and cobalt compounds" 52:337*359 (1991). NCI National Cancer Institute 'Rioassay of 1, 1,2-lrichloroelhane for possible carcinogenicity ' Technical Report Senes Number 74 (1978) Pouam, U C . Wetl.C S . and Carpenter, C P "The toxicological basis of threshold limit values 5 The experiment inhalation of vapor mixtures by rats, with notes up on the relationship between single dose inhalation and single dose oral data." American Industrial hygiene Association Journal. 20.364-369 (1959) Sanders, V M . Whfte. K L , Shopp. G M , and M unson, A.E "Humoral and cel I-mediated immune slatus of mice exposed to 1,1.2-trichloroethanc." Drug and Chemical Toxicology 8(5) 357-372 (1985). Seidenberg, J M , Anderson, D G., and Becker, R A. 'Validation of an nr vbo developmental toxicity screen in the mouse " Teraiogcnests Carcinogenesis, and Mutagenesis. 6 361 -374 (1986) Seidenberg. J M . and Becker, R A "A summary of the results of 55 chemicals screened for developmental loxicity in mice " Terafogenesis Carcinogenesis, and Mutagenesis 7'17-28 (1987) Takahara. K "Experimental study on loxicity of tnchloroclhane I ft Changes in liver function of mice after exposure to 1.1.1- and 1.1 2-trie hlorocthane " Okayama fgakkai Zasshi 98 1099-1109 (1986). Torkels^n. T R. and Rowe. V K "Malogenatcd aliphatic hydrocarbons; 1,1,2-Trichloroethane' fn: Patty's Industrial Hygiene and Toxicology Third revised edition. Volume 11B Tortelson, T R , and Rowe. V K., eds New York, NY John Wiley and Sons pp 3510-3513 (1981). TSCATS (Toxic Substances Control Act Test Submissions) Database (1993) Union Carbide Corporation "Imlial submission Progress report for the month ending August 31. 1961 wilh cover letter dated 052892 ' TSCA 8E submission 88-920003273. microfiche NumberOTS05366l5 Washington. DC: OPPT, US EPA (1961). Union Carbide Corporation "Acute jnhalalion toxicity of 1. 1,2-tnchloroethane and 1,1,2,2-letrachloroethylene in rats " TSCA 81) submission 86-870001395. microfiche Number OTS0515557. Washington. DC: OPPT, US EPA (1987a) Union Carbide Corporation 'Repeated exposure of rats and dogs to vapors ofeight chlorinated hydrocarbons " TSCA 8D submission 86-870001397. microfiche Number OTS0515559 Washington. DC OPPT, US EPA (1987b) Union Carbide Corporation "Recalculation of liver and kidney weights previously reported with revised conclusions or the toxicity of eight chlorinated hydrocarbons." TSCA SD submission 86-870001399, microfiche Number OTS0515561. Washington, DCOPPT, US EPA (1987c). Union Carbide Corporalion 'Inhalation toxicity of letrachloroelhylene and 1, 1,2-lrichloroelhane in rats and rabbit skin irritation oT toluene diisocyanate " TSCA 8D submission 86-870001427. microfiche Number OTS0515589 Washington, DC OPPT, USEPA(I987d). U S FPA (Environmental Protection Agency) 'Health Effects Assessment for 1,1,2-Trichloroethane" (1984a) U S FPA (Environmental Protection Agency) FPA document number EPA 540/1-86-045 (1984b) White. K I , Sanders V M . Rames. D W , Shopp (j M , and Munson, A E. 'Toxicology of l.l.2-lrichloroelhane in Ihc motive " Drug and Chemical Toxicology 8(5) 333-355 (1985a). 27 I tiblc of I ovictly Dalj for MAPs (continued) White. K L Sanders, V M , Harries. I) W Tucker. A N , Sain.l.F,, Shnpp. G M , C archman .R. A .and Munson, A !: " I rnnmnnto Geological rm estimations in the mouse General approach and methods " Oruj? and Chemical Toxicology 8(5) 299-331 (1985 b). 28 1> DO 1 7 9 7 1 9 CONF TDFNTT M c thy 1 meth aery late 80-62-6 Methyl methacrylate 80-62-6 Table of Toxicity Data for HAPs (continued) Route of Epidemiology (Prevalence siudy) Humans Occupational As dental laboratory technicians Epidemiology (Prevalence study) Humans Occupational As denial technicians 5 1o 46 years (mean --12 8 years) 3 lo 29 years (mean =15 6 years) Number studied/ Exposure levelsexposure level Response Siudy Adequacy CommentsReference 2200 to 5600 pg/ml (0 5 lo l .4 ppm) Not quantified 178 (146 males and 32 females) 87 male and female respondents (number/sex not reported), 15 illustrative cases participated in the clinical analysis Eight persons having a mean of 28 years of employment had simple pneumoconiosis. Mean values for percent predicted forced vital capacity (FVC)and forced expiratory volume (FEV) were reduced among male nonsmoker technicians compared lo matched controls. Spirometric values decreased with increasing work-years. Subjective responses: dermatitis in 34% of persons, finger numbness, coldness, and whitening in 25% Neurophysiological evaluation of 15 cases revealed decreased sensory conduction velocities tn the fingers and occasional decreased sensory action potential amplitude associated with numbness, but not with dermatitis Adequate study, but because of exposure to other materials, a clear association with methyl methacrylate could not be made Adequate study, but because of the lack of exposure data and information on other chemical exposures, a clear association with methyl methacrylate could not be made Subjects were simultaneously exposed to other potentially toxic materials, including precious metal alloys and silica Rom et al, I9S4 Physiological tests accompanied subjective responses Effects were more common among persons with longer career and heavier exposure Additional studies provide supporting data. Rajaniemi, 1986 ____________ 1 Chcmtcif Name Methyl methacrylate | Methyl methacrylate fl Methyl methacrylate Tabic of Toxicity Data for 1 lAPs (continued) CAS Number 80-62-6 80-62-6 80-62-6 Study Type Epidemiology {Cohort study) Epidemiology (Cohort study) Epidemiology (Retrospective cohort study) Species Humans Humans Humans Route of Administration Number studied^ Type of ExposureDurationExposure levelsexposure level Occupational As commcrcral producers of melhyl methacrylate (MMA) and ethyl acrylate |EA) 12, 36, or 39 years Not quantified 3 cohorts 3934 men. 6548 men, 3381 nen Response No excess o f mortal ity from cancer was seen in employees hired since the mid-1940s. Excess colon and rectal cancer were noted in employees exposed at least 3 years during the early 1940s to the highest levels of vapor-phase chemicals Study Adequacy Inadequate since exposure levels were not available Occupational Occupational As commercial producers of MMA During plastics manufacture 17 to 23 years Up to 29 years 0.13 to 1.00 ppm, 8-hour TWA Not quantified 1561 men 1372 men No effect was noted on survival or cancer mortality. Total deaths or observed cancer deaths were not increased over the expected The observed number of respiratory cancers was increased, but was not statistically significant When grouped by year of hire, increased unspecified cancers and lymphatic cancers were noted Adequate Inadequate. Exposure data are unavailable Workers were exposed to a mixture, but methyl methacrylate was estimated to be the major constituent (88 to 100%) In the early 1940s, the mix was approximately 88% MMA and 12% EA. Only 2% of the study cohort was lost to follow-up Co-exposure to other possible carcinogens (workers were also exposed to ethyl acrylate) provides a confounder for this study. Walker etal., 1991 Collins etal., 1989 Rohm and Haas, 1989c n o 0 zo --f "oT) \) s0 z-t 0SJ --1 _1 X> 30 Chemical Name I Mclh\l melhacrylnle Table of Toxicity Data for HAPs (continued) CAS Number 80-62-6 Study Type Epidemiology (Retrospective cohort study) Species Humans Route of Administration Type of Exposure Occupational As commercial producers of plastics Duration 1 to 12 years Exposure levels Number studied/ exposure level Not quantified 3934 mates Response Study Adequacy Deaths from cancer of (Jte respiratory tract, skin, stomach, liver, bladder, and kidneys were not higher than the expected U.S. mortality rates <1528 observed; 1869 expected). Deaths from cancer of the colon and rectum were significantly increased over the expected U.S. mortality rates (52 observed; 31 2 expected, SMR * 167, p <0.01); however, the majority ofthese cases do not appear to be relaied to length of exposure or total exposure Quantitative exposure information we not available. Comments Reference Although the cohort size was large, the exposures occurred simultaneously to ethyl acrylate, and the authors concluded that it was impossible to separate exposure to ethyl acrylate from exposure to methyl methacrylate. Rohm and Haas. I9B4 O Ozn v o a \> "H <> Z --t m \J T> 31 Chemical Name Methyl methacrylate Methyl methacrylate 1 Methyl methacrylate Tabic of Toxicity Data for HAPs (continued) CAS Number 80-62-6 80-62-6 80-62-6 Study Type Epidemiology (Retrospeclive cohort study) Species Humans Epidemiology (Case report) Humans Epidemiology -Summary Route of Administration Type of Exposure Occupational During plastics man u fact urc Occupational Medical, while mixing bone cement Duration lip In 37 years Not reported, short lime period during mixing procedure Exposure levels Number studied/ exposure level Not quantified 6667 males al Ihe Bristol plant. 3381 males al Ihe Knoxville plant 3.8 to 7 8 mg/m' (0 9 to 1.9 ppm) 1 operating room nurse Response Study Adequacy Comments Reference Al Bristol, exposure to ethyl acrylate was considered minor to exposure to methyl methacrylate No statistically significant excess of site-specific cancers was noted At Knoxville, cancers of the digestive tract, including colorectal cancer, were statistically significantly lower than predicted values. No association was seen between cumulative exposure "dose* and risk of respiratory cancer or digestive cancers including colorectal cancers Comeal ulceration occurred on repeated occasions when the nurse worked under the same conditions Inadequate Quantitative exposure data arc unavailable, and workers were also exposed to ethyl acrylate Exposures happened simultaneously to ethyl acrylate, and the authors concluded that it was impossible to separate exposure to ethyl acrylate from exposure to methyl melhacrylale. Rohm and Haas. 1990 Limited observations. This effect level was considerably less than Denmark's threshold limit value oMlOmg/m* as reported hi this article Nissen and Corydon, J98S Epidemiology studies were located to identify some qualitative effects of exposure to methyl methacrylate. 1 O o -o zo ~n o \) m T) Z n! -t \> r--I LO I> 32 I Methyl methacrylate 0 Methyl methacryfate | Methyl methacrylate 1 Melhyt methacrylate n oo 2o Ti OM T) s> 2 Nf -< vi W/ Pa I> Table of Toxicity Data for HAPs (continued) CAS NumberStudy TypeSpecies 80-62-6 Acute toxicity Rats 80-62-6 Acute toxicity Mice 80-62-6 Acute toxicity Hals 80-62-6 Acute toxicity Rats Route of Administration Number studied? Type of Exposure_______ DurationExposure levetsexposure levelResponseStudy AdequacyCommentsReference Inhalation Vapor Inhalation Vapor Inhalation Vapor Inhalation Vapor 4 hours followed by a 14-day ohscrvalion period 0, 1191,2159, 2220, 4055, 4446, 4632. or 3 6.000 ppm 5/sex/gioup 4 hours followed by a 14-day observation period 0, 1191, 2159. 2220.4055. 4446, 4632, or 16.000 ppm 5/sex/group 4 hours 1086 to 2715 ppm 10 males/ concentration 1, 2, 3, or 4 hours 96 7 i 0 41 ppm was measured chamber concentration 4 males/grnup Mortality occurred at 16,000 ppm. Rats gained less among higher exposure groups Compound-related hypoactivity, dyspnea, and anesthesia were noted at all doses. Adequate rangefinding lest AH high-dose mice died prior to the end of the study. Compoundrelated hypoactivity, dyspnea, and anesthesia were noted at all doses. No effect was evident on body weight No abnormalities were apparent at necropsy Adequate rangefinding test. LC* {within 24 hours post-exposure) was 1350 (1161-1570) ppm No evidence ofbleeding from any orifice was seen in any treated rats. Irritation or the eyes, nose, and respiratory tract, along with labored breathing, were apparent during treatment. Inadequate No effects were seen at 1 hour of exposure. Interalveolar congestion and hemonilage, pulmonary vasodilation and edema were noted in rats exposed for 2,3, or 4 hours. This test measured limited endpoints A no-effect level is not reported in the document. NTt\ 1986 A no-effect level is not reported in the document NTP. 1986 The study is limited by use of males, only as test animals, the use ofonly 2 exposure groups, and the use of only a 24-hour post exposure observation period. Oberly and Tansy, 1985 This study demonstrates portalof-entry effects at non-lcthal concentrations. Rajeet al. 1985 33 Chemical Name j Melh) 1 methacrylate Methyl methacrylate Methyl meihacrylaie I Mdhyl mclhncr>'tale Tabic of Toxicity Data for 11 APs (continued) CAS Number 80-62-6 Study Type Aculc loxrcity Species Rais 80-62-6 80-62-6 Acute toxicity- Summary Subchrontc toxicity Rats 80-62-6 Subchronic toxicity Mice Roulc o r Admimstralion Type of Exposure Inhalation Vapor Duration 8 hours Exposure levels Number si ud ied/ exposure level 1) 2, 134, 16 0. 20 1, 25 5, 26 5. 300, 31 3.330, 35 6, and 92 3 mg/U2734 8, 3272 0.3906 9, 4908 1.6226 7, 6470 8.7325 5, 7642 9.8058 0, 8692 9. and 22538 1 ppm) 5-10/cxposure level Inhalation Vapor 6 hours/day, 5 days/week for !4 weeks 0, 500, 1000, 2000. and 5000 ppm 10/sex/group tnhalalion Vapor 6 hours/day, 5 days/week for 14 weeks 0, 500, 1000, 2000. and 5000 ppm tO^sex/group Response Study Adequacy Comments Reference Mortality was observed at 25 5 mg/L and higher, with an LCW value of JO33 mg/L; concentrationrelated clinical signs at 13 4 mg/L and higher included slight irritation to the upper respiratory tract, depression, increased urine flow, slight dyspnea, and mild cyanosis This is an adequate scute toxicity study for determining an LCy,. Gross necropsy findings were not reported llaskekl Laboratories, 1937 Other acute inhalation toxicity studies reported similar clinical signs, and indicated effects on the respiratory system (TSCATS, 1992) | Mortality occurred at 2000 ppm and higher. Decreased body weight and compound-related lesions of olfactory epithelium, kidney and liver were noted at 2000 ppm and above, and at a 1000 ppm, females had malacia and gliosis of the brain. Adequate rangefinding study Appropriate protocol was observed A NOAEC and LOAEC were identified at 500 and 1000 ppm, respectively. NTP, 1986 Mortal ity occurred at 2000 ppm and higher Decreased body weight and metaplasia of the nasal epithelium occurred in all treatment groups, and compoundrelated lesions of the kidney, olfactory epithelium, and liver were noted at 2000 ppm and higher Adequate range finding study. Appropriate protocol was observed A LOAEC was identified, and a companion study conducted at industrial Biotest Labs identified a NOAEC of 250 ppm NTP, 1986 34 r> O -O zo T1 Ov T1 > Z 'J -4 K> -t 'Ji > Table of Toxicity Data for HAPs (continued) Chemical NameCAS NumberStudy TypeSpecies Methyl mclhacrylale 80-62-6 Subchronic toxicity Dogs 1 Methyl mclhacrylale 80^2-6 Subchronk toxicity/ ImrmmoloXicity Rats Methyl mclhacrylale 80-62-6 SubchrottK toxicity Rats r> oa zo V \J T T) Z si Route of Administration Number studied/ Type of ExposureDurationExposure levelsexposure levelResponseStudy AdequacyCommentsReference Inhalation Vapor Inhalation Vapor Inhalation Vapor 6 hours/day, 5 days/week for 3 months 0, 100. and 400 ppm 6 males/exposure level 8 hours/day for 3 and 6 months 0 or 116 ppm 50 males/group 4 hours/day. 5 days/week for 32 days 0. and 1104 5 ppm Not reported No toxicity was observed In Ihe 3-month study, there was a marked absence of visceral and subcutaneous fat Exposed rats had significantly lower whole body (226.7 g vs. 213.7 g), lung (0.94 g vs. 0 84 g), and spleen (0.41 % vs 0.J9 g) weights than controls In the 6-month study, mean body and popliteal fat pad weights and levels of serum protein, cholesterol, and blood urea nitrogen were significantly lower than controls During exposure rats preened and huddled with iheir eyes closed. No effects were observed on survival, body or 1 issue weights, blood chemistry, gross metabolic performance, or spontaneous small intestinal motor activity as compared to controls This study is of limited use because only identifies a free-standing NOEL and by the use of loo few animals per group. This study is inadequate because only one concentration level was tested The study is limited by die use of only one lest exposure level and lack of information regarding number of lest animals Purity was not reported, important endpoints were examined Immune function was not assessed No hislopathology was reported Rohm and Haas Company, 1979 Tansy et al 1976 j Oberly and Tansy. 1 199$ I> Table of Toxicity Data for MAPs (continued) Chemrcat NmeCAS NumberStudy TypeSpecies Route of Administration Number jludiedf Type of ExposureIjurationExposure levelsexposure levelResponseStudy AdequacyCommentsReference Methvl methacrylate 80-G2-6 Subchronic toxicity Rats inhalation Vapor Methyl methacrylate 80-62-6 Methyl methacrylate Methyl methacrylate 80-62-6 80-62-6 Subchronic toxicity Mice Inhalation Vapor Subchronic toxicity - Summary Chronic loxicity Hamsters Inhalation Vapor fi hnurs/day, 5 days/wcck for 97 days 0.63, 125, 250, 500. or 1000 ppm 10/sex/c vposurc level 6 hours/day, 5 days/week for 96 days 0* 63, 125.250, 500, or 1000 ppm 10/sex/exposure level 6 hours/day, 5 days/week for 18 months 0. 25, 100, and 400 ppm 66/sex/exposure level No toxicity was observed Decreased body weight gain at 1000 ppm Tendency (statistical significance unknown) towards a shorter life expectancy in males at 400 ppm; otherwise, no toxicity was observed This study is of limited use because ti only identifies a Tree-stand ing NOEL, however, 1000 ppm may be at the threshold for loxicity This appears to be an adequate subchronic toxicity study Purity was not reported; important endpoints were examined, a non significant 10% decrease in body weight gain was observed at 1000 ppm. Purity was not reported; important endpoints were examined. Rohm and Haas Company, 1989a Rohm and Haas 1 Company, 1989a 1 Data on subchronic inhalation toxicity were adequate in 2 species. \ This is an adequate chronic toxicity study. Purity was not reported, important endpoints were evaluated, this study identified a FEL of 400 ppm and a NOAEC of 100 ppm Rohm and Haas Company, 1983 U Q O oo zo -n --i i * O \) -a sD ZM H '0 t Ni 36 Table of Toxicity Data for HAPs (continued) Chemical NameCAS NumberStudy TypeSpecies Methyl methacrylate 80-62-6 Chronic toxicity Rats -- Methyl methacrylate 80-62-6 Meihyl methacrylate 80-62-6 Chronic toxicity Chrome toxicity Rats Rats n oO ZO ---~ni z> \) ^1 vD z SJ H \> f 03 3> Route of Administration Type of Exposure_______DurationExposure levels Number studied/ exposure level Inhalation Vapor 2 years 0,25. 100, or 400 ppm 4449/sex/ex posure level Inhalation Vapor Inhalation Vapor 6 hours/day, 5 days/week for 104 weeks 0,25, 100, and 400 ppm 70/sex/exposure level 6 hours/day. 5 days/wcck for 102 weeks Males: 0, 500. or 1000 ppm Females 0, 250, or 500 ppm 50/sex/group Response Study Adequacy Comments The two highest exposure groups showed exposure related minimal to slight changes (including inflammation, degeneration, atrophy, and hyperplasia) in the olfactory epithelium of the anterior nasal cavity There was also concentration dependant slightlo moderate inflammation and hyperplasia in the respiratory epithelium of the anterior nasal cavity. Mild rhinitis was observed Hi treated rats; otherwise no toxicity was observed Decreased body weight occurred m both sexes in the high-dose group. Treatment-related inflammation of the nasal cavity and degeneration of the olfactory sensory epithelium was seen m both sexes This appears to be an adequate study This is an adequate chronic toxicity study. Inadequate because NOAEC was not identified. Histopathologic observations were limited only to the nasal cavity. The NOEL was 25 ppm Prnity >99.6%, clinical signs and important endpoints were evaluated. Purity >99%; adequate endpoints were examined. Rohm and Haas Company, 1992 Rohm and Haas Company, 1989b NTT, 1986 37 Table of Toxicity Data for MAPs (continued) Chcmtcal NameCAS NumberStudy TypeSpecies Methyl methacrylate RO-62-6 Chronic toxicity Mice Methyl methacrylate Methyl methacrylate 80-62-6 80-62-6 Chronic toxicity - Summary Carcinogenicity Hamslers Methyl methacrylate 80-62-6 Carcinogenicity Rats Methyl methacrylate 80-62-6 Carcinogenicity Rats J Meihyl methacrylate 80-62-6 Carcinogenicity Mice 1 Methyl methacrylate 80-62-6 Careiitoeenicity - Summary Route of Administration Inhalation Inhalation Inhalation Inhalation Inhalation Number studied/ type nfExposure_______ DurationExposure levelsexposure levelResponse Vapor 6 hours/day, 5 days/week for 102 weeks 0, 500, or IOOO ppm 50/sc x/grnup Treated mice had decreased body weight, iTeatment-rclated inflammation of the nasal cavity* degeneration of the olfactory sensory epithelium, and epithelial hyperplasia of the nasal cavity. Vapor Vapor Vapor Vapor 6 hours/day, 5 days/week for 18 months 0, 25.100, and 400 ppm 66/sex/ex posure level 6 hours/day, 5 days/week for 104 weeks 0, 25. 100. and 400 ppm 70/sex/exposure level 6 hours/day. 5 days/week for 102 weeks 6 hours/day, 5 days/week for 102 weeks Males 0,500. or 1000 ppm Females 0, 250, or 500 ppm 0, 500, or 1000 ppm 50/sex/group 50/scx/group No evidence of carcinogenicity was observed No evidence of carcinogenicity was observed No evidence of carcinogenicity was observed in either sex at any treatment level No evidence of carcinogenicity was observed in either sex at any treatment level. Study Adequacy Comments Inadequate because a NOAEC was not identified Purity >99%. adequate endpoints were examined Reference NTP, 19,6 1 Data on chronic inhalation toxicity are available which suggest that the respiratory system is a target organ, but a NOAEC was not identified in these studies (NTP, 1986; TSCATS, 1992). This is an adequate carcinogenicity study Purity was not reported; important endpoints were evaluated. Rohm and Haas Company, I9B3 I This is an adequate carcinogenicity study Purity >99 6%; clinical signs, important endpoints were evaluated Rohm and Haas Company, 1989b Adequate Purity >99%; adequate endpoints were examined. NTP. 1986 Adequate. Ptsity >99%. adequate endpoints were examined. NTP, 1986 Adequate data on carcinogenicity are available in 3 species. i n 3 I ZTi o 9--( 1-9 oV z >N0i H--i \) p0 J> 38 Table of Toxicity Data for HAPs (continued) Chemical Name I Methyl methacrylate CAS Number 80-62-6 1 Methyl mtihacryTale 80-62-6 Methyl mclhacrylale 1 Methyl mclhacrylale 80-62-6 80-62-6 Methyl methacrylate 80-62-6 O oo --------------z o ------------- Study Type Neurotoxicity Species Rats Neurotoxicity Rats Neurotoxicity - Summary Developmental toxicity Rats Development! toxicity Rats Route of Administration Type of Exposure Duration Exposure levels Number studied/ exposure level Response Study Adequacy Comments Reference Ora! Gavagc Inhalation Vapor Inhalation Vapor Inhalation Vapor Daily for 21 days Oor 500 mg/kg/day 60 minutes Oor 400 ppm 2 hours/day, every 3 days on gestation days 6-18 0. 0 52, or 4 48 mgMQ, 120 9, or 1093 9 ppm) 6 hours/day on geslalion days 6-15 0,99.304, 1178, and 2028 ppm 30 males/group Males (number not reported) Not reported 27/exposure level Markedly unpaired locomotor activity and learning; increased biogenic amine level in brain. Depression in the multiple-unit electrical activity in the lateral hypothalamus and ventral hippocampus No maternal toxicity we observed Delayed ossification occurred in both treatment groups, and at 4.48 mg/L increased incidence of resorption occurred Maternal loxkity was observed at all exposure levels, no developmental loxkity was observed The study is limtled by the use of only one exposure level. Authors suggest that the changes in regional brain biogenic amine levels may be partly responsible for altered behavior. Husain etal., 1985 The study is limited by lack of information regarding number of test animals and limited scope of endpoints examined. The study identified a LOAEL for central neuronal activity of 400 ppm Innes aid Tansy. L981 Additional neurotoxicity testing of methyl methacrylate could be required. Available information indicates a potential for neurotoxicity (TSCATS, 1992; TOXLINE, 6/93> Inadequate. The exposure regimen did not follow accepted protocol; exposures were conducted only every 3 days. This report is in abstract form only Luo el al., 1986 This is an adequate developmental toxicity study with no developmental effects observed at levels producing maternal tox icily. Purity 999%. this study identified a LOAEL of 99 ppm for malemtl toxicity and a NOAEL of 2028 ppm Rohm and Haas Company, 1991 sO Z Nl H jO -f O 3> 3<> Chemical Name Methyl methacrylate B Methyl melhacrylaie 9 Methyl methacrylate 1 Methyl methacrylate Table of 1 oxicity Data for MAPs (continued) CAS Number 80-62-6 80-62-6 80-62-6 80-62-6 Study Type Developmental toxicity Species Rais Route of Administration Type of Exposure Inhalation Vapor Duration Exposure levels Number studied/ exposure level 5 hours/day on gestation days 6-15 0, 100, 1000 ppm (Exp 1), 0, 25. 100.and fOOO ppm (Exp IT) 30/exposure level Developmental toxicity Mice Inhalation Vapor 6 hours/day on gestation days 4-13 0, 116, or 400 ppm 18-38/cxposurc level Fmbryotoxicity lest While leghorn chickens Injection into e8Es Solution in acetone Single injection 0,2 3,4 5,0, 18, and 36 pmol/egg 20-30/dose level Developmental ttnirity - Sainmary Response Sludy Adequacy Comments Reference No maternal toxicity; increased number of early resorptions and incidence of relarded skeletal ossification at 1000 ppm Tlits ts a marginally adequate developmental toxicity study with developmental effects observed at levels not producing maternal toxicity. Dams were exposed 5 hours/day, instead of 6 hours/day. This study identified a NOAEL of 1000 ppm for maternal lox icily, and a NOAEL of 100 ppm and LOAELof 1000 ppm for developmental toxicity. Imperial Chemistry Industries, 1977 No maternal toxicity; decreased fetal body weights at M6 and 400 ppm This is an inadequate study because exposure did not include the later stages of organogenesis, only two doses were tested, and no NOAEL was identified for developmental toxicity. Only raw data available from a final report. Rohm and Haas Company, 1976a; 1976b I EDW (embryotoxicity) was 22 0 (confidence limits *9.0 to 56.0) Hmot/egg Malformations, including eye, neck, back, wings, and legs were observed, but a dose-response relationship was not seen. This is not a standard development lest. The relationship of these results with regard to mammalian toxicity is unclear Kodtonen. et al. 1983 Adequate developmental toxicity data arc available tn l species fTSCATS, 19921 1 1 40 Tl Z 'J \) Table of Toxicity Data for HAPs (continued) Chemical Name CAS Number Study Type Species Route of Administration Type of Exposure Number studied/ DurationExposure levelsexposure levelResponseStudy AdequacyCommentsReference Methyl methacrylate Methyl methacrylate 80-62-6 80-62-6 Reproductive toxicity - Summary Pharmacokinetics - Summary No data on the reproductive toxicity of methyl methacrylate were located fFSCATS, 1992, TOXUNE, 6/93) Pharmacokinetics data are available for the oral and inhalation routes of exposure (HEEP, 1985, TSCATS, 1992; TOXLfNE, 6/93). REFERENCES Collins, J I, Page, L C , Caporossi, J.C , Ulidjran, H M., and Saiphcr, J.N. "Mortality patterns among men exposed to methyl methacrylate " Journal of Occupational Mediant 31 (I ):4 I -46 (1989). Haskell Laboralorees "The toxicity and potential dangers of methyl methacrylate (monomer) with attachment and cover sheet dated 061289" TSCA 8D submission 86-890000818, microfiche number OTS0520934 Washington, DC- OPPT. US EPA (1937) HELP "Health and Environmental Effects Profile for Methyl methacrylate." US Environmental Protection Agency (1985) I lusairt. R., Srivastava, S P., and Seth, P.K "Methyl methacrylate induced behavioural and neurochemical changes in rats" Archives of Toxicology 58 33-36 (1985). Imperial Chemistry Industries "Methyl methacrylate monomer teratogenicity studies in the rat with attachments and cover sheet dated 071789" TSCA 8D submission 86-890001390S, microfiche number OTS0521013 Washington, DC: OPPT. US EPA (1977) Irmes, D L.. and Tansy. M F "Central nervous system effects of methyl m> Ujcrylste vapor" Neurotoxicity 2.515-522 (1981). Kortionen. A . Hemtninki, K-, and Vainio, H "Embryotoxic effects of acrolein, methacrylates, guanidines and resorcinol on three day chkVen embryos " Acta Pharmacologica el Toxicotogica 52.95-99(1983) Luo, S-Q . Gang, ft-Q . and Sun S-Z "Study on embryotoxicity and fetotoxicity in rats by maternal inhalation oflow level methyl methacrylate." Toxicology Letters 31(suppl) 80 (1986} Nissen, J.N . and Corydon, L. "Corneal ulcer after exposure to vapours from bone cement (methyl methacrylate and hydroquinone) * International Archives ofOccupational Environmental Health. 56(2). 161-165 (1985). NT? (Nalional Toxicology Program). "NTP technical report on the toxicology and carcinogenesis studies of methyl methacrylate in F344/N rats and B6C3F1 mice (inhalation studies)" NTP TR 314 (1986) Oberly, R, and Tansy. M F. "LC50 values for rats acutely ex posed to vapors of acrylic and methacrylie acid esters." Journal of Toxicology and Environmental Health 16( 6) 811-822(1985) Rajaniemi, R "Clinical evaluation of occupational toxicity of methyl methacrylate monomer to dental technicians." Journal ofthe Society ofOccupational Medicine 36(2) 56-59 (1986). Rajc, R R . Ahmad, S , md Weisbroth, S H "Methylmethacrylate - Tissue distribution and pulmonary damage in rats following acute inhalation " Research Communications in Chemical Pathology and Pharmacology 50( 1) 151 -154 (1985). Rohm and Haas Company "Progress report on teratology studies of mice exposed to methyl methacrylate monomer vapor with attachments and cover sheet dated 071789 (sanitized) " TSCA 8D submission B6-89000H05S, microfiche number OTS052102? Washington, DC- OPPT, US EPA (1976a) Rohm and Haas Company "Final report on teratology studies of mice exposed to methyl methacrylate vapor with attachments and cover sheet dated 071789 (sanitized) " TSCA 8D submission 86-8900013 76S, microfiche number OTS0521011 Washington, DC OPPT, US EPA (1976b). Rohm and Haas Company "Methyl methacrylate three month subchronic vapor inhalation safely evaluation study in Rcaglc dogs with attachments and cover sheet dated 071789 (sanitized)." TSCA 811 submission 86-8900013775, microfiche number OTS052T0I2 Washington, DC OPPT, US Table of Toxicity Data for HAPs (continued) I PA (1979) Rohm and Maas Company "Methyl methacrylate Subchronic, chronic and oncogenic inhalatron safely evaluation studies with attachments, cover sheet and letter (sanitized)." TSCA 8D submission 86-89000144 IS, microfiche number OTS0521055 Washington, DC OPPT. US EPA (1983) Rohm and Haas Company "Interim communication on the results of a mortality study of Bristol plant employees hired prior to 1946 with cover letter dated 031684 " TSCA FY1 submission FYI-OTS-0384-030Q IN, microfiche number 0300 Washington, DC OPPT, US F.PA {1984} Rohm and Haas Company "Suhchronic vapor inhalation study with methyl methacrylate (C50680) in F344 rats with attachments, cover sheets and letter dated 081089 (sanitized)" TSCA 8D submission 86-8900015085, microfiche number OTS0521247. Washington, DC: OPPT, US EPA (1989a) Rohm and Hus Company "2-Year inhalation, dominant lethal assay, evaluation of colorectal cancers at the Sanford plant, mortality patterns and report on methyl methacrylate with cover letter dated 060789 " TSCA 8D submission 86-890000315, microfiche number OTS0519080 Washington, DC OPPT. US EPA (1989b) Rohm and Haas Company "Texas plant mortality study - (1948*1978) with cover letter daied 071289 " TSCA 8D submission 86-890001317, microfiche number OTS0520821 Washington, DC OPPT, US EPA (1989c). Rohm and Haas Company "An evaluation of mortality from cancers ofthe colon and rectum among workers exposed to ethyl acrylate and methyl methacrylate with cover letter dated 012990 " TSCA FYf submission FYI-OTS-0290-0300, microfiche number OTS0000300. Washington, DC' OPPT, US EPA (1990) Rohm and Haas Company "Methyl methacrylate: Inhalation developmental toxicity study in rats (final report) with cover letter dated 041291 " TSCA 8D submission 86-910000781, microfiche number OTS0529413. Washington, DC OPPT, US EPA (1991). Rohm and Haas Company "Histopathologic evaluation of nasal cavities from Fischer 344 rats exposed to methyl methacrylate vapor for two years" Project Number 3302 5E (1992). Rom. W N., Lockey, J E., Lee, J S., Kimball, A.C., Bang, K M , Leaman, H., Johns, R.E., Jr . Pcrrola, O , and Gibbons. H L,. "Pneumoconiosis and exposures of dental laboratory technicians " American Journal of Public Health 74(11): 1252-1257 (1984) Santavirla, S Konttinen, U T., Bergroth, V., and GronHad, M "Lack of immune response to methyl methacrylate in lymphocyte cultures " Acta Orthopaedtca Scandmavtca 62( I) 29-32 (1991) Tansy, M F , Kendall, F M , Benhayem, S . Hohenleitner, F.J , Land in, W.E., and Gold, M "Chronic biological effects of methyl methacrylate vapor. I Body and tissue weights, blood chemistries, and intestinal transit in the rat " Environmental Research 11{l).66-77 (1976) fOXLINE National 1 tbrary of Medicine Online Database. (1993). TSCATS (Toxic Substances Control Ad Test Submissions) Database (L992). Walker. A M .Cohen A J, Loughlm, J E., Rothman, K J, and DeFonso, L R.'Mortality from cancer of the colon or rectum among workers exposed to ethyl acrylate and melhy! methacrylate " Scandanavian Journal Work Environment and Health 17:7-19(1991) O oo zo ~n a \> Tt sO Z Nl --1 U) 1-H U I> 42 Chemical Name | Phthalic anhydride Phthalic anhydride | Phthalic anhydride 1 Phthalic anhydride | Phthalic anhydride 1 Phthahc anhydride Table of Toxicity Data for HAPs (continued) CAS Number *5-44-9 Study Type Clinical evaluation Species Human *5-44-9 Clinical evaluation Human *5-44-9 85-44-9 *5-44-9 *5-44-9 Epidemiology (Crosssectional health slutfy) Hivnans Epidemiology {Crosssectional health study) Humans Epidemiology - Summary Acute toxicity - Summary Route of Administration Type of Exposure Number studied/ DurationExposure levelsexposure levelResponseStudy AdequacyCommentsReference Inhalation Fumes Inhalation Dust Not reported Not reported Not reported Not reported * months to 25 years Minimal (16 workers) to high (1 worker) estimated exposures 20 males total Not reported Not reported 2 males Not reported Not reported 91 males and 14 females Not reported Not reported 129 males and 10 females 4 Workers had elevated total antibody binding to phthalic anhydridehuman serum albumin {PA-HSA) and elevated specific JgG and IgE to PA-HSA. The worker with high exposure had allergic rhinitis associated wtlh phthalic anhydride Adequate to demonstrate sensitization to phthalic anhydride. Workers were also exposed to trimellitic anhydride, however, there was little cross reactivity between the specific antibodies for these anhydrides. Bernstein et al. 19*2 Ocular itching, rhtnonhea, chest tightness, and wheezing which stopped following removal from exposure. There was an increase in serum-specific IgE to PA-HSA in both workers Adequate to demonstrate sensitization to phthalic anhydride. Two other workers exposed to bexahydrophthalic anhydride and himk anhydride showed cross reactivity having heightened phlhalic anhydride antibodies. Bernstein et al., 19*4 No potential for allergenic effects were observed as screened for by an increase in eosinophils. Inadequate because incidence and exposure data were not provided Although the study population was 105, only 14 were exposed to phthalic anhydride. KoppersCo fnc., 1982a No effects were observed in pulmonary function, renal function, urinalysis, or immunological findings. Inadequate because exposure data were not provided This plant also produced maleic anhydride, amino resins, and alkyl resins Koppcrs Co Inc, 1982b Several epidemiology studies suggest the potential for phthalic anhy&ide to induce respiratory hypersensilivity {Clement, I990d) No data on the acute inhalation toxicity of phlhalic anhydride were located (Clemenl, !990d. TSCATS. 1992) Oicmical Name I Phlhalic anhydride I Phthalic anhydride 1 Phthalic anhydride I Phthalic anhydride I Phthalic anhydride I Phlhalic anhydride 1 Phthalic anhydnde Tahlc of Toxicity Data for MAPs (continued) CAS Number 85-44-9 85-44-9 85-44-9 85-44-9 85-44-9 85-44-9 85-44-9 Study Type Subchmmc toxicity Species Rats Route of Admmislralion Type of f'xposurc Inhalation Vapor Duration 6 hours/day for 5 days, rested for 3 weeks, ihen challenged with a single 6 hotir exposure Rxposurc levels 500 ng/m' (0 08 ppm) Number studied/ exposure level 20/cxposure level Subchronic toxicity -Summary Chronic toxicity Summary Carcinogenicity Rats Oral Diet 105 weeks 0.7500 or 15,000 ppm 50/sex/group; 20 matched controls of each sex Carcinogenicity Mice Oral Diet Carcinogenicity Summary Neurotoxicity Summary 72 weeks 12,500 or 25,000 ppm for males and 6250 or 12,500 ppm for females 50/sex/group, 20 matched controls of each sex Response Study Adequacy Comments Reference Increased numbers of hemorrhagic foci were observed, indicative of respiratory sensitization This is not an adequate suhehrome toxicity study because only one endpoint was evaluated and only one exposure level was used. Although only one exposure level was used, this was likely the highest vapor concentration obtainable Amoco Corporation, 1988 Additional testing could be required on the subchrontc inhalation toxicity of phthalic anhydride. No data on the chronic inhalation toxicity of phthalic anhydride were located (Clement, )990d; TSCATS, 1992). Under the conditions of the assay, phthalic anhydride was not carcinogenic There was, however, a significant trend in alveolar/bronchiolar adenomas in female rats Thts is an adequate oral study. Survival was not affected by treatment. NTP, 1979 Under the conditions of the assay, phthalic anhydride was not carcinogenic This is an adequate oral study Survival was not affected by treatment NTP, 1979 No data on the carcinogenicity of phthalic anhydride following inhalation exposure were located; an adequate oral study m two species is available (Clement, 1990d; TSCATS, 1992). No data on the neurotoxicity of phthalic anhydride were located (Clement !990d; TSCATS, 1992). | J 1 D OO O TJ '' vO 2* 44 Table of Toxicity Data for HAPs (continued) Chemical Name ' -.....- Phlhalic anhydride Phlhalic anhydride Phlhalic anhydride Phlhalic anhydride CAS Number 85-44-9 SS-44-9 Study Type Developmental toxicity Species Mice Route of Administration Type of Exposure Duration Injection IP Administered on gestation days 8-10 Developmental toxicity - Summary Exposure levels Number studied1 exposure level 0, Treatment values not reported; highest dose was reportedly wiihtn 95% confidence limits of the calculated LDfl,. Nol reported Response The compound was considered to be a "low hazard" with regard to teratogenicity 85-44-9 Reproductive toxicity - Summary 85-44-9 Pharmacokinetics - Summary Study Adequacy Comments Reference This is not an adequate developmental toxicity study because of insufficient reporting of experimental design This study was designed to test the relative toxicity of a number of compounds as a percent of the LD% dose. Fabro dal., 1982 Additional testing could be required on the developmental toxicity of phlhalic anhydride No data on the reproductive toxicity ofphlhalic anhydride were located (Clement. I990d; TSCATS, 1992). Limited information regarding absorption, metabolism, ml excretion of phlhalic anhydride were available m humans (Clement. J990d). REFERENCES Amoco Corporation Letter daled 1/28/98 from Amoco Corporation to US EPA informing that the results of the report study on phlhalic anhydride will be forwarded later TSCA 8E submission 89-880000017, microfiche number OTS0513426, Washington, DC OPPT, US EPA (1988). Clement "Drtfl inhalation reference dose for phlhalic anhydride <85-44-9)." Prepared by Clement Associates, Inc for Environmental Criteria and Assessment Office, (I990d). Bernstein, DI, Patterson, R.. and Zeiss. C.R. 1982 Clinical and immunologic evaluation of trimellitic anhydride - and phthalrc anhydride-exposed workers using a questionnaire with comparative analysis of enzyme-linked immunosorbent and radioimmunoassay studies Journal ofAllergy a ('finical Immunology 69 3 M -318 Rennie in, DI. Gallagher, IS . [TSouza, L. and Bernstein, I L. 1984. Heterogeneity ofspecific-lgE responses in workers sensitized to acid anhydride compounds. Journal ofAllergy and Clinical Immunology 74:794-801. Fabro. S . Shull. G . and Brown, N A "The relative teratogenic index and teratogenic potency: Proposed components of developmental toxicity risk assessment" Teratogenem, Carcinogenesis, and Mutagenesis. 2:61-76 (1982). Koppers Co Inc "1979 Cross-sectional hcallh study of workers at nine Koppers cod tar plants. Combined Report* TSCA 8D submission 87-8210574, microfiche number OTS0206278 Washington, DC OPPT, US EPA (1982a) Hoppers Co Inc. "Occupational health evaluation of the BridgeviUe, Pennsylvania plant of Koppers Company Inc organic materials group Final Report " TSCA BD submission 87-8210482, microfiche number OTS0206278, Washington, DC: OPPT, US EPA (1982b) NTP/NCI National Toxicology Program/National Cancer Institute. "Bioassay of phlhalic anhydride for possible carcinogenicity " DHFW Pubhcalmn No. (NIH) 79-17! 5 NTP TR 159 (1979) TSCA7S (Toxic Substances Control Act fcsi Submissions) Database (1992) Table of 'loxtcity Data for HA Ps (continued) Chemical Name Naphthalene Naphthalene | Naphthalene Naphthalene CAS NumberStudy TypeSpecies 91-20-3 Epidemiology (Cohort study) Humans 91-20-3 Epidemiology (Case study) Humans 91-20-3 91-20-3 Epidemiology (Case study) Humans Epidemiology Summary Route of Administration Number studied^ Type of Expt>sureDurationExposure levelsexposure levelResponseStudy AdequacyCommentsReference Inhalation Inhalation Oral fumes or dusl Vapor Not reported s? years Nol reported Exposed to fumes from hundreds of mothballs for "several years" in the home Air samples collected indicated 20 ppb, but levels were probably higher with fresh mothballs i3 monlhs. frequency not reported Not reported 21 workers S adults and 1 child 1 pregnant 26-year old Cataracts developed in 8/21 of the workers; 7/8 of the affected workers were less than SO years old. Vomiting and abdominal pain were observed Hi all individuals, and anemia was reported in "several" individuals Maternal hemolytic anemia; newborn hemolytic anemia, jaundice, lethargy, and anorex ia were noted This is an inadequate epidemiology study because of the small population and lack of exposure information. This is an inadequate epidemiology study This is an inadequate epidemiology study. This study was reported in Italian with an English abstract (rhetti aid Maria 1956 This is a summary of a case history of the effects of naphthalene inhalation on the inhabitants of homes in which a large number (300500) of mothballs were distributed. This is a case report of transplacental naphthalene poisoning Linick, 1983 Anziulewtcz et a 1959 No adequate epidemiology studies were located (ATSDR, 1989; TSCATS, 1992, TOXLINE. 6/93). o o 2 TM1 D O oV m 2-f H \l x> 46 Table of Toxicity Data for HAPs (continued) Chemical Name | Naphthalene CAS Number 91-20-3 Naphthalene Naphthalene 91-20-3 91-20-3 I Naphthalene 91-20-3 II---------------------- o -- O 2O n D \j Tl >) 2 \j -* W CD 1> Study Type Acute toxicity Species Rats Route of Administration Type of Exposure Duration Inhalation Vapor 4 hours, then observed for 14 days Exposure levels Number studied/ exposure level 77 7 ppm 5/sex Acute loiicity - Summary Repealed dose study Mice Inhalation Vapor 6 hours/day, 5 days/week, for 2 weeks 0. 10, or 30 ppm 5/sex/group Subchrouie toxicity - Summary A7 Response Study Adequacy Comments Reference No mortalities were observed. Lacrimatiort, mouth breathing, and closed eyes were the only clinical signs. No gross pathologic lesions were observed No treatment-related effects were noted on survival, body weight or clinical signs Small but not significant alterations were noted in hematologic parameters among high-exposure females (increased leukocytes, decreased hemoglobin and mean cell volume) but not in males. An inadequate range of endpoints were studied No hislopathology was performed Punty was 100%; the concentration used was the highest concentration obtainable under the experimental conditions of this laboratory. This study reported signs of irritation at saturated levels of the compound. Phanrufccm Research International, 1985 Adequate acute inhalation toxicity data are not available on naphthalene (TSCATS, 1992). The study is inadequate for evaluating subchronic effects because animals were exposed for an insufficient duration. Abnormally high death rates were reported in the control group. NTP, 1992 No adequate data on Ihe subchronic inhalation toxicity of naphthalene were located (ATSDR. 1989, TSCATS, 1992; TOXLTNE, 6/93) Chemical Name I Naphthalene I Naphthalene I Naphthalene Naphthalene Naphthalene Naphthalene Tabic of Toxicity Data for HAPs (continued) CAS Number 91-20-3 91-20-3 91-20-3 91-20-3 91-20-3 91-20-3 Study Type Chronic toxic tly Species Mice Chronic toxicity Summary Carcinogenicity Mice Carcinogenicity Toxicity Mice Carcinogenicity Summary Neurotoxicity Summary Route of Administration Type of Exposure Inhalation Vapor Duration 6 hours/day, 5 days/week for 104 weeks Exposure levels Number studied/ exposure level 0. 10, and 30 ppm ?5/scx/exposure level Inhalation Vapor Inhalation Vapor 6 hours/day, 5 days/week for 104 weeks 0, t0, and 30 ppm 75/sex/exposure level 6 hours/day, 5 days/week for 26 weeks 0, tG, and 30 ppm 30 females/ exposure level Response Study Adequacy Comments Reference Chronic inflammation in nose and lungs at 10 and 30 ppm, metaplasia of olfactory epithelium and hyperplasia of respiratory epithelium in nose at 10 and 30 ppm This is an adequate chronic toxicity sludy This study identified a LOAEL of 10 ppm NTP. 1992 Incidence of pulmonary alveotar/bronchiolar adenomas was increased in females at 30 ppm. An adequate chronic inhalalion toxicity study was located in 1 species (NTP, 1992). This is an adequate carcinogenicity study The authors concluded that there was no evidence of carcinogenic activity m males and some evidence m females NTP, 1992 If || H Increased adenomas per tumor-bearing mouse lung at 10 and 30 ppm, but the number of tumors in tumor-bearing control mice was significantly lower than the pooled controls of 6 other concurrent studies on other chemicals. This is an adequate strain A mouse bioassay, but not an adequate lifetime cancer bioassay This is a strain A mouse study with a normally high incidence of lung tumors in controls. The authors concluded that the adenoma response was not significant. Adkins el al. 1986. An adequate carcinogenicity study was located in 1 species (NTP, 1992). Naphthalene has been selected for inhalation studies in the rat by NTP; gavage study was withdrawn (CHE MTRACK, 7/93) No data on the neurotoxicity of naphthalene were located (ATSDR, 1989; TSCATS. 1992; TOXLTNE. 6/93) There is a 90-day subchronic study in progress that will be under consideration by the OPPofEPA n oa Zo "--ni --* oV T1 O Z NJ Hw --i >0 3> 48 Chemical Name Naphthalene Naphthalene Tabic of Toxicity Data for HAPs (continued) CAS Number 91 -20-3 91-20-3 Study Type Developmental lox icily Species Mice Developmental toxicity Rats Roule of Administration Type of Exposure Number studied/ DurationExposure levelsexposure level__________________ ResponseStudy AdequacyCommentsReference Oral Gavage Oral Gavage Daily on gestation days 7-M Oor J00 mg/kg/day Daily on gestation days 6-15 0. 50. 150, and 450 mg/kg/day 50/exposure group 25-26/exposure group Reduced body weight gain and increased mortality were observed in dams The number of live young at birth was decreased Transient clinical signs (lethargy, slow respiration, prone body posture, and rooting behavior), transient reduced food and water consumption, and reduced body weight gain were observed in all dams Significantly decreased body weight gain was seen at 150 mg/kg/day. No significant changes m fetal growth, viability, or morphological development were observed This sludy is inadequate because the young were not examined for malformations and only one dose group was used, This is an adequate developmental study. 300 mg/kg/day was determined to be the MTD in Booth etal., 19*3 The NOAEL for maternal effects is 50 mg/kg/day, and IheLOAEL is 150 mg/kg/day, although no LOAEL was observed for fetal effects, a significant dose-related tread towed decreased fetal weight and increased malformations was noted. Plasterer et al. 1985 Navarro etal, 1991 o DD 2 ~n O --t V \) >> 2 H >. --( O X> 49 Chemical Name Naphthalene Naphthalene Naphthalene Naphthalene 1 Naphthalene Tabic of Toxicity Data for HAI's (continued) CAS Number 91-20-3 91-20-3 91-20-3 91-20-3 91-20-3 Study Type Developmental to X icily Species Rabbits Route of Admmisiratton Type of Exposure Oral Gavage Developmenlal toxicity Rabbits Oral Gavage Developmenlal toxicity Summary Reproductive toxicity Mice Reproductive toxicity Mice Oral Oral Gavage Gavage Dural ion Daily on gc slat ion days 6-IK Daily on gestation days 6-19 Daily for 14 days Daily for 90 days Exposure levels 0, 40, 200, and 400 mg/Vg/day 0, 20, SO. and 120 mg/kg/day Oor 267 mg/kg/day Oor 133 mg/kg/day Number studied' exposure level !8/cxposure group 25 to 27 females/group 40 to 112/sex/group 40 to 112/sex/group Response Sludy Adequacy Comments Reference Ctinical signs (decreased activity, dyspnea, cyanosis, ocular and/or nasal discharge, and salivation) were observed tn the dams from the 200 and 400 mg/kg/day groups No effects were seen on maternal survival, body weights or body weight gain. No effects were noted on reproductive parameters. No congenital abnormalities were observed. No effects were reported in does or fetuses This is an adequate study, although the sample sire is slightly low This study is inadequate because it did not lest to the MI D as indicated by maternal toxicity Purity was not reported, this study identified a NOAEL of 40 ppm and a LOAELof 200 ppm for maternal toxicity and a NOAEL of 400 ppm for developmental toxicity Doses of 1 SO mg/kg were determined to be lethal in a pilot sludy Pharmakon Research International, 1986 j Navarro et al., 1992 No effects on testicular weights. No effects on testicular weights. Adequate developmenlal toxicity data for the oral route were available tn 2 spcctes (ATSDR, 1989, Navarro et ak, 1991, ISCATS, 1992) Inadequate These data were from a subchronic study. Shopp et al, 1984 Inadequate These data were from a subchromc study. IShoppetal, 1984 | r> o 2 5rn ^ 2M -f -t. X> 50 o r-x ri ZQ n QV T^ 2: 'n! -i T> -1 V Table of Toxicity Data for HAPs (continued) Chemical Name Naphthalene Naphthalene Naphthalene CAS Number 91-20-3 91-20-3 91-20-3 Study Type Short-term reproductive toxicity Species Mice Roule of Administration Type of Exposure Oral Gavage Duration Daily on gestation days 7-14 Exposure levels Number studied/1 exposure level Oor 300 (pre determined MTD) mg/kg/day 50 sperm-positive females Reproductive toxicity - Summary Pharmacokinetics - Summary Response Decreased maiemal survival and decreased body weight gain Significantly decreased number of live pups and fitter weight, hut not significantly decreased weight/pup Study Adequacy Comments Adequate reproductive short term screen. Results show developmental effects. Reference Booth el a!., 1983 Data on the reproductive toxicity of naphthalene were inadequate. Limited information is available regarding the distribution, metabolism, and excretion, of orally administered naphthalene in animals (ATSDR, 1989; Iyer el al., 1991), as well as the mechanism of action of pulmonary necrosis (Buckpitt and Franklin, 1989). REFERENCES Adkins. B, Jr. Van Slee. E W.. Simmons. J E , and Eustis S.L "Oncogenic response of strain AH mice to inhaled chemicals" Journal of Toxicology ami Environmental Health T 7 311 -322 (1986) Anriulewicz. J A . Dick, H J., and Chianrfli. E E "TransplaceniaJ naphthalene poisoning." American Journal ofObstetrics and Gynecology 78(3) 519-521 (1959) ATSDR (Agency for Toxic Subslances and Disease Registry) "Toxicological Profile on Naphthalene." (1989) Buckpitl, A R , and Franklin, R 8 "Relationship of naphthalene ml 2-mcthylnaphthalene metabolism to pulmonary bronchiolar epithelial cell necrosis" Pharmacology and Therapeutics 41.393-41011989) CHEMTRACK National Toxicology Program Results Report "Results, status and publication information on all NTP chemicals produced fromNTP CHEMTRACK system " July (1993). Booth, G M . Bradshaw, W S . and Carter. M W. "Screening of priority chemicals for potential reproductive hazard (final report)." NTIS PB83-2 )30l 7 (1983) Ghctli, G , and Mariani, 1. "Alleraziom oculari da naftalina." Mediant del Lavoro. 47(10):533-538 (1956). Iyer. P . Marlin, J ., and Irvin. T R "Role ofbiotraiisformatKm in the in vrfropreimplanlafion cmbryotoxicity of naphthalene." Toxicology 66 257-270 (1991) Limck. M "Illness associated with exposure lo naphthalene in mothballs-lndiana." MMWR 32(2):34>35 (1983) Navarro. H A , Pnce. C J, Marx, M C., Myers. C.B., Meindel, J J., and Schwetz, B A. "Developmental toxicity of naphthalene in Sprague-Dawlcy (CD) rats on gestational days 6 through 15 (final sludy report and appendix)" NTIS PB92-135623, Report No. RT1-376 December 5 (1991). Navarro. II A , Pnce. C J , Marr. M C , Myers. C B_, and Heindel, J J "Final report on the developmental toxicity of naphthalene (CAS no 91-20-3) in New Zealand While (trade name) rabbits." NTP. NTIS/PB92-2I983I (1992) 51 lahlo of Toxicity Data for IIAPs (continued) NTP (National Toxicology Program) "NTP technical report on the toxicology and carcinogenesis studies of naphthalene in B6C1TI mice " NTP TR 410 (1992) Pharmakon Research International, Inc "Naphthalene acute inhalation toxictly sludy " TSCA 81) submissron 86-8700005?8, mjcrofichc number OTS0515636 Washington. T)C OPPT, US EPA (1985). Pharmakon Research International "Developmental toxicity study m rabbits using test article 5601-56-1 " TSCA 81) submission 86-870000563, microfiche number OTS05I3641 Washington, DC OPPT, US EPA (1986) Plasterer. M R . Bradshaw. W S . Booth. G.M., Carter, M W , Schuler. R L, and Hardin. B D "Developmental toxicity of nine selected compounds following prenatal exposure in the mouse Naphth alette, p-nitrophenol. sodium selenite, dimethyl phlhalate. ethylene thiourea, and four glycol ether derivatives " Journal of Toxicology and Environmental Health 15 25-38 (1985) Shopp, C M . White. K I., Jr . Ilolsapple. M P , Barnes. D W , Duke, S S., Anderson, A C . Condie. L W . Jr . Hayes, J.R . and Borrellcca. J l: "Naphthalene toxicily in CD-I mice General toxicology and immunotoxicology." Fundamental and Applied Toxicology. 4 406-419 (1984). TOXLINE National Library of Medicine Online Database (1993) TSCATS (Toxic Substances Control Act Test Submissions). Database (1992) n o z5 T| i-t T-* oV m vD z Nj H T* W 3> 52 Chemical Name l.l'-Bi phenyl M'-Biphenyl l.l'-Biphenyl 1,1'-Biphenyl l.l -Biphenyl oo 2O oM 'D vD 2 Nl --! > J> Table of Toxicity Data for HAPs (continued) CAS Number 92-52-4 Study Type Epidemiology (Case studies) Species Kumars 92-52-4 92-52-4 92-52-4 Epidemiology Summary Acute toxicity Rats Acute toxicity Mice 92-52-4 Acute toxicity Summary Route of Administration Type of Exposure Inhalation Occupational Duration Exposure levels Approximately 100 days/ycar for 11 years 4 4 to 12* mg/m1 (0 7 to 20 3 ppm) Number studied/ exposure level 33 (32 men and \ woman) Inhalation Vapor Inhalation Vapor fj hours 0 2 ppm 6 males 4 hours 14, 38, and 43 ppm 10/sex/group Response Study Adequacy Comments Reference Complaints attributed to biphenyl exposure include headache, gastrointestinal dtscomfort, polyneuritic symptoms, and general fatigue. 1 man died as a result of acute yellow liver atrophy mid B workers had evidence of hepatic and nervous system toxicity which the authors concluded were related to exposure 0/6 mortalities; no toxic signs; gross autopsy revealed nonnalappearing viscera. LC >43 ppm; hyperactrv ity amt mild respiratory discomfort noted during exposure, and gross pathology indicated mild lung congestion at all exposures Inadequate because there were no controls used and detailed reference rates were not provided. Workers were preparing biphenyl impregnated paper for wrapping fruit. Hakkinen el al. 1973 Adequate epidemiology data were not located for inhaled 1.1'biphenyl (HEED, 1990; TSCATS, 1992). Inadequate. Only one exposure level was used; an elTect level was not identified. Monsanto Co., 1983 Inadequate because histopathology was not studied. No effect level was identified. Sun Co., I9&3a Adequate acute inhalation toxicity data on 1,1 '-biphenyl were not located (HEED. 1990; TSCATS. 1992). 53 Chemical Name | T T-Riphenyf A l.l'-Biphcnyl 1,I'-Biphcnyl 1. I'-Biphcnyl 1,1 '-Biphenyl l.l'-Biphenyl 1,1 '-Biphenyl Tabic of Toxicity Data for HAPs (continued) CAS Number 92-52-4 92-52-4 92-52-4 92-52-4 92-52-4 92-52-4 92-52-4 Sludy Type Subchrontc toxictty (range finding) Species Mice Route of Administration Type of F:xposurc Inhalation Vapor Subchronic toxicity Mice Inhalation Vapor Subchronic toxicity - Summary Chronic toxkity Summary Carcinogenicity Rats Oral Diet Carcinogenicity - Summary Neurotoxicity Summary Duration 7 hours/day, 5 days/week for 2 weeks 7 hours/day, 5 days/week for 13 weeks 700 days Exposure levels 0, 24 80, and 54 75 ppm (mean measured) 0, 25, and 50 ppm (nominal) 0,0 001,0.005, 001,005,0 1, 0 5, or \% Number studied? exposure level 10/scx/group 50/sex/group 15/sex/dose group Response Study Adequacy Comments Reference Hyperactivity during exposure; no histopatho>ogical effects in lungs, trachea, liver, kidneys, or spleen. Treatment-related hyperplasia of tracheal epilhelia was noted, along with congestion of the lung, liver, and kidney. Histopathological examination revealed no treatment related incidence of tumors This appears to be a range-finding sludy with a duration too short to assess subchronic toxicity. Inadequate because only 2 dose levels were used; a NOAEL was not identified The concentration tested is likely the highest concentration obtainable The trachea] effect may have resulted from irritating effects of the chemical. Sun Co . 1983b Sun Co., 1983c Adequate subchronic inhalation data on U'-biphenyl were not located (HEED, 1990; TSCATS, 1992). Chronic inhalation data on 1.1'-biphenyl were not located Evidence of chronic effects in humans has been reported (see Epidemiology section above) (HEED, 1990, TSCATS, 1992). Inadequate because insufficient numbers oftest animals were used. Reversible kidney lesions were observed at 0.5 and 1% and food consumption was decreased at 1%. Ambrose el al, i960 Carcinogenicity data on inhaled U'-biphenyl were not located, adequate oral data woe not located {KEEP, 1984; TSCATS, 1992; CHEMTRACK, 7/93). Neurotoxicity data on inhaled U'-biphenyl were not located (HEEP, I9M; HEED. 1990; TSCATS. 1992). n oa zo -n i--( !-> o \> T[ vO Z NJ H --1 (FI J> 54 CONFTDFNTTAl \\ vO Nl I* c* Chemical Name l.l'-Biphcnyl l.l -Biphenyl l.l'-Bipbenyf U'-Brphenyl | 1 1 RipSe-ivI Table of Toxicity Data for HAPs (continued) CAS Number 92-52-4 92-52-4 92-52-4 92-52-4 92-52-4 Study Type Developmental toxicity Species Rats Route of Administration Type of Exposure Oral Gavage Duration Gestation davs 6-15 Exposure levels 0, 125, 250, 500, or 1000 mg/kg/day Number studied/ exposure level 1S to 20 mated females/group Developmental toxicity - Summary J-Generat>oTi reproductive toxicity Rats Oral Reproductive tmkily - Seminary Pharmacokinetics - Summary Feeding Ft, parents from age 4 months through mating, gestation, lactation; continuous dosing of F, and F, parent general ions 0.0.01,01. or 1 0% dietary levels 3 males; 9 females/group Response Study Adequacy Comments Reference Maternal and cmbryoloxictty occurred at 1000 mgftg/dty (mortality of S dams during the treatment period, preceded by a sharp reduction in body weight and diarrhea), increased resorptions, and 5 dams were found notlo be pregnant, possibly due to interference with implantation). No effects were noted on dams or development of offspring in the other test groups. Adequate study. An appropriate range oflest levels and number of test animals were used, appropriate endpoints were examined. Kheraelal, 1979 Developmental inhalation toxicity data on 1,1 -biphenyl were not located (HEEP, 1984; HEED, 1990, TSCATS, 1992) An adequate study conducted by the oral route is available in rats. Decreased fertility and litter size of high-dose females and decreased growth rale of pups in the fiigh-dose group There was no evidence of cumulative toxicity over 3 generations. Inadequate because too few animals were used and histopathology was not performed. The authors attributed the effects in the high dose group to a decrease in food consumption. Dow Chemical Co., 1983 Reproductive inhalation toxicity data were nol localed. Adequate oral dais are available for 1 species (HF EP. 1984, MEED, 1990; TSCATS. 1992). Pharmacokinetics data on inhaled 1.1-biphenyl were not located. (HFEP. 1984. HFFD. 1990. TSCATS. 1992). 55 T able of ioxicity Data for I TAPs (continued) REFERENCES Smhrose, A M . Booth, A N . DcEEK, f , and Cox, A J., Jr "A toxicological study of biphenyl, a citrus funpistal " I'uod Rcieanh 25 328-336 (1960) t HEM TRACK Nalional Tox ecology Program Results Report "Results, status and publication information on all NfP chemicals produced from NT P CflEMTRACK system'July (1993) rhm Chemical Company "Toxicological study of diphenyl in citrus wraps with cover letter" TSCA RD submission R7R213721, microfiche number OTS02064 56 Washington. I)C OPPT. US EPA (1983) Hakkinen. I, Siltanen. E . ITemberg. S., Seppalainen, A M , Karli, P., and Vilckula. E "Diphenyl poisoning in fruit paper production " Arches of Environmental Health 26.70-74 (1973) 111 ED "Health and Environmental Effects Document for l,t`-Biphenyl " US Environmental Protection Agency (1990) 1IKEP. "Health and Environmental Effects Profile for l J-Biphenyl.* US Environmental Protection Agency (I9R4) Khera. K S, Whalen, C, Angers, G, and Trivett, G "Assessment of the teralogenic potential of piperonyl butoxide. biphenyl, and phosalonc in the rat." Toxicology and Applied Pharmacology. 47:353-358 (1979) Monsanto Company Toxicological investigation of biphenyl." TSCA 8D submission 878213572, microfiche number OTS02O6411 Washington. DC OPPT, US EPA (I9R3) Sun Company Jnc. "Acute inhalation toxicity of biphenyl with cover letter." TSCA 8D submission 878213530. microfiche number OTS0206401 Washington, DC OPPT, US EPA (1983a) Sun Company Inc. "Subacute inhalation toxicity of biphenyl" TSCA 8D submission 878213531 microfiche number OTS020640I Washington. DC' OPPT, US EPA (1983b) Sun Company Tnc *90-Day inhalation toxicity study of biphenyl (99 + % purity) in CD( mice " TSCA 8D submission R7R2I3532, microfiche number OTS02Q640T Washington, DC OPPT. US EPA (1983c) TSCATS (Toxic Substances Control Act Test Submissions) Database (1992) O OZ ZC Tf t--t --> D 'o .r, Z Nl --i & M I> 56 Table of Tox icily Data for HAPs (continued) Chemical Name Flhylbenyene CAS Number T00-41 --4 Study Type Epidemiology (Cohort study) Species Humans Flhylbenrenc 100-41-4 Epidemiology (Controlled human experimental) Humans Ethylbenzene | Fthylbenzene 100-41-4 100-41-4 *---------------------o bo zo Tl -- Z \> Tl cO ZM -! fs -1 00 I> Epidemiology Summary Acute toxicity Rais Rome of Number studied/ Administration Type of ExposureDurationFxposure levelsexposure levelResponseStudy Adequacy Comments Reference Occupational Commercial product ion of ethylbenzene 29 years Inhalation Vapor 8 hours Inhalation Vapor 4 hours Not reported 200 males 100 ppm 18 volunteers 2000,4000, and 8000 ppm, and saturated vapors 6/group No effects were noted on complete blood count, hemoglobin concentration, or blood chemistry values Urinalysis indicated mandelic acid, phenol, and mercapturates were within maximum allowable concentration (MAC) range. Marginal. Quantification of exposure levels was not reported Workers were also exposed to benzene. Bardodej and Cirek, 1988 There were no adverse health effects. Only traces of ethylbenzene were found in expired air and only negligible amounts were excreted in the urine; at unspecified higher concentrations, irritation of the eyes and respiratory tract occurred and subjects developed headaches and fatigue 73k study is inadequate because it was designed only as a biotransformation study of ethylbenzene and thus, only a limited number of endpoints were measured This study identifies aNOAEL of 100 ppm for subjective symptoms in humans. Bardodej and Bardodejova, 1979 Mortalities were 0/6,3/6, 6/6, and 6/6 for 2000 ppm, 4000 ppm, 8000 ppm, and saturated vapors, respectively Adverse effects have been reported m workers exposed to ethylbenzene vapor; however, concomitant exposure to other compounds limits interpretation of these studies (Clement, I990g>, This is not an adequate acute toxicity study because only one sex was tested Purity was not reported; clinical signs were not reported and LC,, was not calculated Union Carbide Corporation, 198? 57 Chemical Name iThvfbcnzcne Kihyl benzene Ethylbenzene Tabic of Toticity Dala for I !APs (continued) CAS Number 100-41-4 Study Type Acute to * icily Species Mice 100-41-4 100-41-4 Acute toxicity Summary Subchronic toxicity Rats Rome of Administration Type of Exposure Inhalation Vapor Duration 30 minutes t-.xposure levels Number studied/ exposure level 410, 860. 1875 3970, and 9640 ppm 4 mates^group Inhalation Vapor 6 houtVday, 5 days/week for 2, 5. 9, or 16 weeks 0, 50, 300, and 600 ppm 5 males/group Response Decrease in respiratory rate was observed at all concentrations and sedation occurred at 9640 ppm Study Adequacy Inadequate The group size was small and the only effect examined was respiratory rate. Comments At the lower exposures, the onset of respiratory depression was slow. Reference i Nielsen and Alarie, L982 Additional testing could be required on the acme inhalation toxicity 1 of ethylbenzene because of the limited range of endpoints reported. | No e fleet was noted on weighl gain. Increased relative kidney weight was noted at 2 and 9 weeks in high-dose animals, but not at 16 weeks. Other effects noted at 600 ppm included changes in hepatocyte ultrastructure, but no necrosis; altered liver and kidney metabolizing enzymes, slightly increased excretion of kidney GSH, but no change in hepatic glutathione This is not an adequate study because ofthe small group size, use of only males, and the limited endpoints examined. This study provides evidence that ethylbenzene can induce drug metabolizing enzymes Elovaara el al, 1985 1 r> oo 2o T) C7 \) ^ 0 2M -f s) I> 58 Table of Toxicity Data for HAPs (continued) (hem ical Name ( AS NumberStudy TypeSpecies Route of Number studied/ Administration Type of ExposureDurationExposure levelsexposure levelResponseStudy AdequacyCommentsReference i Ethylbenzene 100-41-4 Short-term exposure Rats, mice, and rabbits Inhalation Vapor 6 hours/day for 4 days 0. 400, 1200. and 2400 ppm S male rats and mice and 4 male rabbits/exposure level Mortality of rats (2400 ppm) and mice (1200 and 2400 ppm), with Iscrimaticm, shallow breathing, and prostration prior to death. Congestion of the nasal mucosa, lungs, liver, and kidneys m rats (2400 ppm) and mice (1200 and 2400 ppm) was observed in animals that died and may not be treatment related Transient increased laefimation was observed in rabbits at all exposure levels. This study is inadequate because of the small group size and the use of only male animals No histopathology was performed This study identifies a FEL of 1200 ppm for mice and of 2400 ppm for rats, andaNOAELof 2400 ppm for rabbits. This study demonstrates possible portal-ofentry effects, however, since effects on the lungs were observed only in animats that died, the congestion may be merely related to not being Med. Biodynamics Inc., 1987 Ethylbenzene 100-41-4 Subchronic loxicity Rats, mice, and rabbits Inhalation Vapor So zo Tj 6 hours/day 5 days/wcek for 4 weeks 0.99, 382. and 782 ppm (rats and mice); 0. 383.782, or 1610 ppm (rabbits) 5/sex/exposwe level Salivation, lacrimation, and increased relative liver weights in rats at 382 ppm and greater; hematological effects in rats at 782 ppm and greater; no adverse effects in mice, decreased body weight gains in rabbits at 782 and 16)0 ppm. This is an inadequate study Too few animals per group were used and exposure was for a short duration. Purity 99.7%; most important endpoints were evaluated, this study identifies a NOAELof382 ppm and a LOAEL of 782 in rats and rabbits, and a NOAELof 1610 ppm m mice Craggetal, 1989 ov "n > Z vj --' yi -t O T> 59 Chemical Name Ethylbenzene Ethyl benzene Ethylbenzene Ethylbenzene Flhylbenzenc Table of Toxicity Data for HAPs (continued) CAS Number IMMI-4 100-41-4 100-41-4 100-41-4 100-41-4 Sludy Type Subchronic toxicity Species Rats Route of Adminislralion Type of Exposure fnhalalion Vapor Duration 6 hnurs/day, 5 days/week for 90 days Exposure levels Number sludiedt exposure level 0, 100.250, 500, 750, and 1000 ppm 10/sex/c xposurc level Subchronic toxicity Mice Inhalation Vapor 6 hours/day, 5 days/week for 90 days 0,100, 250, 500, 750, aid 1000 ppm 10/sex/exposure level Su be hronlc to* ici ty - Sirnm a ry Chrome toxicity Not reported Inhalation Not reported Chronic toiicily -Sammary 2 years Not reported Not reported Response Study Adequacy Comments Reference Dose-related increased incidence and severity of regeneration of renal tubules, increased relative kidney (500 ppm and higher) and liver weights (250 ppm and higher) Increased relative liver (750 ppm and higher) and kidney weights (1000 ppm) A ! 3-week study has been completed, the 2year histopathology evaluation is in progress. This is an adequate subchronic toxicity study This ts an adequate subctironic toxicity study. Purity >99.5%; this study identified a NOAEL of 100 ppm and a LOAEL of 2 50 ppm for increased relative lives weights No histdogica) evidence ofeffects was observed in the spleen or thymus. Purity >99.5%; this study identified a NOAEL of 500 ppm Bid a LOAEL of 750 ppm for increased relative liver weights, no corresponding histological ev idence of adverse effects was observed in the liver, spleen, thymus, or kidney. NTP, 1992 KIP, IW1 Adequate inhalation subchrontc data were available (Clement, I990g; NTP, 1992). The study is not available to be evaluated. This test is currently in progress CHEMTRACK, 1994 No data on the chronic inhalation toxicity of ethylbenzene were available; however, NTP is conducting an inhalation btcassay (Clement. 1990* TSCATS. !992;TOXLlNE. 6/93) I 60 o o z o o ~n i--i S__i oV "Tf z -0 XI -pHf Cn i--i a> Chemical Name Ethylbenzene Plhylbcnzene Ethylbenzene Ethylbenzene Ethylbenzene . 0 33 2O 3 3 \) 3 >0 2 nj 1 '3 -> V 2> Table of Toxicity Data for HAPs (continued) CAS Number 100-41-4 Study Type Species Carcinogenicity Not reported 100-41-4 Carcinogenicity Summary IOCMI-4 Neurotoxicity Ruts I0MM Brain chemistry assay Rabbits 100-41-4 Neurotoxicity - Summary Route of Administration Type of Exposure Inhalation Not reported Duration 2 years Exposure levels Number studied/ exposure level Not reported Not reported Inhalation Vapor Inhalation Vapor 14 hours/day, 7 days/week for 1 week 12 hours/day. 7 days 0. 1500, 2000, or 3000 ppm for 1 5 hours, 0, 1000,1500, or 2500 ppm for 2 more hours, and 0, 500, 1000, or 1500 ppm until the end of the study (The concentration was reduced because of overt toxicity ) 0 or 750 ppm 12 males/group 8 males/group Response A 13-week study has been completed, the 2year hislopathology evaluation is in progress In all but the group exposed to 1500 followed by 500 ppm, there was a dear impairment of auditory sensitivity which was more noticeable at 16 kHz than 8 kHz. Study Adequacy The study is noi available to be evaluated Comments This test is currently in progress Reference CHEMTRACK, 1994 No data on the carcinogenicity ofethylbenzene were located (Clement, I990g, TSCATS, 1992). Hislopathology is being evaluated in an NTP inhalation carcinogenicity study tn rats and mice (CHEMTRACK, 1994). This is an inadequate since the concentration was reduced during the study lo mitigate overt toxicity. This study was part of a study of a large group of solvents that indicated that many solvents produce ototoxic effects. Pryor and Rebert, 1993 Marked depletion of striatal and hiberoinfiindibular dopamine was noted in treaied animals Not a standard neurotoxicity test Results suggest that dopamine meiabolism is a toxicity target for ethylbenzene. Romineffi et at., 1986, Mutti etal, 1988 Ototoxic effects in rats indicate the potential for ethylbenzene to be a neurotoxic agent. 61 Chemical Name Ethvfbenzcnc Ethylbenzene Ethylbenzene Table of Toxicity Data for HAPs (continued) CAS Number 100-4 1-4 Study Type Developmental toxicity Species Rats 100-41-4 Developmental toxicity Mice 100-4 M Developmental toxicity Rabbits Route of Administration Type of Exposure Inhalation Vapor Duration 6 hours/day or continuous exposure on gestation da>s 7-15 Exposure levels Number studied/ exposure level 6 hours/day: 0 or 600 ppm; or 17 or 19/exposure level Continuous exposure. 0, 600, 1200, and 2400 mg/m' (0, I3B2, 276 3, and 552 6 ppm) Inhalation Vapor Inhalation Vapor Continuous exposure on gestation days 6-15 0 and 500 mg/m1 (0 and 115 1 ppm) 20/group Continuous exposure on gestation days 7-20 0, 500, and 1000 mg/m1 {0. US,l, and 230 3 ppm) 60, 9. and 3 respectively Response Study Adequacy Comments Reference All dams survived, no other maternal effects were reported In the 6 hour/day exposure group, no embryonic or fetal effects were noted. In the continuous exposure group, significantly (jkOOS) increased percent dead or resorted fetuses and skeletal retardation was seen at 600 mg/m1 and higher, and at 2400 mg/m1, decreased fetal weight and increased incidence of extra ribs and skeletal malformations were seen. Marginally adequate study The TSCA guidelines require 20 animals/group No effects were noted on maternal survival. Increased incidence of anomalies of the uropoietic apparatus occurred in treated mice. No other effects were reported. Inadequate because only one exposure level was used. No effects were noted on maternal survival, weight gain, or relative liver weight. Decreased fetal body weight occurred at 500 mg/m', and all dams aborted at 1,000 mg/m1. Inadequate, the number of animals exposed was too small. It is unclear whether effects were seen in the dams. The tabular presentation included survival of dsns, but no other maternal endpoint Ungvary and Tatrai, 1985 Results were presented in summary form Ungvary and Tatrai, 1985 The study suggests that abortions are induced at concentrations (hat are not toxic to the dams. Ungvary and Tatrai, L98S 62 `-f -j OV 5^ 2: vj Table of Toxicity Data for HAPs (continued) Chemical Name Ethylbenzene CAS Number I00-4M Ethylbenzene 100-41-4 l-'thjlbenzene 100-41-4 Ethylbenzene 100414 Ethylbenzene o 100414 DO. Study Type Developmental toxicity Species Rats Route of Administration Type of Exposure Inhalation Vapor Duration 7 hours/day on gestation days 1-19 Exposure levels 0, *00. or 1000 ppm Number studied/ exposure level Not reported, target number of htters/group was 30 Developmental loxicity Rabbits Inhalation Vapor 7 hours/day on geslalion days 1-24 0, *00, and 1000 ppm 29-30/exposure level Developmental toxicity Ruts Inhalation Vapor Developmental loxicity Summary Reproductive toxicity - Summary 7 hours/day, 5 days/week for 3 weeks, followed by mating, then exposure daily through 19 days of geslalion 0, 100, and 1000 ppm 38 sperm positive Response Study Adequacy Comments Reference Maternal (increased liver, kidney, and spleen weights [relative or absolute not repented]} and developmental toxicity (increased incidence of extra ribs) at 1000 ppm, This is a marginally adequate study. Purity was not reported. This study identified a NOAELof 100 ppm and a LOAEL of 1000 ppm for maternal and developmental toxicity. Hardin et >1, 1981 No maternal or developmental toxicity was observed (increased maternal liver weight and slightly decreased number oflive kits/litter at 100 and 1000 ppm were not considered treatment-related) This study is inadequate because no toxicity was produced Purity was not reported in Hardin eta!., 1981, but in the Andrew et a), 1981 report, it is repotted as >99% purity Andrew el aL, 1911 Maternal toxicity (increased relative liver, kidney, and spleen weights; reduced number of sperm-positive Tats that were pregnant following pregestational exposures) at high-dose Developmental loxicity (increased incidence of supernumerary ribs and decreased crown-ramp length) at 1000 ppm Adequate study. Purity >99%. Although only 2 exposure levels were used, a NOAEL (100 ppm) ml LOAEL (1000 ppm) were identified for both maternal and developmental loxicity. Andrew et al, 1981 Adequate developmerrial toxicity data were located in 1 species (Hardin eta)., 1981-A ndtewetal., I9S1). No data on the reproductive toxicity of ethylbenzene were located (Clement, 1990g;TSCATS, 1992; TOXUNE. 6/93). O N) Si !_n 63 Tabic of l ovicitv Data for IIAPs (continued) Chemical Name CAS Number Study Type Species Route oT Administration Type of Exposure Pharmacokinetics - Summary Duration Exposure levels Number studied/ exposure level Response Study Adequacy Comments Reference Information on the absorption, metabolism, and excretion of inhaled ethylbenzene is available in humans and animals; pharmacokinetics information on orally administered ethylbenzene is available for animals (Clement, 1990g)_______________________________________ 4KFERENCES \ndrew. F D. Buschbom, R.L. Cannon. W C , Miller, R A . Montgomery, L F., Phelps, D W, and Sikov, M R "Teratologic assessment of ethyl benzene and 2-elhoxyethanol" Prepared for NIOSH (National Institute for Occupational Safety and Health) Contract No 210-79-0037. NTIS PB83-0807 (1981) lardodcj. Z , and Cirek, A. 'Long-term study on workers occupationally exposed to ethylbenzene " Journal of Hygiene, Epidemiology, Microbiology and Immunology 32(1) 1-5 (1988) lanlodcj. Z, and Bardodejova, E. 'B ^transformation of ethyl benzene, styrene, and alpha-methylstyrene in man." American Industrial Hygiene Association Journal. pp 206-209, Mareh-April (1970). liodynamics. Inc. "A four-day inhalation study of ethylbenzene in the rat, mouse, and rabbit.' TSCA 8D submission 86870000423, microfiche number OTSQ513170 Washington, DC- OPPT, US EPA (1987) 7HEMTRACK. National Toxicology Program Results Report "Results, status and publication information on all NTP chemicals produced from NTPCHEMTRACK system " (1994). .Tcment "Draft inhalation reference dose for ethylbenzene (100-41-4) * Prepared by Clement Associates, Inc for Environmental Criteria and Assessment Office (I990g) >agg. S T . Clarke, E A , Daly, I W., Miller, R R . Terrill, J B . and Ouellette, R.E "Subchronic inhalation toxicity of ethylbenzene in mice, rats, and rabbits." Fundamental and Applied Toxicology. 13(3) 399-408 (1989) 'lovaara. E . Engstrom. K , Nickels, J., Alto, A., and Vainios, H. "Biochemical and morphological effects of long-term mhalalion exposure of rats to ethylbenzene." Xenobiotica 15(4):299-308 (1985) lard in. B D , Bond,G P , Sikov, M R . Andrew, F D , Beliles, R P., and Niemeier, R W "Testing of selected workplace chemicals for teratogenic potential " Scandanavtan Journal of Work Environment and Health 7(supp1 4)66-75 (1981). <luni. A. Falzoi, M , Romanclfi. A , Boccht, M C., Ferroni. C , and Francbini. 1 "Brain dopamine as alargel for solvent toxicity Effects of some monocyclic aromatic hydrocarbons" Toxicology 49 77-82 (1988) 'Jtclsen. G D , and Alarie, Y. 'Sensory irritation, pulmonary imtation, and respiratory stimulation by airborne benzene and alkylbenzenes Prediction of safe industrial exposure levels and correlation with their thermodynamic properties." Toxicology and Applied Pharmacology. 65:459-477 1982) 'TTP (National Toxicology Program) "Toxicity studies of ethylbenzene in F344fN rats and B6C3FI mice (inhalation studies)" NIH Publication No. 92-3129 (1992) hynr. G T., and Rebert, C S "Neurotoxicity of inhaled substances." SRI International Final Report IjSU- 1644; Prepared under contract No 271 -90-7202 (1993) tomanelli. A . Falzoi, M, Mutti, A , Bcrgamaschi, E.t and Franchini, I "Effects of some monocyclic aromatic solvents and their metabolites on brain dopamine in rabbits ' Journal ofApplied Toxicology. 6(6) 431-435 (1986) fOXLINE National Library of Medicine Online Database (1993) fSC ATS (Toxic Substances Control Act Test Submissions) Database (1992) 64 n O3 2O T} --i 3 \) 'Tl 2M -i 'J\ in I> Table of Toxicity Data for HAPs (continued) Ungvary, G., and Tatrai. E 'On the embryotoxic effects of benzene nnd its alkyl derivatives in mice, rals and rabbits Archives of Toxicology Supplement 8 425-430 (1985) Union Carbide Corporation 'Range finding tests on m-xylcnc and ethyl benzene.' TSCA 8D submission 86-870001406. microfiche number OTS05I5568 Washington, DC OPPT, US EPA (1987). c> oz oo Tf *--( >-> o \j Tl vD ZM -f tn x-4> cr 65 Table of Toxicity Data for MAPs (continued) Chemical NameCAS Number 1 1 Ethylene drchloridc 107-06-2 Ethylene dichloride T07-06-2 Ethylene dtchloride 107-06-2 Ethylene dichforide 107-06-2 Study Type epidemiology (Health surveys) Species Humans Epidemiology (Case reports) Humans Epidemiology - Summary Acute immumoloxicity Rats Roule oT Admi rostral ion Type of ExposurefXirarionFixposurc levels Occupational exposure Aircraft industry workers, soft lank producers Up lo approximately 4 years TWA 10-15 ppm Occupational exposure Oil refinery workers Not reported 10 to 200 ppm Inhalation Vapor 3 hours (5 hours for bacierictdal activity assays) 0,100. and 200 ppm Number studied/ exposure level ResponseStudy AdequacyCommentsReference 83 workers 16 males Males; number not reported Liver and gall bladder disease, nervous system dysfunction, and gastrointestinal disorders were observed Burning sensation in the eyes, lacrimatkm, dizziness, fatigue, drowsiness, nausea, occasional vomiting, constipation, loss of appetite, liver, and G1 tract effects woe noted No effects were seen on pulmonary bactericidal activity, nor on alveolar microphage in vitro phagocytosis of chicken red blood cells, cytostasis, cytolysis of tumor target cells. Lymphocyte function was not affected. Inadequate because controls were not utilized. This is a translation of a Russian study. Kozik, 1957 This study provides qualitative information on effects of ethylene dichloride. Symptoms disappeared upon change of workplace, but reappeared upon reexposure Celnaiowicz, 1959 Epidemiological data are available regarding exposure to mixtures containing ethylene didiloride (TSCATS, 9fi>3> Numerous accounts of acute aid repealed occupational exposures report fatal and non-fatal outcomes; none provide exposure data, and subjects were usually simultaneously exposed toother potentially hazardous materials Death was generally attributed to respiratory and circulatory failure (HAD, 1984). Inadequate. Only limited specialized endpoints were studied This study evaluated (he effects ofethylene dichloride on pulmonary defense mechanisms Sherwood el al, 1987 n oV zm o M o -n V o z-t --` XI X:Ji' I> 66 r> o -H zo fl --1 V "n v> z Nj H 'J\ < 00 x> Chemical Name Ethylene dichloride Ethylene drchloride Ethylene dtehloride Ethylene dtehloride Ethylene dichloride Elhylene trichloride Table of Toxicity Data for HAPs (continued) CAS Number 107-06-2 107-06-2 107-06-2 107-06-2 107-06-2 107-06-2 Study Type Acute imrmjmotoxicity Species Mice Acute upper respiraiory tract irritation study Rats Acute toxicity Mice, rats, and rabbits Acute loxrcity Rats Acute toxicity Ruts Acute toxicity Rats Route of Administration Type ofExposure Inhalation Vapor Inhalation Vapor, head only Inhalation VapOT Inhalation Vapor Inhalation Vapor Inhalation Vapor Duration 3 hours (S hours for bactericidal activity assays) Exposure levels N umber studied/ exposure level 0,2.5, 5, and 10 ppm 18-36 females/ group 10 minute 1 hour B concentrations ranging from 640 to 12,000 ppm 4 males/group 200 ppm 10/group 4 hours 1000 ppm 6 males or females 0 1 to 7.0 hours to decreasing concentrations 200 to 12,000 ppm 4-6/group {sex not reported) 0 5 to 8 hours 6 concentrations - from-300 lo 3000 ppm 10 to 44 males/exposure level Response Study Adequacy Comments Reference Increased susceptibility lo pulmonary bacterial infection was noted at 5 ppm; no effects were noted on this parameter or on survival at 2 5 ppm. Inadequate Only limited specialized endpoints were studied. This study evaluated the effects of ethylene dichloride on pulmonary defense mechanisms Sherwood el al., 1987 No appreciable respiratory rate depression was observed and an RD could not be determined. This is not a standard acute toxicity test. This substance docs not appear to be an irritant to (he upper respiratory tract. E I. DuPont de Nemours St Co, 1982 4/10 mice died; no mortalities were seen m rats or rabbits. Inadequate Only one exposure level was used and limited endpoints appear to have been examined. This is a brief summary of a study; no supporting data arc provided. Union Carbide Corp, 1987 4/6 died during the 14 day observation period. Inadequate. Use of controls was not reported, laid die number of exposure levels and animals/group is unclear Graded concentrations were tested, but only data on 1000 ppm were provided. Carpenter et al., 1949 Adverse effects (not described) occurred with exposure to 20} ppm for 5 S hours up to 12,000 ppm for 0 1 hour. Inadequate Exposure was not for a set duration, and low numbers of test nimafs were used. CNS depression occurred prior to death. Spencer et al, 1951 Mortality occurred m all treatment groups except 300 ppm for 7 hours. Inadequate. ^Exposure times varied and use of controls was not reported Liver and kidney appeared to be target organs. Spencer et >1., I9SI 67 Table of Toxicily Data for HAPs (continued) rbcmical NameCAS NumberStudy TypeSpecies Route of Number studied^ Administration Type of bxposuretXiralionfxposurc levelsexposure levelResponseStudy AdequacyCommentsReference nhylcnc dichloridc Ethylene dichloride 107-06-2 107-06-2 Acute toxicily Rats, mice, guinea P'gSx rabbits, cats, hogs, and raccoons Acute toxicity - Sum miry Inhalation Vapor Ethylene dichforide (07-06-2 Subchronic toxicity Rabbits Inhalation Vapor Fthylene dichloridc 107-06-2 Subchronic toxicity Rats, guinea pigs, rabbits, and cats Inhalation Vapor 1 5 So 7 hours 2 hours/day, 5 days/week. 90 days 6 hours/day. 5 days/week, 6 weeks 1500 and 3000 ppm 3000 ppm 0, 100, and 500 ppm 13-20 rats, 20-23 mtce. 12-14 guinea pigs, 16 rabbits. 3 cals, 2 hogs, and 2 raccoons Mortality occurred at 3000 ppm in all species except raccoons. 4/20 rats and 20/20 mice died after exposure to 1500 ppm for 7 hours Inadequate. Exposure times varied, only 2 exposure levels were used, and use of controls was not reported. Lungs and kidney appeared to be target organs. lleppel et at, 19 Adequate acute inhalation toxicity data were not located, but available animal data support findings in humans; acute toxicity signs include squinting and lamination of the eyes, rubbing of tl nose, vertigo, static and motor ataxia, unconsciousness, incoordination of extremities, and congestion of the liver, spleen lungs, adrenal glands, and kidneys. Death was usually ascribed respiratory and circulatory failure (HAD, 1984). (0 (sex not reported) Anemia, gramifobtastic, and erythroblastic hyperplasia of bone marrow, altered lives and kidney function, and vascular degeneration and focal necrosis of the liver and kidney were observed. This study is limited by use of only one test exposure and no reported use of controls Results suggest that ethylene dichloride affects formed elements of the blood Lioia and Elmin 1959 10 (rats and guinea pigs) and 4 (rabbits and cals), sexes not reported Mortality was high in all species following exposure at 500 ppm; necropsy revealed lesions hi the liver, kidney, adrenals, heart, and lungs. At 100 ppm, cats had decreased weight gain. No other effects were noted in animals exposed to 100 ppm. This study is limited by the use of only 2 test levels. ANOAEL of 100 ppm was identified for rats, guinea pigs, and rabbits; a NOAEL was not identified for cats Hofmann et al., 1971 r> oo 2n O O \) T1 sD 2 SJ -f 's> -H sO 2> 68 Table of Toxicity Data for HAPs (continued) Chemical NameCAS NumberStudy TypeSpecies Route of Administration Number studied/ Type of Fxposure________DurationExposure levelsexposure levelResponseStudy AdequacyCommendsReference Ethylene dichloride 107-06-2 Subchronic loxicity Rais, guinea pifiSs rabbits, and cats Inhalation Vapor Ethylene dichlonde 107-06-2 Repealed exposure; pulmonary defense evaluation Ruts Inhalation Vapor Ethylene dichlonde 107-06-2 Ethylene dichlonde 107-06-2 n o z> z-n o Repeated exposure, pulmonary defense evaluation Mice Inhalation Subfhrwiif toxicity - Summary Vapor 6 hours/day, 5 days/week for 26 weeks 5 hours/day, 5 days/week for E2 exposures 5 hours/day for 5 days 0 and 500 ppm for ! 3 weeks, followed by 1000 ppm for an additional 13 weeks 0, 10, 20, 50. or 100 ppm 0 or 2 5 ppm 4 cats, 4 rabbits, 10 guinea pigs, and 10 rats equally divided by sex No adverse effects were seen after 13 weeks at 500 ppm, so animals were exposed for an additional 13 weeks to 1000 ppm. No evidence of toxicity was seen in rats, guinea pigs, or rabbits. In cats, renal injury with histological alterations and increased blood urea developed after the additional highexposure Males, number not reported No effects were seen on pulmonary bactericidal activity, nor on alveolar microphage rn vitro phagocytosis of chicken red blood cells, cytostasis, or cytolysis of tumor target cells. Lymphocyte function was not affected. 18-36 females/ group No effects were noted on survival or bactericidal activity at 2 5 ppm. This is not a standard protocol for subchronic toxicity because exposure levels were changed during the study This is not a standard subchronic toxicity test. This is not a standard subchronic toxicity test Ethylene dichloride was not toxic to rats, guinea pigs, or rabbits at high levels of exposure; ALOAEL of 1000 ppm was identified in cats Limited endpoints were examined. Limited endpoints were examined. Hofmann et al, 1971 Sherwood et al, 19*7 Sherwood et al, 1917 Adequate subchronic inhalation toxicity data were nol located fTSCATS. 9/93; HEEP, 19*5; HAD, I9M) Limited available da in 5 species suggest ethylene dichloride es moderately toxic and tf the liver and kidneys arc the primary targets. Z) M 'D s> --t O T> Table of Toxtcity Data for HAPs (continued) Chemical NameCAS NumberStudy TypeSpecies Ethylene dicbloridc 107-06-2 Chronic toxic ely Rats Ethylene dichloride 107-06-2 Chronic toxicity Mice Eibylene dichloride 107-06-2 Chronic toxicily Rats, guinea pie. rabbits, and monkeys Route of Administration lype of ExposureDurationExposure levels Number studied/ exposure levelResponseStudy AdequacyCommentsReference Inhalation Vapor InhalatTon Vapor Inhalation Vapor 7 hoiirs/day. 5 davs/wcek for 7R weeks 7 hours/day, 5 days/week for 78 weeks 7 hour$/day, 5 days/week for 1 70 to 24* days 0,5. 10, and 50 ppm, and 250 ppm reduced to 150 ppm 0, 5, 10, and SO ppm, and 250 ppm reduced to 150 ppm 100, 200 (rats and guinea pigs only), and 400 ppm (all species) 90/sex/group 90/sex/group 15/sex rats, 8/sex guinea pigs, 2 male, 1 female rabbit; and 2 male monkeys A high incidence of mortality in the 250 ppm group led to reduced concentration of 150 ppm from week 10 to the end of the study Increased SGPT, tglutamtne transpeptidase (females only), blood glucose and uric acid levels were noted at 50 and 150 ppm, and SGOT and cholesterol levels were depressed at these levels. Adequate study, adequate lest levels were used over an adequate lifespan. A high incidence of mortality m the 250 ppm group led to reduced concentration ofl50 ppm from a few days (not quantified) to end of the study. No treatment* related increases in incidence of tumors were observed Adequate study using adequate test levels over an appropriate duration 400 ppm = NOAEL m rabbits, 200 ppm = NOAEL in rats, 100 ppm * NOAEL in other species Guinea pigs showed decreased body weight, increased relative liver weight and slight hepatic degeneration at 200 ppm. Mortality occurred in all species but m rabbits at 400 ppm. This study is inadequate because of (he short duration of exposure Animals were observed for hfe. The report indicates a NOAEL of 150 ppm was identified. Data suggest that guinea pigs may be more sensitive to inhaled ethyl dichloride than rats, but use of small numbers of test animals weakens (his conclusion. Maltoni d al_, 1980 (also presented as an abbreviated report in Dow Chemical Co., 1987) Maltoni et al., 1980 (also presented as an abbreviated report in Dow Chemical Co , 1987) Spencer et al. 1951 Chemical Name Ethylene dichlonde Elhylene dichlonde 1 Ethylene dichloride n zo D O n o \> z"n vO \J O' V 3> Table of Toxicity Data for HAPs (continued) CAS Number 107-06-2 107-06-2 I07-06-2 Study Type Species Chronic toxicity -Summary Carcinogenicity Flats Carcinogen icily Mice Route of Administration Type of Exposure Duration inhalation Vapor 7 hours/day. 5 days/week, for 78 weeks inhalation Vapor 7 hours/day, 5 days/week for 78 weeks Exposure levels Number studied/ exposure level 0. 5, TO. and 50 ppm, and 250 ppm reduced to 150 ppm 90/sex/group 0, 5, 10. and 50 ppm. and 250 ppm reduced to 150 ppm 90/sex/group Study Adequacy Comments Reference A high incidence of mortality in the 250 ppm group led to reduced concentration of 150 ppm from week 10 to end of the study No treatment-related increases in incidence of tumors was observed; however, a non significant, nonconcentratkm-related increase in benign mammary tumors (fibromas and fibroadenomas) was noted in treated mimals. A high incidence of mortality in the 250 ppm group ted to reduced concentration of 150 ppm from a few days (not quantified) to end of the sludy. No treatmentrelated increases in incidence of tumors was observed. Adequate chronic inhalation loxicity data are available in two species, with the liver as an apparent target organ. Adequate study examining appropriate endpoints Clear evidence of carcinogenicity was not observed during the lifetime of the rats. Mafloni el a), 1980 (also presented as an abbreviated report in Dow Chemical Co., 1987) Adequate study examining appropriate endpoints. Evidence of carcinogenicity was not observed during the li fetime of the mice Maltonictri, 1980 (also presented as an abbreviated report m Dow Chemical Co. 1987) 71 Chemical Name Ethylene dichtoride | Ethylene dichloride Fable of Toxicity Data for lfAPs (continued) CAS Number 107-06-2 Study Type Species Carcinogenicity Rats ! 07-06-2 Carcinogenicity Rtfs Route of Administration Type of Exposure Inhalation Vapor Dural ion 7 hourVday, 5 daysAveck for 24 months Exposure levels Number studied/ exposure level 0 and 50 ppm 50/scx/group Oral Gavagc 5 days/week for 78 weeks 0, TWA 47, and 95 mg/kg/day 50/sex/trealinent group, 20/sex/control group Response Study Adequacy There were no significant changes in body weight or tumor incidence. This study is inadequate because only one exposure level was used and this was nol the highest concentration that could be tested Increased mortality occurred at 47 mg/kg/day and higher, Dose-related increased incidence of squamous cell carcinoma of the foiestomach, hemangiosarcomas of the circulatory system, and subcutaneous fibromas occurred in treated male rats. Incidence of combined mammary fibromas and adenocarcinomas was also dose-related in females Adequate. Comments Addition of disulfiram to the diet, which produced higher ethylene dichlonde levels, resulted in increases in liver, mammary glid (females) and testicular tumors Evidence of carcinogenicity was seen in both sexes. Reference Cheeveret a!, 1990 NCI, 1978 n o znS--( Oo o \) T| vO zH' 1 CF' U) I> 72 Table of Toxicity Data for HAPs (continued) Chemical Name Ethylene dichloride Ethylene dichloride E-lhylcne dichloride CAS Number 107-06-2 Sludy Type Species Carcinogenicity Mice Administration Type of Exposure Dural ion Oral Gavage 5 days/week. 7B weeks 107-06-2 Carcinogenicity - Summary 107-06-2 Nearotoikity - Summary Exposure levels exposure level 0. TWA for males - 97 and 195 mg/kg/day; TWA for females = 149 and 299 mg/kg/day 50/sex/treatment group; 20/sex/controt group Response Increased mortality occurred in high-dose females; no other e ffects on survival were reported. Increased mammary adenocarcinomas aid endometrial stromal polyps and sarcomas were seen in females, increased hepatocellular carcinomas were seen in males, and increased alveolar/bronchiol ar adenomas were seen in both sexes. Study Adequacy Adequate Comments Reference Evidence of carcinogenicity was seen in both sexes NCI. I97R An adequate carcinogenicity study is available for rats and mice (Malloni et al. 1980), and oral gavage and drinking water 13-week studies have been completed in rats and mke (NTP, 1991), no indication of continuing studies by NTP was reported (CHEMTRACK, 1993). Neurotoxicity data on ethylene dichloride were not located in the available literature (TSCATS, 9/93: HEEP. 1985; HAD, 1984). n 5o ^1 z ~n H --* o \) "T vO Z \! H O' '-H 3> 73 Chemical NameCAS Number ................ Ethylene dichlondc 107-06-2 Ethylene dichlondc $07-06-2 Ethylene dichlondc Ethylene dichloride 107-06-2 107-06-2 Table of Toxicity Data for DAPs (continued) Study Type Developmental toxicity Species Rats Route of Administration Type ofl-.xposurc Inhalation Vapor Developmental toxicity Rabbits Inhalation Vapor Developmental tonicity - Summary Single generation reproduction study Ran Inhalation Vapor Duration 7 hours/day. gestation days 6 through 1S 7 hours/day, gestation days 6 through 18 6 hours/day, 5 days/week during a pre breeding period of 12 weeks through breeding, gestation, and lactation Number studied/ Exposure levetsexposure levelResponse Study Adequacy CommentsReference 0, 100, and 300 ppm 16 to 30 bred females/group 0, 100, and 300 ppm 19-21 bred females/group 0, 25. 75, and 150 ppm 30/sex/group Maternal mortality (twothirds of exposed dams) occurred at 300 ppm. No evidence of maternal or developmental toxicity was seen at 100 ppm Maternal modality occurred at both treatment levels No developmental effects were noted at any treatment level No observable signs of toxicity were seen at any treatment level m dosed parents or offspring. This study is inadequate because only 2 test concentrations were used, and because there was an insufficient number of pregnant rats at 100 ppm A threshold for maternal toxicity was not identified The NOAEL for maternal toxicity was 100 ppm. There was extreme malemal toxicity at 300 ppm (including ataxia and lethargy) and L0/L6 rats died, In addition, there were no pups bom to the surviving dams. Shell Oil Co., 1979 (also cited in Raoet al, 1980) This study is marginally adequate because only 2 test concentrations were used. A maternal NOAEL was not identified Shell Oil Co., L979 (alsocited in Raoet al., 1980) Adequate inhalation or oral developmental toxicity studies were not located in the available literature (HAD, 1984; KEEP, 198S, TSCATS, 9/93) This study is limited by lack of identification of an effect level A free-standing NOEL of 150 ppm was identified. Raoet al., 1980 Murray et al, 1980 n o z Zo) n --< --1 oV z xj --I CT' (jn 3> 74 o o c? ZO Tf --t ZV "Ti & Z SI --i TX --f s 3> Table of Toxicity Data for HAPs (continued) Chemical Name Ethylene die blonde Ethylene dichloride Eth> lene dichloride CAS Number 107-06-2 Study Type Multigeneral ion reproduction study Species Mice Route of Administration Type of Exposure Ora3 Drinking waler Reproductive toiicity - Summary Pharmacokinetics - Summary Continuous among P,, generation for 5 weeks premating through 2 weeks after weaning; FI generation for 11 weeks premating through gestation Exposure levels Number studied/ exposure level 0.30,90, and 290 mg/L 10 males and 30 fcmaWgroup Response No observable signs of toxicity were seen at any treatment level in dosed parents or offspring of either generation Study Adequacy This study is limited by lack of identification of an effect level in either generation. Comments A free-standing NOEL of 290 mg/L in drinking water was identified. Reference eet al, 1982 Adequate reproductive toxicity data were not located in the availaM literature (HAD, 1984; HEEP, 1985, TSCATS, 9/93).__________ Data regarding absorption, distribution, metabolism, nd exaction of inhaled and orally ingested ethylene dichloride are available and indicate that this substance is rapidly absorbed, distributed throughout body tissues, metabolized by hepatic microsomal systems, and eliminated primarily by urinary excretion or via the lungs (HEEP, 1985).___________________________ REFERENCES Carpenter, CP, Smyth, H P, and Pozzani, D C. The assay of acute vapor toxicity, and the grading and interpretation of results on ninety-six chemical compounds." Journal ofIndustrial Hygiene and Toxicology. 31(6):343-346 (1949). Cetnarowicz. J 'Experimental and clinical investigations into the actions of dichloroelhane" Folia Medico Cracov 1.169-192 (Polish article summarized from English trans)alion)(1959) Cheever, IC.L, Choi ale is, f.M, Ef-Hawari, A.M., Kovalch. RM., md Weisburger, E.K 'Ethylene dichloride The influence ofdisulfiram or ethanol on oncogenicity, metabolism, and DNA covalent binding in rats " Fundamental and Applied Toxicology 14:243-261 (1990). CHEMTRACK National Toxicology Program Results Report "Results, status and publication information on all NT? chemicals produced from NTP CHEMTRlACK sysiem " July (1993). Dow Chemical Co "Studies on long-term effects on rats and mice of ethylene dichloride, admimsleied by inhalation ' TSCA 8D submission 86-870002194. microfiche number OTS0515984 Washinglon, DC: OPPT, US EPA (1987). E I DuPont dc Nemours A Co "Upper respiratory tracl irritation in rats * TSCA 8D submission 86-87001042, microfiche Number OTS0514944 Washinglon. EXT: OPPT US EPA (1982) HAD "Health Assessment Document for 1.2-Dichloroelhane " US Environmental Protection Agency. (1984) 75 Tabic of To\ictty Data for MAPs (continued) III I P "Heallh and Environmental Effects Profile for Dichloroclhcnes " US Environmental Protection Agency (T985) Hcppef, L A . Neal. P A . Perrin. T l-, Endicott, K M . and Porterfield, V T "The toxicology of 1,2-dichlorocthanc (ethylene dichloridc) IN Its acute loxicily and Ihc effect of proteclive agents " Journal of Experimental Pharmacology and Therapy. 83.53-63 (1945). HofmannJI T . Rimsliel. II, and Jobsl. P "Inhalation toxicity of 1.1 -and 1.2-dichlorocthane " Archives of Toxicology 27(3):248-26S (1971) kn/ik. I V "Problems of industrial hygiene in using dichlnroelhane in Ihc aircraft industry " Gigtena de Truda t Profcisionatn)* Zabolevoma I 31-38 (1957). Lane. R.W . Riddle. B l.. and ftorzclleca, J F "Effects of 1,2-dichloroelhane and I. I. I -tnchloroelhane in drinking water on reproduction and development in mice " Toxicology and Applied Pharmacology 63 409-421 (1982). Lioia, N., and Elmino, O "Toxicily of 1.2-dich)oroethane I Behavior of the formed elements of the blood and marrow" Folia Medico 42 1238-1254 (1959) Maltoni. C . Valgimigli, L., and Scamato, C. "Long-term carcinogenic bioassays on ethylene dichloride administered by inhalation to rats and mice " In. Banbury Report No. 5. Ames. B , Infante, P, and Reitz, R, eds. Cold Spring Harbor Laboratory pp 3-33 (1980) Murray. S S, Rao. K S, Young,) T. Calhoun, L.L., Hanley, T R Jr., Deacon, M.M., Pliny, M.K . and John, J A "Ethylene dichloride Single generation inhalation reproduction study in rats with cover letter" TSCA FYI submission FY1-AX-0680-007S, microfiche number OTS000078 Washington, DC OPPT, US ERA (1980) NCL National Cancer Institute. "Bioassay ofl,2-dichloroeth8nc for possible carcinogenicity " Technical Report Series Number 55 (1978) Rao, K..S . Murray, J S. Deacon. M M , John. J A., Calhoun, L.L, and Young, J.T "Teratogenicity and reproduction studies in animals inhaling ethylene dichloride " Banbury Report. 5 149-166 (1980) Shell Oil Co. "The effects of inhaled ethylene dtchkmde on l!te embryonal and fetal development in rats and rabbits with attachments" TSCA BD submission 86-870001578, microfiche ntimberOTS05l6l59. Washington, DC OPPT, US EPA (1979) Sherwood, R L., O'Shea, W., Thomas, P T., Ralajczak, H V., Aranyi, C., and Graham, J A. "Effects ofmhaia'ion of ethylene drchfnnde on puTmonary defenses of mice and rats " Toxicology and Applied Pharmacology 91:491-496 (1987). Spencer. H C., Rowe, V K . Adams, E M , McCollister, D D, and Irish, D.D "Vapor toxicity of ethylene dichloride determined by experiments on laboratory animals." Journal of Industrial Hygiene and Occupational Medicine. 4.482-493 (1951) TSCATS (Toxic Substances Control Act Test Submissions) Database (1993) Union Carbide Corporation "The toxicity of ethylene dicMoride " TSCA 8D submission 86-870001403, microfiche Number OTS0515565 Washington, DC OPPT US EPA (1987) n o c? zTf D i-t r-*- oM ~n z--t Vl V- i*--t vj x> 76 Table of Toxicity Data for HAPs (continued) Chemical Name Ethylene glycol CAS Number 107-21-1 Study Type Epidemiology {Human acule exposure) Species Humans 1 Ethyleneglycol 107-21-1 Epidemiology (Human repealed exposure) Humans Ethylene glycol Ethylene glycol t Ethylene glycol 107-21-1 107-2 l-l 107-2 M n oo "----------- z o ----------- i-f *-* 0 \) T[ ,0 Z NJ H O' !-f 00 1> Epidemiology - Summary Acute toxicity Summary Subchronic toxicity Rats, guinea pigs, rabbits, monkeys, and dogs Route of Admin istratmx) Type of Exposure Duration Inhalation Aerosol Not reported Inliaialion Aerosol 20-22 hours/day for 7 or 30 days Inhalation Vapor Continuously for 90 days Exposure levels Number sludicdt exposure level Response 3,67, MO, and 200 mg/m* (l 2, 26 4, 55.1, and 78 8 ppm) Oor 30 mg/m1 (0 or 11 8 ppm) Nol reported 4 men/pre hminary exposure group 20 men/main study group Subjective reports of irritation at 140 mg/m* and intolerable at 200 mg/m1; no effects were reported at 3 or 67 mg/m\ No effects on hematology, clinical chemistry, urinalysis, EKG, EEG, psychological testing of reaction time; visualmotor coordination, perception, or mental ability 0 or 12 mg/m* (0 or 4 7 ppm) 15 rats/sex/ exposure group; 15 guinea pigs/sex/ exposure group; 3 male rabbits/ exposure group; 3 male monkeys/ exposure group; and 2 male dogs/ exposure group Mortality was observed in 1 /15 Tats, 3/15 guinea pigs, and 1/3 rabbits; increased pulmonary inflammation was observed in all species; ocular irritation and edema was observed in rabbits, and 2 rats became blind Study Adequacy Comments There are no guidelines for acute toxicity studies in humans This study reported only subjective responses, no controls were reported Reference Wills ctil , 1974 Studies of experimental exposures of humans are note required under TSCA. This study identifies aNOAEL of 30 mg/m1. Wills et a , 1974 A limited study m humans indicates that ethylene glycol is irritating (not further defined) to intolerable. No other epidemiology studies were located (HEA. 1987; SRC, 1987; TSCATS, 1992), No data from animal studies on the acute inhalation toxicity of ethylene glycol were located (HEA, 1987; SRC, 1987; TSCATS, 1992; NTP, 1993), A limited number of endpoints were evaluated; however, this study demonstrates portal-of entry effects. This study identifies a LOAEL (and possibly a FEL) of 12 mg/m1 for rats, guinea pigs, rabbits, monkeys, and dogs Coonct al. 1970 77 Chemical Name Fthv Icnc glycol Ethylene glycol Ethylene glycol Ethylene glycol lablc of Toxicity Data for MAPs (continued) CAS Number KJ7-2M 107-21-1 107-21-1 107-21 -1 Study Type Subchronic toxicity Species Rats. guinea pigs. rabbits, monkeys, and dogs Route of Administration Type of Exposure Inhalation Vapor Subchronic toxicity - Summary Chronic toxkity Summary Carcinogenicity Mice Oral Diet Duration 8 hours/d a>, 5 days/wcek for 6 weeks 2 years Exposure levels Number studied^ exposure level Response Study Adequacy Comments Reference 0 10, or 57 mg/m1 (0, 3 9, or 22 4 ppm) Males 0.6250. 12,500, or 25.000 ppm (approximately 1500.3000. or 6000 mg/kg/day) Females 0. 12,500,25,000, or 50,000 ppm (approximately 3000, 6000, or 12.000 mg/Vc/day) 15 rats/sex/ exposure group; 15 guinea pigs/sex/ exposure group, 3 male rabbits/ exposure group. 3 male monkeys/ exposure group, and 2 male dogs/ exposure group No mortality was observed, nonspecific inflammatory changes in the hearts and lungs were observed in all species at 57 mg/m1, but not at 10 mg/m1 60/sex/group No chemical-related neoplasms were seen in mice of either sex at any treatment level. The range of exposures encompassed levels that produced systemic toxicity A limited number ofendpoints were evaluated, however, this study demonstrates portal-of entry effects. This study identifies aNOAELof 10 mg/m1 and a LOAEL of 57 mg/m' for rats, guinea pigs, rabbits, monkeys, and dogs. Coon el al, 1970 Inadequate data are available for evaluating the subchronic inhalation toxicity of ethylene glycol The available data indicate a potential for portal-of-entry effects (HEA, 1987; SRC, 1987). No data on the chronic inhalation toxicity of ethylene glycol were located (HEA, 1987. S RC, 1987; TSCATS, 1992, NTP, 1993) Chronic oral toxicity data indicate that ethylene glycol is toxic to mice and that target organs are liver, lungs, and kidneys (NTP, 1993). This is an adequate dietary study; appropriate endpoints were examined following an acceptable protocol. No effect was noted on survival ofeither sex at any dose NTP, 1993 r> 3 z3 3 O --t --* oV "n z >0 Si --f O' --* vO > 78 Chemical Name Ethylene glycol 1 Ethylene given! Ethylene glycol 1 Ethylene glycof n o z 0 Q "Hn >--1 z> V' v0 z H--* Nj O x> Table of Toxicity Data for HAPs (continued) CAS Number 107-21-1 Study Type Species Carcinogenicity Rats Route of Administration Type of Exposure Oral Diet Duration 24 months 107-2 M Carcinogenicity Mice Oral Diet 24 months 307-21-1 Carcinogenicity Summary 107-21-7 Neurotoxicity - Summary Exposure levels Number studied/ exposure level 0 04. 0.2. or 1.0 g/kg bw/day 26/sex/group 0 04. 0 2, or 1 0 g/kg bw/day ] 6/sex/group Response Sludy Adequacy Comments Reference There was no statistically significant increase in tumor incidence in rats This appears to be a well conducted study, although group size was only halfofthat recommended in Ok TSCA test guidelines. The high dose was the maximum toleraied dose, with all of the males at this dose dying by 18 months. DePass et al. 1986a There was no statistically significant increase in tumor incidence in mice This appears (o be a well conducted study, although only 16 animals/ sex/group were used rather than the 50 recommended in the TSCA test guidelines. There was a nonstatistically significant increase in lymphosarcomas cn the high dose females by 1 of 3 tests used The tumors appeared to develop earlier in this group. DcPtsj et il I9*6i No data on the carcinogenicity of ethylene glycol following inhalation exposme were located (HEA, 1987; SRC, 1987; TSCATS, 1992). Adequate onl dietary carcinogenicity studies conducted in mice provided no evidence of carcinogenic activity of ethyleneglycol. This compound was withdrawn from NTP feeding bioassay (CHEMTRACK, 7/93). No neurotoxicity data on ethylene glycol woe located (HEA, 1987; SRC, 1987, TSCATS, 1992). 79 Chemical Name 1 thylcne glycol Ethylene glycol 1 able of Irixicily Data far MAPs (continued) CAS Number 107-21 -1 107-21 -1 Study Type Developmental tonicity Species Rais Developmental tonicity Mice Route of Administration Inhalation Inhalation Type ofi'xpnsurc Aerosol Aerosol Duration 6 hours/day on gestation days 6-1 S 6 hours/day on gestation days 6-15 Exposure levels 0, 60, 400. and 1000 ppm (0, 150. 1000, and 7500 mg/mb 0. 60. 400. and 1000 ppm (0, 150, 1000 and 2500 mg/m1) Number studied/ exposure level 25/cxposure group 25/cxposure group Response Study Adequacy Comments Reference Increased maternal absolute and relative liver weights (this may not be a toxic effect) at 1000 ppm, increased delayed ossification in the fetal hindlimbs at 400 and 1000 ppm Decreased maternal body weight at 400 and 1000 ppm; developmental toxicity observed at 400 and 1000 ppm included increased number of late resorptions and increased incidence o f external, visceral, and skeletal malformations This is an adequate study, although assessment of concentrationeffects relationships may be difficult This is an adequate study, although assessment of concentrationeffects relationships may be difficult. The author concluded that, due to grooming, oral intake was greater than inhaled intake of the compound; this study identified aNOAEL oflOOO ppm (2500 mg/m') for maternal toxicity, and a NOAEL of60 ppm (150 mg/m1) and a LOAEL of400 ppm (1000 mg/m1) for developmental toxicity. The author concluded that, due to grooming, oral intake was greater than inhaled intake of the compound; this study identifies aNOAEL of 60 ppm (150 mg/m1) and a LOAEL of 400 ppm (1000 mg/m1) for maternal and developmental toxicity. Union Carbide Corp., 1985 Union Carbide Corp,, 1985 I-thyfene glycol I f lhvh -lc glycol F lhylene glycol 107-21-1 I07-2I-I 107-21 -1 Table of Toxicity Data for HAPs (continued) jludyType Developmental toxicity Species Mice Developmental toxicity Mice Developmental loxicity Rais Route of Administration Type of Exposure Dural ion Exposure levels Number studied/ exposure level Response _________ Study AdequacyCommentsReference Inhalation (nose-only exposure or whole-body exposure) Aerosol Inhalation (nose-only or whole-body exposure) Aerosol Oral Dietary 6 hours/day on geslation days 6-15 Nose-only- 0, 500, 1000. and 2500 mg/m1 (0, 196 9. 393 8, and 984 6 ppm) Whole-body, as positive control* 0 and 2100 mg/m1 (0 and 827 1 ppm) 6 hours/day on gestation day 6 Nose-only 2500 mg/m1 (984 6 ppm) Whole-body 2100 mg/m1 (827 1 ppm) Gestation days 6-15 0,40, 200, 1000 mg/Vg/day 30/cxposure group 5/exposure group 20 femafes/group Maternal kidney weights were increased at 1000 and 2500 mg/mJ (no accompanying histologic changes were seen). Developmental toxicity (decreased fetal body weights and increased incidence of skeletal variations) was observed at 2500 mg/m1, These satellile females were sacrificed immediately after one exposure and washed in hot water to determine the amount of ethylene glycol on the fur. The quantity available for potential ingestion following whole-body exposure to 2100 mg/m1 was 1390 mg/kg, and after nose-only exposure to 2500 mg/m1 was 330 mg/kg. No maternal toxicity was seen at any treatment level Slightly increased pre implantation toss and significantly increased incidence ofpoorly ossified and unossified vertebra! centra were noted at 1000 mg/kg/dav This appears to be an adequate study Appendices containing individual animal data were not submitted with the report, but averages for all data points were presented in 12 accompanying tables. This appears to be an adequate study Adequate. This study identifies aNOAEL of 2500 mg/m1 for maternal toxicity, and a NOAEL of 1000 mg/mJ and a LOAEL of 2500 mg/m1 for developmental toxicity. TyL 1988 This is a useful satellite study that may explain the relatively greater severity of effects following wholebody exposure. Tyl, 1985 This study identified a maternal NOAEL of lOOOmg/kg/day and a developmental LOAEL of 1000 mg/k g/day. Maronpotcla), 1983 Chemical Name U 1 ihylcnc gfvcol Ethylene glycol Table of Toxicity Data for HAPs (continued) CAS Number 107-21-1 107-21-1 Study Type Developmental toxicity screen Species Mice Developmental toxicity Mice Roule of Administration Type of Exposure Oral Ciavage Oral Gavage Duration ! dose/day on gestation days 7-14 1 dose/day on gestation days 6-15 Exposure levels Number studied/ exposure level Oor 11090 mg/kg/day (maximum tolerated dose) 50/cxposure group 0, 750, 1500, and 3000 mg/kg/day 23-24/exposure group Response Study Adequacy Comments Reference Decreased maternal body weight gain, fetal weight, and litter viability were seen in treated mice Maternal toxicity was noted at mid- and highdose (decreased body weight gain and gravid uterine weight) Developmental toxicity (decreased average fetal body weight/littef) was noted in all treatment groups, and number of live fetuses/lhter was decreased at high-dose, Malformation incidence (gross, visceral, and skeletal) was increased at all treatment levels Inadequate because only one exposure group was used and a NOAEL was not identified. Inadequate because a NOAEL for developmental effects was not identified Developmental screen A maternal NOAEL of 750 mg/kg/day was identified, but developmental effects were noted at all treatment levels. A similar study by Price et al., (1984b) found a decrease in number of live fetuses/litter and a decreased average fetal body weight/litter at 2500 mg/kg/day and higher Hazelton, 1987 (a NIOSH report, also reported as Schuler et al., 1983) Price et!, 19*4 O Oo zo n i o \} TT vD Z SJ --1 Nj ~i {*> > 82 Chemical Name | Rlhylenc glycol | Ethylene glycof Ethylene glycol O Z> ZO T| O \) Tf vO Z SI H SI -< I> Table of Toxicity Data for HAPs (continued) CAS Number T07-21-I 107-21-1 107-2 l-l Study Type Developmental loxicity Species Rats Route of Administration Type of Exposure Oral Gavage Developmental toxicity, pilot study Rabbits Oral Gavage Developmental toxicity Summary Duration 1 dose/day on gestation days 6-20 1 dosc/day on gestation days 6-19 Exposure levels 0.250. 1250, and 2250 mg/Vg/day 0, 100. 500. 1000. and 2000 mg/kg/day Number studied/ exposure level 16-20/exposure (45/rtplicate) 23-24/group Response Study Adequacy Comments Reference Maternal toxicity was observed at 1250 mg/kg/day and above (treatment-related renal pathology) At 2250 mg/kg/day, decreased body weight, body weight gam, and decreased absolute and relative kidney and postpartum uterine weights were observed Developmental toxicity occurred at 2250 mg/kg/day (decreased live litter size, neonatal pup body weight, and increased mortality) Adequate Maternal NOAEL was 250 mg/kg/day and LOAEL was 1250 mg/kg/day. Developmental NOAEL was 1250 mg/kg/day and LOAEL was 2250 mg/kg/day Price etal, 1988 Maternal toxicity was observed at 2000 mg/kg/day (42% mortality, earty deliveries and spontaneous abortion, renal pathology). No evidence ofcmbryotoxkity or teratogenicity was noted at any treatment level Adequate Although rabbits appear more sensitive to maternal toxicity than other species tested, they seem to be more resistant to developmental toxicity. Tyl etal. 1991 Adequate developmental studies are available Inhalation developmental toxicity studies were available m 2 species (TSCAT5,1992). 83 Chemical Name F ihvlcne glycol Flhylene glycot Ethylene gfycol Tabic of Toxicity Data lor MAPs (continued) CAS Number 107-21-1 Study Type Species Multi generation reproductive toxicity Rats 107-21-1 Continuous breeding study Mice 107-21 -1 Continuous breeding study Mice Route of Administration Type of I'xposure Oral Diet Duration Continuously Tof 3 generations Oral Drinking water Continuously for 2 generations Oral Drinking water Continuously for 2 generations Rxposure levels Number studied/ exposure level 0. 40, 200. and 1000 tng/kg/day 10-20/sex/ exposure group/ generation 0, 0 25%, 0 5% and 1 0% Authors estimated doses ofO.0 41, 0 84 and 1 64 g/kg. 20/scx/generation 0, 0 5%, 1 0% and 1 5% Authors estimated doses of 0.0 9, 18. 28g/kg 20/sex/general ion Response Study Adequacy Comments Reference No general toxicity effects were observed, nor were there effects on fertility index, gestation in I7*, F,,or Fj rats, histopathology of testes, epididymis, accessory sex glands, uterus, or ovaries in any generation through F> rats. No effects were observed in the 0.25% groups At the 1% level, there was a decrease in the number of htters/fetal pairs, live pups/Iitter, and live pup weight (this also occurred in the 0.5% group) En the 1% level, there was an increase in facial and skeletal abnormalities. At the 1 5% level, there was decreased fertility index, female pups/1 itter, pup weight, and increased pup death during weaning At L 0% and higher, there was facial abnormalities, and ablepharon. In the high dose males, sperm mobility was decreased, the number of abnormal sperm increased, and there was degeneration of the testes This study is of limited use since there was no evidence of general toxicity in any treatment group, and thus, the dose levels may not have been adequate Adequate data indicate that ethylene glycol is a reproductive toxicant when administered continuously to mice in drinking water Adequate data indicate that ethylene glycol is a reproductive toxicant when administered continuously to mice in drinking water. This study identifies aNOAEL of 1000 mg/kg for parental and reproductive toxicity A pitot study indicated that levels of 2.5% and 5 0% were lethal. The NOAEL level we 0 5% DePass et at, 1986b Lamb et al, 1985 Gulali et al., 1986 84 n o z-n --( o o --1 o *o ^0 zH--t Nj Ni yi X> Table of Toxicity Data for HAPs (continued) Chemical Name I Ethylene glycol CAS Number 107-21-1 Study Type Species Route of Administration Type of Exposure Reproductive toxicity - Summary Duration Exposure levels Number studied1' exposure level Ethylene glycol 107-21-1 Pharmacokinetics - Summary Response Sludy Adequacy Comments Reference Sufficient evidence is available to indicate that ethylene glycol is a reproductive toxicant in male mice exposed continuously to 11% lest material by the otbI route m drinking water. Reproductive toxicity in female mice has not been ruled out. Information on pharmacokinetics of oral and inhaled ethylene glycol is available in humans and animals (HEA, 1987; TSCATS, 1992; NTP, 9993). It is rapidly absorbed, metabolized, and eliminated m all species tested, and rales vary with dose and route ofexposure. REFERENCES CHEMTRACK National Toxicology Program Results Report "Results, status and publicatron information on alt NTP chemicals produced from NTP CHFMTRACK system." July (1993) Coon. R A . Jones. R A., Jenkins, L J , Jr . and Siegel. J "Animal inhalation studies on ammonia, ethylene glycol, formaldehyde, dimethyl amine, and ethanol " Toxicology and Applied Pharmacology. 16:646-655 (1970). DePass. I, R , Carman, R.H, Woodside, M D . Giddens. W E . Maronpol. R R , and Weil. C S "Chronic toxicity and oncogenicity studies of ethylene glycol in rats and mice " Fundamental and Applied Toxicology 7547-565 (1986a) DePass. L R . Woodside. M D. Maronpol, R R , and Weil. C.S "Three-generation reproduction and dominant Telhal mutagenesis studies of clhylene glycot in the ral" Fundamental and Applied Toxicology. 7:566-572 (1986b) Dow Chemical Corporation "Initial submission Development! toxicity evaluation of ethylene glycol in mice by nose only or whole body exposure with cover letter dated 050792" TSCA 8ECP submission 88-920002497, microfiche number OTS0537307 Washington, DC: OPPT, US EPA (1992) Crutali. D.K . Hommel-Bames, L., Welch, M., Russell, S . Poonacha, K B.. and Lamb, J.C "Final report ethylene glycol Reproduction and fertility assessment in CD-I mice when administered in drinking water" Prepared for the National Toxicology Program. (1986). Hazelton Labs "Screening of priority chemicals for potential reproductive hazard" Prepared forNJOSH, Cincinnati. OK (1987) IfEA "Health Effects Assessment for Elhylene Glycol ' US Environmental Protection Agency (1987). Lamb. J C , IV. Maronpol, R R, Gulati, D K , Russell. V S, Hommel-Bames, L, and Sabbanva), P-S "Reproductive and development! toxicity of ethylene glycol in the mouse" Toxicology and Applied Pharmacology 81 100-112 (1985) Maronpni, R R., Zelenak. J P, Weaver, E.V, and Smith, N J. "Teralogemcity study of ethylene glycol in rats." Dreg Chemistry and Toxicology. 6(6) 579-594 (1983). NTP (Naiional Toxicology Program) "NTP lechnical report on the toxicology and carcinogenesis studies of ethylene glycot m R6C3F, mice (feed studies) " NTP TR 413 (1993) Price,C J, Tyf, R W . Piserchia, P.V . Feldman, D B , DcWoskm. R B , and Man. M C "Teratologic evaluation of ethylene glycol administered to CD-I mice on gestational days 6 through 15 " Prepared for National Center for Toxicological Rcsearch^Je/Terson, Arkansas (1984) Price C L, licorge, J I), Marr. M C., Kimmel, C A , Schweiz. B A , and Morrissey. R E "Developmental loxicity evaluation of ethylene glycol in CD rats" Prepared for National Center for Toxicological Research, Jefferson, Arkansas (1988) SRC (Syracuse Research Corporation) "Reference doses (RIDs) for inhalation exposure, ethylene glycol " SRC TR 87-3 22 (1987) Table of Toxicity Data for MAPs (continued) rscATS (Toxic Substances Ccmltnl Acl feel Submission',) Database (t Wit fyl, B W . Fisher, I, C . Kubena. MF, Vrbanic. M A , and loser). P E "Developmental toxicity evaluation of ethylene glycol (EG) applied culancously to CD-1 mice. Teratology Society Abstracts p 498 (1988) 1>!, R W Price, C J Mart, M C Myers, C El, llcindel, J J , and Schwetz. BA "rrnal report on the developmental loxictly oTelhylcne glycol in New Zealand while rabbits Prepared for U S Department of Health and Human Services (1991) Union Carbide Corporation "Summarized results of sttrdy to determine the teratogenic potential ofethylene glycol by exposure ofCD rats and CD-1 mice lo an aerosol ofethylene " TSCA fYl submission OTS-1085-0323 SU, microfiche number 0323. Washington, DC. OPPT, US EPA (19*5) Union Carbide Corporation. "Initial submission Ethylene glycol Developmental toxicity evaluation ofthe aerosol in CD-I mice by nose only or whole body exposure (final report) with cover letter dated 103191 ' TSCA 8ECP submission 88-920000119, microHebe number OTSOS34569. Washington. DC OPPT. US EPA (1991) Wills. 111, Collision, r . Harris, E S , McChesney, E W . Russell, J C , and Semite, D M. "Inhalation of aerosolized ethylene glycol by man dm,cal Toxicology 1(5) 463-426 (1914) p OV -n P <D 2 s! -i St --> X > Chemical Name Methyl isobulyl ketone 1 Methyl isobutyl ketone Methyl isobutyl ketone Methyl isobulyl ketone Table of Toxicity Data for HAPs (continued) CAS Number 108-10-1 Study Type Epidemiology (Case studies) Species Humans 1M-I0-1 Epidemiology (Case studies) Humans I0S-I0-I Epidemiology (Case studies) Humans 108-KM Epidemiology - Summary Route of Administration Type of Exposure Inhalation Vapor Inhalation Vapor Inhalation Vapor Duration Exposure levels Number studied/ exposure level Response Sludy Adequacy Comments Reference 20*30 minutes of highexposure; lowexposure for rest of work day 15-30 minutes of highexposure, lowexposure for rest of work day 2 hours with exercise SO ppm (low exposure) and 500 ppm (highexposure) 50 ppm (low exposure) and 100-105 ppm (high-exposure) )0, 100, and 200 mg/m1 (2 4. 24.4. and 48 8 ppm) MIBK; or 100 mg/m1 (24.4 ppm) MIBK plus ISO mg/m1 (39 6 ppm) toluene 19 workers 14 cases 9 males exposed to various concentrations in sequence Over 50% of the workers complained of nausea, headache, burning Hi the eyes, and weakness Somnolence, insomnia, and intestinal pain were also reported. 4 of the workers had enlarged livers. A few workers complained of gastrointestinal and CNS symptoms 2 ofthe workers had enlarged livers. Inflation (p 0 066) and undefined CNS symptoms (p = 0 101) were reported. Effects from MIBK alone were noted at all treatment levels and showed an exposure-related trend. Effects were greater from exposure lo a mixture of MIBK and toluene than to the single substance. No effects were noted on simple reaction time, ability to do mental arithmetic, or mood This sludy indicates a potential for neurotoxicity, but it is inadequate foT determining a NOAEL or LOAEL. This study indicates a potential for neurotoxicity, but it is inadequate for determining a NOAEL or LOAEL. There are no guidelines for tests in humans A LOAEL could not be determined because the effects may have resulted from short-duralion exposures to high levels or from longduration exposure to low levels This was a subgroup of the 19 workers studied by LHiari et if., 1964 five years later Linari et al., 1964 Armeli et al., 1968 The small number of subjects and borderline statistical significance limits these data. Hjelmctel., 1990 Anoiher study briefly reported headache, nausea, and respiratory irritation in workers exposed to 100 ppm (Elkins. 1959) . 87 Chemical Name 1 Methyl isobutyl ketone Melhyl isobutyl ketone Methyl isobulyl ketone | Melhyl isobulyl ketone fable of Toxicity Data for MAPs (contsnued) CAS Number 108-10-1 108-10-1 108-10-1 108- HM Study Type Acute toxicity Species Mice Route of Administration T ype of Exposure Inhalation Vapor Duration 30 minutes Acute toxicity Summary Subchronic toxicity Rats, dogs, mice, and monkeys Inhalalion Vapor Subchronic loxicity Rats, dogs, mice, and monkeys Inhalation Vapor Continuously for 2 weeks Continuously for 90 days Txposure levels Number studied/1 exposure level Response Study Adequacy Comments Reference 19,500 and >20.000 ppm 10/exposure group Anesthesia was produced in 7/10 animals at 19,500 ppm, however, all recovered normally following removal. Deep anesthesia was observed in mice at >20,000 ppm, and these mice did not recover. Mice dying had some congestion of the lungs. This study demonstrated the anesthetic effects of methyl isobulyl ketone following acute exposure to high levels; however, only a limited number of endpoints were evaluated. This sludy identified a LOAEL of 19,500 for anesthesia from acute exposure E I DuPont de Nemours, 1983 Data on the acute inhalation toxicity of methyl isobutyl ketone were inadequate <1 fEA. 1987. TSCATS. 1992). | 0, 100, and 200 ppm 0 or 410 ppm 50 rats/exposure group, 40 mice/ exposure group, 8 dogs/exposure group; 4 monkeys/ exposure group 100 male rats/ exposure group, 8 male dogs/ exposure group. 2 male monkeys/ exposure group Increased relative kidney weights at 100 and 200 ppm, and increased relative fiver weights at 200 ppm This is an adequate range-finding study. This study did not identify a NOAEL for rats, mice, dogs, and monkeys MacEwen et al., 1971 No effects were observed in dogs and monkeys, rats had increased relative fiver and kidney weights, and hyaline droplet degeneration of the proximal tubules with occasional tubular necrosis These results are of questionable relevance because of the specialized conditions used in the study This study was earned out under unusual conditions (oxygen-rich environment and low atmospheric pressure). This study identified a LOAEL of 410 ppm foe rats and NOAEL of 410 ppm Tor dogs and monkeys MacEweti ct al, 1971 Table of Toxicity Data for HAPs (continued) Chemical Name Methyl isobirtyl ketcme CAS Number 108-10-1 j Methyl isobmyl ketone 108-10-1 Methyl rsobirtyl ketone 9 Methyl isobulyl keione 1 Methyl tsohcrtyl ketone ros-io-i 108-10-1 I0H0-? 1 Methyl isobulyl ketone 108-10-1 o B------------ O D 2O n -------- o 'J ^ 'O 2 si Study Type Subchronic toxicity Species Rats Rome of Administration Type of Exposure inhalation Vapor Duration 6 hours/day* 5 days/week for 14 weeks Exposure levels Number studied/ exposure level 0, 50.250, and 1000 ppm 14/sextexposure level Subchronic loxicity Mice Inhalation Vapor Subchronic toxicity - Summary Oroak toxicity Sam miry Carciaogeakity - Summary Neurotoxicity Baboons Inhalation Vapor 6 hours/day* 5 days/week for 14 weeks 0, 50, 250, and 1000 ppm 14/sex/exposure level Continuously for 7 days 0 or 50 ppm 4 juvenile males *9 Response Study Adequacy Comments Reference Increased absolute and relative liver weights and total urinacy protein iit males at 1000 ppm, increased serum cholesterol and urinary glucose m males at 250 and 1000 ppm; increased incidence ofhyaline droplets in renal proximal tubules in males at 250 and 1000 ppm. Increased absolute liver weight was seen m males at 250 ppm and b igher, and increased relative 1 iver we igbts Hi males at 1000 ppm. Minima] effects in accuracy were observed in a delayed mitch-losample discrimination task, but response trine was slowed. This is ait adequate subchronic toxicity study This study identifies a NOAEL of 50 ppm and aLOAEL of 250 ppm for increased serum cholesterol and urinary glucose. Phillips et al, 198 This ts an adequate subchronic toxicity study. This study identified a NOAEL of250 ppm Phillips etal* 1987 Adequate subchronic inhalation toxicity studies were available Hi 2 species. No data on the chronic inhalation toxicity of methyl Isobutyl lector* were located (HEA, 1987; TSCATS, 1992). No data on the carcinogenicity ofmethyl isobulyl ketone were located (HEA, 1987, TSCATS, 1992). Methyl isobutyl ketone has been nominated for NT? testing; the route was not specified (CHEMTRACIt, 7/93). This study reported equivocal effects for ncuroloxicity following short term exposure This study Identified a LOAEL of SO ppm for behavioral changes Geller et al., 1979 > Chemical Name Mclhsl isobutyl ketone Methyl tsobulyl ketone Methyl isobutyl ketone Table of Tovicily Data for HAPs (continued) CAS Number 108-10*1 Study Type Neurotoxicity Species Hens 108-10-1 Neurotoiicity - Summary IOS-IO-1 Developmental toxicity Mice Route of Admrnistraticn Type of I'xposurc Inhalation Vapor Duration Continuously for 90 days, followed hy a 30-day observation period Exposure levels Number studied^ exposure level 0 or 1000 ppm 5/cxposure level Inhalation Vapor 6 hours/day on gestation days 6-15 0.300, 1000, and 3000 ppm 25/exposure level Response Study Adequacy Comments Reference Leg weakness was observed during exposure, followed by subsequent recovery Maternal toxicity (decreased body weight gain, loss of coordination, negative tail and toe pinch, partial paralysis, muscular weakness in hindltmbs, piloerectkm, lacrimation, and red perioral encrustation) was observed at 3000 ppm; decreased fetal body weights and increased incidence of unossified skeletal elements at 3000 ppm This is an inadequate study because only one exposure level was used and the group size was small This study identifies aLOAEL of 1000 ppm. Abou-Doniael al, 1985 Available data indicate a potential for neurotoxicity (see also developmental toxicity studies) (HEA, 1987) TSCA Section 4 inhalation neurotoxicity studies in rats are in progress (US ERA, 1993) This is an adequate study, This study identified a NOAEL of 1000 ppm and a LOAELof 3000 ppm for maternal and developmental toxicity Union Carbide, 1984 n o sy 2o ~n o \) -"n o 2 NJ -f CO 2> 90 pt DO zo "H --A --i av z^ ' -i ?: --1 ' 0 3> Table of Toxicity Data for HAPs (continued) Chemical Name Methyl isobutyl ketone 1 Methyl isobutyl ketone 1 Methyl isobulyl ketone I Methyl isobutyl ketone CAS Number 108-10-1 108-10-1 108-10-1 108-10-1 Study Type Developmental toxicity Species Rats Route of Administration Type of Exposure Duration Exposure levels Number studied/ exposure level Inhalation Vapor 6 hours/day on gestation days 6-15 0.300, 1000. and 3000 ppm 25/exposure level Developmental toxicity Summary Reproductive toxicity - Summary Pha rmscoki netics - Sum mary Response Study Adequacy Comments Reference Maternal toxicity (decreased body weight gain, loss of coordination, negative tail and toe pinch, partial paralysis, muscular weakness in hindhmbs, piloereclkm, lacrimation, and red perioral encrustation) was observed at 3000 ppm, decreased fetal body weights and increased incidence of unossified skeletal elements at 3000 ppm This is an adequate study This study identifies aNOAELof 1000 ppm and a LOAEL of 3000 ppm Tot maternal and developmental loxicity. Union Carbide, 1984 Adequate developmental toxicity studies am available in 2 speci (HEA, 19S7, TSCATS, l992;TOXLrNE, 1992). No data on the reproductive toxicity of methyl isobutyl ketone v located (HEA, 1987; TSCATS, 1992; TOXL1NE, 1992). Limited information on the absorption and excretion of methyl isobutyl ketone was available in animals for the oral aid inhalat routes (HEA, 1987, TSCATS, 1992; TOXLINE, 1992). REFERENCES Abou-Donia. M B., Lapadula. D.M , Campbell, G., and Ttmmous, P R "The synergism of n-hexanc-induced neurotoxicity by methyl isobutvl ketone following, subchronic (90 days) inhalation in hens Induction of hepatic microsomal cytochrome P-450 * Toxicology and Applied Pharmoco SI 1-16 (1985) Armcfi. G. I.man. F, and Marlorano, G "Rifievi cMmci ed ematochimici in operai esposti allazione di un chetone superiore (MlftK) ripcluti a distanza di 5 anni " Lavoro Vmano 20 41W24 (1968) OfFMTRACK National Toxicology Program Results Report "Results, status and publication information on all NTP chemicals produced from NTP CHKMTRACK system " July (1993) EI DuPont de Nemours "Industrial Hygiene Bulletin" -- prepared by Shell Chemical Corporation with cover letter. TSCA 8D submission~8782I~t796, microfiche number OTS205872 Washington, DC OPPT, US EPA (1983) Elkins, H B "The Chemistry oMnduslrial Toxicology" Second Edition. New York, NY John Wiley and Sons p 121 (1959). 91 Table of Toxicity Data for H A Ps (continued) Cicllct. I .Clause, F Kaplan II , and Hartmann. R 1 "Effects of acetone, methyl ctEyl kctr.nc aril methyl isnbutyl ketone on a nvUch-to-samplc task inlhctahoon " Pharmacology Biochemistry and Behavior 11 401-406 (1979) HI-A "llcallh T'flccls Assessment for Methyl fsobutyl Ketone." US Environmental Protection Agency (1987) Hiclm. E W .llaghcrg.M . Iregrcn. A . and Lof, A. "Exposure to methyl isobutyl ketone Toxicokinetics and occurrence of m-ilauvc am) CNS symptoms in man " International Archives of Occupational Environmental Health 62 19-26(1990) l.inart. E Coscia. (i ( , Marlnrano. G, and Perrelli, G "L'aminoaciduria nelta intossicazione professionale da piombo " Archiver ofScience and Medicine. 116 326-347 (1964) MacF.wen. J D , Vemot I 11, and Haun. C C. "Effect of 90-day continuous exposure to methyl isobutyl ketone on dogs, monkeys and rats (final report) " Prepared for the Aerospace Medical Research Laboratory. (1971) Phillips. R D . Morgan, F..J , Dodd. D F... Fowler, EH., Kary, CD., and ODonoghue. J "A 14-week vapnt inhalation toxicity study of methyl isobulyl ketone " Fundamental and Applied Toxicology 9(3) 380-388 (t9S7) TOXUNF National Library of Medicine Online Dartabase (1993) TSCAT.S (Toxic Substances Control Act Test Submissions) Database (1992) Union Carbide Corporation "Teratologic evaluation of melbyl isobutyl ketone in Fischer 344 rats and CD-I mice following inhalation exposure (final report) Part 1 and 2 with cover letter and abstract dated 1005M " TSCA 4d submission 40-8444071. microfiche number OTS0507469. Washington, DC OPPT. US EPA (19*4) USEPA(US Environmental Protection Agency) "Mulli-substance rule for tesling of neurotoxicity; Final Rule " federal Regisler 56FR40262 July 27 (1993) Table of Toxicity Data for HAPs (continued) Chemtcal NameCAS NumberStudy TypeSpecies Route of Administration Maleic anhydride 108-31-6 Epidemiology {Case study) Humans Inhalation Maleic anhydride 108-31-6 Epidemiology (Acute toxicity) Humans Inhalation | Maleic anhydride I Maleic anhydride 108-31-6 108-31-6 Epidemiology - Summary Acute toxicity - Summary Number studied/ Type of Exposure_______ DurationExposure levelsexposure levelResponseStudy AdequacyCommentsReference Aerosol Aerosol 1 monlh Not reported 1 male 5 minutes, 1 hour, and 4 hours 2 S, 4 5, W, 20. and 30 ppm for 5 minute exposure, 6 ppm for 1 hour exposure; 5 ppm for 4 hour exposure 5-10 subjects/ exposure group A 64 year old man developed a cough, rhinitis, breathlessness, and wheezing He had a positive patch test for MA, and he developed an asthmatic reaction starling 2 minutes after exposure to 0 09 mg/m' of respirable MA dust Greater that slight eye irritation was observed at 20 ppm and higher; greater than slight nose irritation and pulmonary discomfort was observed at 30 ppm and higher, no effect on CNS or respiratory function This was an acceptable bronchial provocation test Purity = 98% Lee et at., 1991 This study demonstrates the irritative properties to humans of maleic anhydride following acute exposure. Purity >99%; this study identifies a NOAEL of 10 ppm and a LOAEL of 20 ppm Chevron Chemical Company, 1984 Several studies indicated that occupational exposure to maleic anhydride in the workplace adversely afreets respiratory organs, skin, id eyes (ACCIH. 1986). Additional acute inhalation toxicity testing of maleic anhydride could be required. Limited available acute toxicity data indicate irritative portal-of-entry effects n OD 2O T) --I p-s o x> "D sO 2 sj -t 33 -< -Is- X> 93 Chemical Name Maleic anhydride Maleic anhydride Table of Toxicity Data for I iA Ps (continued) CAS Number 108-31-6 Study Type Subchronic toxicity I0S-3I-6 Subchronic toxicity Species Rats, hamsters, and rhesus monkeys Route of Administration Type of Exposure Inhalation Aerosol Duration 6 hours/day, 5 days/wcck for 6 months Rats Inhalation Aerosol 6 hours/day, 5 days/week for 21-22 exposures (*=30 days) [Exposure levels Number studied/ exposure level 1,3, or 10 mg/m1 (0 2. 0.7, or 2.5 ppm) 15/sex/group (rats and hamsters) 3/scx/group (monkeys) 0.0 012,0 032. and 0 0860 mg/L (12,32, and 86 mg/m1) (0, 2 9,7 9. and 21 4 ppm) 10/sex/exposure group Response Study Adequacy There were no treatment related deaths. There were intermittent reduced body weights in the mid dose rats and reduced body weights from day 40 to the end of the study in male rats. There was no effect on body weight in the other species. Nasal and ocular irritations were observed m alt groups; this was considered reversible. There were no treatmentrelated hematological or clinical chemistry, urinalysis, or pulmonary function effects Reduced body weights at 0 032, aid 0.0860 mg/L, numerous upper respiratory lesions were observed at 0.012,0 032, and 0.0860 mg/L, and numerous lung lesions were observed at 0.032 and 0.0860 mg/L The study appears to be adequate in rats and hamsters. This is an inadequate study since aNOAEL was not identified. Comments Portal-of-entry effects are observed Reference Short et al, 1988 This study identifies a LOABL of 0.012 mg/L This study demonstrates portalof-entry effects following short term exposure Gotdenlhal et al., L984a O Oa ZO -n t-t i-j o \> vD Z Nl -t 00 -h yi i> 94 CONFTDFNTTAl Z) o V >0 c? 'T Chemical Name Maletc anhydride II Maleic anhydride f Maleic anhydride I Maleic anhydride Table of Toxicity Dala for HAPs (continued) CAS Number 108-31-6 1 OS-31-6 108-31-6 108-31-6 Study Type Subchronic toxicity Species Rais Route of Administration Type of Exposure Inhalation Aerosol Duration 6 hours/day, 3 days/week for 6 months Exposure levels Number studied/ exposure level 0, 00011, 0 0033, and 0 010 mg/L (0. 0.3,0 8, and 2 5 ppm) 15/sex/exposure group Subchronic toxicity Hamsters Inhalation Aerosol 6 hours/day, 5 days/week for 6 months 0, 0.0011, 0 0033, and 0 010 mg/L (0, 0 3.0 8. and 2 5 ppm) 15/sex/exposure group Subchronic loxicrly Monkeys Inhalation Aerosol 6 hours/day, 5 days/wcek for 6 months 0,0 0011, 00033, and 0010 mg/L (0, 0 3,0 8, and 2 5 ppm) 3/sex/exposure group Stibchrouie loxkity - Summary Response Study Adequacy Comments Reference Reduced body weights at 0.0033 and 0.010 mg/L, Dose-related red-tinged nasal discharge and sneezing. Brain cholinesterase was increased at 0 0033 ml 0.010 mg/L, however the authors did not consider this effect lo be treatment related. No histological evidence of damage to (he respiratory tract was observed This appears lo be an adequate subchfonic toxicity study This study identifies aNOAELof 00011 and a LOAEL of 00033 mg/L Ulrich etai. 1984 Nasal discharge, ocular irritation, dyspnea, and gasping were observed at 0.010 mg/L Brain cholinesterase was increased at 0 010 mg/L No histological evidence of damage to die respiratory tract was observed. This appears to be an adequate subehronre toxicity study This study identifies aNOAELof 00033 and a LOAEL of 0.010 mg/L. Ulrich 19*4 Nasal and ocular milalion, and slight dyspnea with coughing and sneezing were observed at 0.010 mg/L. No histological evidence of damage to the respiratory tract was observed This subchronic toxicity study is not adequate because of the small numbers of animals used/ treated group This study identifies aNOAELof 00033 and a LOAEL of 0 010 mg/L Ulrich et !., 19*4 Subchronic inhalation toxicity studies in several species reported orimarily respiratory effects CHEEP, 1986). 95 Chcmacaf Name Maleic anhydride Maleic anhydride Maleic anhydride Maleic anhydride Maleic anhydride Maleic anhydride Tabic of Toxicily Data for MAPs (continued) CAS Number 108-31-6 Study Type Species Chronic toxicity - Summary Route of Administration Type of Exposure Duration 108-31-6 Carcinogen icity Rats Oral Diet 2 years lixposure levels Number studied/ exposure level Response 0. 10. 32, and 100 mg/kg/day 126/sc x/gFOup No treatment-related increased incidence of neoplastic lesions was noted. 108-31-6 108-31-6 108-31-6 Carcinogenicity Summary Neurotoxicity - Summary Developmental toxicity Rats Oral Gavage 108-31-6 Developmental toxicity - Summary Daily on gestation days 6-15 0, 30. 90, and 140 mg/kg/day 25/exposure group Reduced body weight gain was observed in dams at all exposure levels. No developmental toxicity was observed. Study Adequacy Comments Reference No data on the chronic inhalation toxicity of maleic anhydride were located (KEEP, 1986. TSCATS, 1992). Inadequate Retrospective analysis indicates (hat the doses received ranged from 44 to 92% of the target doses; some uncertainty exists as to whether animals received anhydride or whether it was converted in the feed to acid. C1IT. 1984 ___________ No data on the inhalation carcinogenicity of maleic anhydride were located, adequate oral data were not located (HEEP, 1986, TSCATS. 1992; CHEMTRACK, 7/93). No data on the neurotoxicity of maleic anhydride were located (HEEP, 1986, TSCATS, 1992). This is an adequate study This study identifies a LOAEL of 30 mg/kg for maternal toxicity and a NOAEL of 140 mg/kg for developmental toxicity. Goldenthal etal, 1984b An adequate developmental toxicity study using the oral route was available in ] species; no developmental toxicity studies on inhaled maleic anhydride were available (HEEP, 1986, TSCATS. 1992}. n o z o o T--(< o \) T1 zH1 sj a) si I> 96 n oz ^1 n To1 Z '\"lV ----f( oTe > Table of Toxicity Data for HAPs (continued) Chemical Name Maleic anhydride Maleic anhydride Maleic anhydride CAS NumberStudy TypeSpecies Route of Administration Number studied Type of Exposure_______ DurationExposure levelsexposure levelResponse Study Adequacy Comments Reference 108-31-6 Reproductive toxicity Rais Oral Gavage 108-31-6 Reproductive toxicity - Summary 108-31-6 Pharmacokinetics - Sum mi i y Daily during an 80-day premat in g period, mating, gestation, and lactation for 2gencralions 0, 20, 55. and 1 50 mg/kg/day 10-20/sex/ exposure group/ generation 65 and 100% mortality in males and females, respectively, reduced body weight gain, and renal cortical necrosis was observed at the highdose level. Pup growth was decreased at 150 mg/kg. The high mortality was the result of Ravage errors This is an adequate 2-generation study, reporting reproductive toxicity at dose levels producing parental toxicity This study identi lied a NOAEL of 55 mg/kg and a LOAEL oT 150 mg/kg for parental and reproductive toxicity Monsanto Co , 1984 An adequate 2-generalion reproductive toxicity study using the oral route was avail abk in I species; no reproductive toxicity sludies on inhaled maleic anhydride were available (HEEP, 1986, TSCATS, 1992) Limited data on the absorption and distribution of orally administered maleic anhydride were available in dogs (HEEP, 1986, TSCATS. 1992) REFERENCES ACG1H (American Conference of Governmental Industrial Hygienists) "Documentation of the threshold limit values and biological exposure indices." Cincinnati, OH p 353 (1986) CHEMTRACK National Toxicology Program Results Report 'Results, status and publication information on all NTP chemicals produced from NTP CHEMTRACK system" July (1993). Chevron Chemical Company, Inc "Sensory threshold sludies on maleic anhydride" TSCA 8D submission 8782 14794. microfiche number OTSQ206657 Washington. DC OPPT, US EPA (1984). C1IT Chemical Industry Irmstitute of Toxicology "Chronic dietary administration of maleic mhydride. Volume t Narrative" TSCA FYI submission EYI-1283-0277, microfice number OTS0000277-0. Washington, DC: OPPT, US EPA (1983) Goldenthal, E I. Jessup, D C., GeiJ, R G., and Leong. B.K.J "Four-week inhalation study in rats (1RD-77-JG8). with cover memo " TSCA 8D submission 8782 M771, microfiche number OTS0206655 Washington, DC: OPPT, US EPA (1984a). Goldenthal, E 1, Jessup, DC , and Rodwell, D E. "Teratology study in rats (IRD-77-] 10) with cover memo " TSCA 8D submission S7B2I4774. microfiche number OTS0206655. Washington, DC OPPT, US EPA (1984b) HEEP "Health and Environmental Effects Profile for Maleic Anhydride" US Environmental Protection Agency (1986) Lee, H S , Wang. Y T . Cheong, T H, Tan. K.T.Chee. B E . and Narendran, K. "Occupational asthma due lo maleic anhydride" British Journal of Industrial Medicine 48 283-285(1991) Monsanto Company "Three-general ion reproduction study in rats (modified to a two-generation study) volume I of 3 " TSCA 81) submission 8782 14777 microfiche number OTS0206655. Washinglon. DC OPPT, US EPA (1984) 97 fable of Toxicity Data for I lAPs {continued) Short R D , Johannsen, I R . and Ulrich,1 I "A 6-monlh muilixpccics inhalation study with maleic anhvdridc I'uiulamenlat ami Applied to 517-524 (IRSfl) I SCAT S | Toxic Substances Control Act Test Submissions) Database (1992) Ulrich, CT , Hlair, M . Rop, DA .and Arceo. R J "Six-month mult ispecies inhalation toxic its study MRU-77-109} with cover memo "TSCA 8D submission 878214772. microfiche number OTS0206655 Washington, DC OPPT, US EPA(!984) r> oa zo ~n a \) -zn vVDi H CD i--i \Q T> 98 Table of Toxicity Data for HAPs (continued) Chemical Name Chlorobenzene Chlorobenzene D Chlorobenzene Chlorobenzene Chlorobenzene ob o CAS Number 108-90-7 108-90-7 108-90-7 (08-90*7 108-90-7 Study Type Species Epidemiology Summary Route of Administrate n Type of Exposure Duration Exposure levels Number studied'' exposure level Acute toxicity Mke and guinea Pifis Inhalation Vapor 2 hours Nol reported Not reported Acute toxicity Rats and guinea Pigs Inhalation Vapor 30 minutes 0, 2990,5850, and 7970 ppm 5/sex/exposurc level Acute toxicity Summary Subchronic toxicity Rats, rabbits, and guinea Pigs Inhalation Vapor 7 hours/day, 5 days/week for 44 days 475 or 1000 ppm Not reporled Response Study Adequacy Comments Reference LC in guinea pig was 50 mg/m1 LC m mice was 20,000 mg/m* Slight eye and nasal irritation at 2990 ppm, narcotic effects at 5850 and 7970 ppm, no mortality At low exposure, liver, kidney, and lung lesions were observed in guinea pigs. These signs were observed tn til species at the high exposure level. One study reported neurotoxicity in humans occupationally exposed to chlorobenzene, however, this study did not report exposure levels (Rozenbaum et al., 1947). Incomplete report of data. Insufficient information was provided regarding number of animals tested and exposure levels. Lecca-Radu, 1959 (English translation not available, as cited in Wiflhitc 1990) This study demonstrates neurotoxicity following acute exposure. Purity was not reported; this study identifies a NOAEL of 2990 ppm and a LOAELof 5850 ppm for rats and guinea pigs UBTL, 1991 Adequate acute inhalation toxicity data are not available for chlorobenzene. One study indicates a potential for acute neurotoxicity (TSCATS, 1992). Tests were conducted for an inadequate duration at only two exposure levels. It is not known how many test animals were used. Hardcopy of original study was not available for review. Deichmann, 1981 Chemical Name I Chlorobenzene 1 Chlorobenzene j Chlorobenzene Chlorobenzene Chlorobenzene Chlorobenzene Table of Toxicity Rata for llAPs (continued) CAS Number 108-90-7 108-90-7 108-90-7 108-90-7 108-90-7 108-90-7 Study Type Subchronic toxicity Species Mice Route of Admmistralio n Inhalation 1 ype of Pxposurc Vapor Duration 7 hourx/day, 7 days/week for 3 months kxposurc levels Number studied/ exposure level 0 1 mg/T, (22 ppm) 5 males and 5 females/exposure group Subchronic toxicity Mice Inhalation Vapor 7 hours/day. 7 days/wecV for J weeks 0 and 2 5 mg/I, (0 and 543 ppm) 5 males and 5 femaies/exposure group Subchronic toxicity Rats Inhalation Vapor Subchronic toxicity Rabbits Inhalation Vapor Subchronic toxicity - Summary Chronic toikity Summary 7 hours/day, 5 days/weeV for 24 weeks 0. 73. or 248 ppm 32 males/group 7 hours/day. 5 days/week for 24 weeks 0. 73. or 248 ppm 32 males/group Response Study Adequacy Comments Reference Agitation and increased movement were noted in treated animals, but no other changes in behavior. Leukopenia and lymphocytosis were noted Half of the animals died after dosing. Loss of appetite, general emaciation, neutropenia, and marked somnolence were observed. There was a statistically significant drop in WBC and an indicat ion that there was damage to the bone marrow. Microscopic les ions in adrenal cortex, kidney, liver congestion, and decreased SCOT at 73 and 248 ppm. Decreased LDH and liver congestion at 73 and 248 ppm Inadequate This study examined limited endpoints and only one lest exposure level was used RfTects were similar to those of benzene Zub, 1978 Inadequate This study examined limited endpoints and only one test exposure level was used. At twice this concentration, all animals died. Zub, 1978 The study is limited by use of only 2 exposure levels and treatment of males only Purity - 99% chlorobenzene; this study identifies a LOAELof73 ppm Diffey, 1977 The study is limited by use of only 2 exposure levels and treatment of males only. Purity -99% chlorobenzene, this study identifies a LOAEL of 73 ppm Dilley, 1977 Adequate subchronic inhalation toxicity data are not available Studies available suggest a potential for liver and kidney effects (ATSDR, 1990; SRC. 1990). No data on the chronic inhalation toxicity chlorobenzene were located (ATSDR. 1990, SRC. 1990; TSCATS. 1992). !00 n Dz "nt o o '--1 o \> z vN0} Hi--t xO O zTJ --1 O --> V Tf z--t "4 r-t V' T> Chemical Name 1 Chlorobenzene Chlorobenzene Chforobenzene Chlorobenzene Chlorobenzene Table of Toxicity Data for HAPs (continued) CAS Number Study Type Species Route of Administrate Type of Exposure Duration Exposure levels Number studied/1 exposure level Response Study Adequacy Comments Reference 108-90-7 Carcinogenicity Rats Oral 108-90-7 Carcinogenicity Mice Oral Gavage Gavage 1PS-90-7 108-90-7 Carcinogenicity - Summary Neurotoxicity Rats Inhalation Vapor 108-90-7 Neuroloikity Summary 5 daysAveek for 103 weeks 0, 60, or 120 mg/kg 50/sex S days/week fen 103 weeks 0,60, or 120 mg/kg (females), or 0, 30, or 60 mg/kg (males) 50/sex 14 bours/day. 7 days/week for 1 weeks 0. 1500, 2000, or 3000 ppm for 2 hours, 0, 500. 1500, or 2000 ppm for the remaining 5 hours and after the 5th day; 0. 500,1000, or 1500 ppm on the 6lh day, and 0, 500, 1000, or 250 ppm on the 7th day,res pect ivefy. (The concentration was reduced because of overt toxicity ) 12/males/group Small increase in neoplastic nodules in male rats ofthe high dose group. No increased incidence of tumors. Adequate oral study Adequate oral study. Considered equivocal evidence of carcinogenicity NT?, 1985 Considered noncarcinogenic in mice NTP, 1985 In all but the group exposed to L500 followed by 500 ppm, there was a clear impairment of auditory sensitivity which was more noticeable at 16 kHz than 8 kHz No data on the inhalation carcinogenicity of e ilorobenzene were located (TSCATS, 1992). Adequate oral data indicate equivocal evidence of carcinogenicity (NTP, 1985). This is an inadequate since the concentration was reduced during die study to mitigate overt toxicity This study was part of a study of a large group of solvents that indicated that many solvents produce otoioxk effects. Pryor and Rebert, 1993 Ototoxic effects in rats indicate the potential for chlorobenzene to he i neurotoxic agent 01 Chemical Name Chlorobenzene I Chlorobenzene Chlorobenzene Chlorobenzene Table of Toxicity Data for MAPs (continued) CAS Number Study Type Species 108-90-7 Developmental toxicity Rats Roulc of Administrate n Inhalation Type nl Exposure Vapor Duration 6 hours/day on gestation days 6-1 5 108-90-7 Developmental toxicity Rabbits Inhalation Vapor 6 hours/day on gestation days 6-18 108-90-7 Developmental toxicity Rabbits Inhalation Vapor 108-90-7 Developmental toxicity- Summary 6 hours/day on gestation days 6-18 Exposure levels Number studied/ exposure level Response Study Adequacy Comments Reference 0, 75, 210. or 590 ppm 0, 75, 210, or 590 ppm 0.10, 30, 75, or 590 ppm 32-33/exposure group 30/expostire group 29-32/exposurt group Decreased maternal body weight gain (only for days 6-8), and increased absolute and relative Uver weights at 590 ppm, increased incidence of skeletal abnormalities (delayed ossification, brio bed centra, and cervical spurs) at 590 ppm Maternal loxicrty in the form of increased absolute and relative liver weight at 210 ppm; increased resorption rale and number of malformed fetuses at 590 ppm This is an adequate study, reporting developmental toxichy at an exposure level producing minimal maternal toxicity This is an adequate stqdy, reporting developmental toxicity at exposure levds producing maternal toxicity Purity 99 9% The LOAEL for maternal and developmental toxicity was 590 ppm and the NOAEL for both effects was 210 ppm. Purity 99.9%; th is study identifies a LOAEL of 590 ppm for maternal and developmental toxicity A number of malformations were observed in other concentration groups, but there was no lohnet al, 1984; Dow Chemical Co . 1982 John eta)., 1984, Dow Chem ical Co, 1982 Maternal toxicity in (he form of increased liver weight at 590 ppm, and there was a significant increase in resorption in this group This is an adequate study, reporting developmental toxicity at exposure levels producing maternal toxicity. related trends There was an increase in extra ribs at the lowest concentration that was not considered biologically significant. John till. 1984, ! Dow Chemical Co. 1982 Adequate developmental toxicity data were available in 2 species (ATSDR, 1990; TSCATS, 1992); therefore, no additional developmental toxicity data are needed. | E O zo a o -n o^ Tt '0 z i--i LO 3> 102 o oz Tt Ti z^ x> Table of Toxicity Data for HAPs (continued) Chemical Name CAS Number Study Type Species Route of Administrate n Type of Exposure Duration Exposure levels Number studied? exposure level Response Study Adequacy Comments Reference Chlorobenzene u Chlorobenzene 1 Chlorobenzene 108-90-7 Reproductive toxicity Rats Inhalation Vapor 108-90-7 108-90-7 Reproductive toxkfty - Summary Pharmacokinetics - Summary 6 hourVday. 7 days/week for 2 generations 0. 50, 1 SO, or 450 ppm 30/sex/group? generation Parental toxicity (hepatocellular hypertrophy, renal degeneralion, and teslkular degeneration of Ihe germinal epithelium) at 150 and 450 ppm; other than affect on the testis, no reproductive parameters were affected This is an adequate 2-genetalion reproductive toxicity study This study identified a NOAET of 50 ppm and a t.OAEL of 150 ppm for liver and kidney effects; however, the authors considered the observed effects on the liver to be equivocal Nahrial I9S7 An adequate 2-generation reproductive toxicity study was available in rats (ATSDR. 1990; TSCATS, 1992). Information on absorption, metabolism, and excretion of chlorobenzene was available in humans and rats for (he oral and inhalation routes of exposure (ATSDR, 1990). REFERENCES ATSDR (Agency for Toxic Substances and Disease Registry) "Toxicological Profile on Chlorobenzene " (1990). Deichmann. W B "Halogcnafcd cyclic hydrocarbons/ In Potty's industrial Hygiene and Toxicology. Third revised edition. Vol 2B. Clayton, G D., and Clayton. F E., editors New York: John Wiley and Sons, pp. 3605-3611 (1981) Dilfey.) V . Toxic evaluation of inhaled chlorobenzene (monochlorobenzene) (final report)" PB 276 623 Prepared for NIOSH (1977). Dow Chemical Company "Monochlorobenzene - Inhalation teratology study in rats and rabbits " TSCA 8D submission 87-821 f 237, microfiche number OTS0206M8 Washington. DC OPPT, US EPA (1982). John, J.A . Hayes, W C , Hanley. T R, Jr. Johnson. K.A., Gushow, T.S., and Rao, K S "Inhalation teratology study on monochlorobenzene m Tats and rabbits." Toxicology and Applied Pharmacology 76.365-373 (1984). Lecca-Radu, R "Modifications of blood carbonk anhydrasc and leucocytic imfopheno) oxidase in chronic benzene and monochforobcnzene intoxication * fgiena. 8 231 -240 (1959) Nair, R S, Barter, I A., Schroedcr. R E., Knezevkh, A . and Stack, C R "A two-generation reproduction study with monochlorobenz.enc vapor in rats." Fundamental and Applied Toxtcalagy. 9 678-686(1987). NTP (National Toxicology Program). "NTP technical report on the toxicology and carcinogenesis studies of chlorobenzene in FJ44/N rats and F16C3FI mice (Ravage studies)H PB86-I497M NTPTR 261 (1985). Pryor. G T . and Rebert. C S "Neurolox icily of inhaled substances " SRI International Final Report LSU-1644; Prepared under contract No 271-90-7202 (1993) 103 Table of Toxicity Daia for HAPs (continued) Rozenbaum, N D Block, RS . Krcmncva,.SN , Ginzburg, S L .and Pozhatiskn, I V "Use of chlorobenzene as a solvent from the standpoint of industrial hygiene." Gtgtena t Sanitaria 12 21-24 (1947) SRC (Syracuse Research Corporation) "Interaction Profile on Chlorobenzene " SRC TR 90-061 (! WO) I SCATS (Toxic Substances Control Act Test Submissions) Database (t992) UBTT Inc "Initial submission A Utah biomedical test laboratory report on NlOSff sponsored inhafalion study for IDFII, values (final report) with cover letter dated 102291 " TSCA Sf-CP submission 88-920000156, microfiche numberOTS05J4605 Washington, DC: OPPT, US EPA (circa 1991) Zub, M "Reactivity of the while blood eel! system 1o toxic action benzene and its derivatives " Acta fitohgtea Cmcoviensra 2II63-1 74 (1978) 104 3> IIN J O IJ N O 'J 9 6 ^ 6 < ;i o a Table orToxicity Data for HAPs (continued) | Phenol Phenol Phenol CAS Number 108-95-2 108-95-2 108-95-2 1 Phenol 108-95-2 Phenol 108-95-2 1 Phenol ^ 108-95-2 *---------b n -------- 2O Study Type Epidemiology (Case report) Species Humans Epidemiology - Summary Acute toxicity/ fmmunotoxicity Mice Acute toxicity Rats Acute toxicity Mke Acute toxicity - Summary Route of Administratrort Number studied/ Type of Exposure_______ DurationExposure levelsexposure levelResponseStudy AdequacyCommentsReference Inhalation and dermal Not reported Inhalation Vapor Inhalation Not reported Inhalation Not reported Intermittent exposure for an unspecified length of time Not reported 5 replicate challenges of single 3-hour exposures approximately 5.6 ppm 24 hours/day foe 15 days 0 and 26 ppm 4 exposure level (concentration not reported) for 5 minutes Not reported 1 male | Muscle pam and weakness that may 1 represent a neurological effect Inadequate. This is not a controlled neurotoxicity study. Merliss. 1972 Adequate epidemiology data for inhaled phenol were not located m the available literature (ATSDR, 1989; TSCATS, 1992). appoximately 30/group for the streptococcus infectivity study and 18/group for the pulmonary bactericidal activity assay. Phenol did not produce significant changes in mortality from streptococcal challenge. There were no significant effects on bactericidal activity Inadequate. The exposure level was too low and the exposure lime was too short to be an adequate study of immunotoxicity Males and females; number/group not reported Increased activity, motor disorders, involuntary muscle twitching, especially in the neck region, diving treatment; and increased plasma potassium and magnesium levels. Inadequate. Number of test animals was not reported and an insufficient number of exposure levels was used. Effects were observed after 3 days of exposure. Dafin and KristofTersson. 1974 Males, number/ gToup not reported 0 1 RDW (50% decrease in respiratory rate) was 17 ppm and irritation of the upper respiratory tract was observed. Inadequate Number of test siimals and range ofexposure levels is unknown The authors estimated that 17 ppm would be in uncomfortable concentration for humans DeCeauntzctal. 1981 Adequate acute inhalation toxicity data were not located lor phenol (ATSDR. 1989. TSCATS, 1992) o 'o 'n & 2M H sD -H O' ]> 105 Chemical Name Phenol Phenol Phenol Phenol Phenol Table of Toxicily Data for HAPs (continued) CAS Number 108-95-2 Study Type Subchronic toxicity 108-95-2 Subchronic toxicity 108-95-2 Subchronic toxicity 108-95-2 Subchronic toxicity 108-95-2 Subchronic toxicity Species Rats Route of Administration Type of Exposure Duration Inhalation Vapor 7 hours/day, 5 days/wcck for 74 days Rabbits Inhalation Vapor 1 hours/day, 5 days/week for 88 days Guinea P'gs Inhalation Vapor 7 hours/day, 5 days/wcck Tor 74 days Rats, mice, and monkeys Inhalation Vapor Continuous exposure for 90 days Not reported Inhalation Not reported Not reported Exposure levels Number studied/ exposure level 26 ppm 15/group, sex nol reported 26 ppm 6/group, sex nol reported 26 ppm 12/group; sex not reported 0 and 5 ppm 50 rats, 100 mice, and 10 monkeys; all males Not reported Nol reported Response Study Adequacy Comments Reference No effects noted on survival, clinical signs, nor gross or histopalhology Inadequate No controls were used, sex of test animals is not known, and an insufficient number of test concentrations was used. Pulmonary congestion and hyperplasia, myocardial degeneration, centrolobular degeneration ofthe liver, and edema of the liver Inadequate. No controls were used, sex oftest animals is not known, and art insufficient number of test concentrations was used 5 animals died after 20 exposures; liver and heart necrosis, pneumonia, renal cortical injury, and hind limb paralysis were noted. Inadequate. No controls were used, sex of test animals is not known, and an insufficient number of test concentrations was used No effects on survival, hematology, or pathology were noted in any species. Inadequate. Only one test concentration was used. Results are not yet available Adequacy cannot be determined 26 ppm represents a free standing NOAEL. Deichmann el al, I 1944 1 Only frank effects were reported Deichmann el al, 1944 Only frank effects were reported. Deichmann ct al, 1944 1 There were some very minimal htslopa(hologctl changes in the lungs of mice, but the authors did not consider them meaningful. Sifidage. 1961 This study is currently in proEtess. US EPA, 1993 106 n oz o o n n .-* O \J vO z Nj --f sD H 3> Chemical Name Phenol Phenol Phenol Phenol I PhcnoT o oo 2o --. --i D \J "n J> 2 --! vO l--t 05 2> Table of Toxicity Data for HAPs (continued) CAS Number 108-95-2 Study Type Species Route of Administration Type of Fxposure Subcbroitic toxicity - Summary Duration 1 OS-95-2 108-95-2 Chronic toxicity - Summary Carcinogenicity Rats Oral Drinking water 105 weeks 108-95-2 Carcinogenicity Mice Oral Drinking water 105 weeks 108-95-2 Carcinogenicity- Summary Exposure levels Number studied/ exposure level 0. 2500, or 5000 50/scx/day ppm 0,2500, or 5000 50/sex/day ppm Response Study Adequacy Comments Reference Equivocal evidence of carcinogenicity. At the low dose, but not the high dose, there was an increased incidence of leukemia, lymphoma, and pheochromocytomas in the adrenals of male rats. Increased uterine endometrial stroma! polyps relative to matched controls were observed in high-dose females (5/48), but this did not exceed those observed hi historical controls (frequency not reported) Adequate subchronic inhalation toxicity data were not located for phenol (ATSDR, I989;TSCATS, 1992). Subdironic toxicity testing is currently being required under NPRM (US EPA, 1993) Chronic inhalation toxicity data were not located for phenol (ATSDR, 1989; TSCATS, 1992). Inadequate because the centred groups had an unusually high spontaneous tumor incidence. A dose-response effect was not found. NCI, 1980 Inadequate since it was concluded that atoxic dose was not obtained. No tumors could be clearly associated with phenol NCI, 1980 Carcinogenicity data for inhaled phenol were not located; adequate oral data were not found (ATSDR, 1989, TSCATS, 1992); phenol has been nominated for study by NTP. route not specified (CHEMTRACK, 7/93). 107 t hem tea! Name | Phenol Phenol Phenol j Phenol Phenol Tabic ofToxicily Dala for MAPs (continued) CAS Number HI8-95-2 108-95-2 108-95-2 108-95-2 108-95-2 Study Type Neurotoxicity Species Rats Neurotoxicity Guinea P'gs Neurotoxicity Rats Neurotoxkityacute and subchronic Not reported Neurotoxicity - S unimary Route of Administration Type of Exposure Inhalation Not reported Inhalation Vapor Oral Gavage Inhalation Nol reported Duration 24 hours/day for t5 days 7 hours/day, 5 days/week for 74 days 1 exposure Not reported Exposure levels Number studied/ exposure level Response Study Adequacy Comments Reference 0 and 26 ppm 26 ppm 207 mg/kg Not reported Males and females tested number not reported 12/group; sex not reported Males, number nol reported Not reported Increased activity and involuntary muscle twitching, especially in the neck region, during treatment. S animals died after 20 exposures Hind limb paralysis was noted Twitching around the eyes and ear muscles immediately after exposure, followed by convulsions and coma. Violent clonic spasms of the whole body persisted for ] 5 to 30 minutes Results are not yet reported. Inadequate Insufficient endpoints were examined, number of animals is unknown, and insufficient exposure levels were tested. Effects first observed after 3 days Datin and KristoffeTSSon, 1974 Inadequate No controls were used, sex of test animals ts not known, and an insufficient number of lest concentrations used The study was terminated after 29 exposures because of poor condition of the animals. Deichmann et al., 1944 Inadequate. Number of lest animals is unknown, only one exposure level was tested, and insufficient endpoints were examined This study was primarily designed to assess the tissue distribution of phenol. Liao and Oehme, 1981 Adequacy cannot be determined These studies are currently in progress. US EPA, 1993 Adequate neurotoxicity data were not located for phenol (ATSDR, 1989; TSCATS, 1992). Acute and subchronk inhalation neurotoxicity testing is currently being required under NPRM (US EPA. 19931 | 1 1 1 108 r> o Q zo n --H a \> -n z-i vO Nl vO r-t vD a> g o n f t d f n t t At Z) x> X o o Table of Toxicity Data for HAPs (continued) ^he~nk3 I Varn^c_______ | Phenol CAS Number 108-95-2 Study Type Developmental toxictly Specter Rats 1 Ptwiwt Phenol 108-95-2 Developmetrial toxicity Mice 1 OS-95-2 Developmental lox icily Not reported Route of Numtwi studied^ Administration Type of ExposureDural iouExposure levelsexposure levelResponseStudy AdequacyCommentsReference Oral Gavage Oral Gavage Oral Gavage Geslation days 6-15 0, 30, 60, and 120 mg/kg/day 20 to 22 pregnant females/group Gestation days 6-15 0, 70, 140. and 280 mg/kg/day 5 to 27 pregnant females/group Nol reported _ -Nat re ported Not reported No statistically significant signs of maternal toxicity were observed There was an increased proportion oT litters with resorption sites in the 30 and 60 mg/kg/day groups, but not in the 120 mg/kg/day group. A dose-related decrease in mean live felal body weight was statistically significant at 120 mg/kg/day Adequate. Dose-relaied decreased maternal weight gain and fetal growth retardation and an apparent though not statistically significant, dose-related increase in cleft pal ale were observed Adequate. ResuHrare noryet reported 'Adequacy cannot be determined. The NOAEL for maternal toxicity wan 120 mg/kg/day For determining the NOAEL and LOAEL for developmental toxicity, it may be necessary to review the raw data from this study in order to determine the significance of the effects on resorption. At a minimum, the LOAEL is *20 mg/kg/day and the NOAEL is 60 mg/kg/day. However, upon further review of the resorption data, the LOAEL may be 30 mg/kg/day, (he lowest level tested. Appropriate endpoints were evaluated. "This study is currently in progress. Jones-Price el al. 1983a Jones-Price et al, 1983b USEPA, 1993 109 Table of loxicity D.Ha Tor 11 APs (continued) Chemical NameCAS NumberStudy TypeSpecies Rome of Administration Number studied/ type of TsposurcDurationExposure levelsexposure levelResponseSludy AdequacyCommentsReference Phenol I Phenol Phenol L Phenol li>8-95-2 108-95-2 108-95-2 108-95-2 108-95-2 Developmental toxicity - Summary' Multigeneration reproductive tox icily Rats Oral Reproductive loxicity Not reported Inhatalion Reproductive toxicity - Summary limiting water Nol reported 2-5 generations Not reported 100, 500. or 1000 ppm (5 generations); 3000 or 5000 ppm (3 generations), 7000 or 8000 ppm (2 generations) Not reported Nol reported Nol reported Pharmacokinetics - Summary No effects were noted in any generation until 10,000 ppm where reproduction was "retarded" There was no reproduction at 12,000 ppm. No inhalation developmental toxicity studies on phenol were located Adequate oral developmental toxicity studies Hi 2 species were located {ATSDR, 1989. TSCATS, 1992} Developmental neuroloxicily testing is currently being required under NPRM (US EPA. 1993). 1 Inadequate. The number of lest animals was not reported and test doses did not lead to effects The authors attributed some of the observed effects on the animals not drinking the water. Heller and Pursed, 1938 Results are not yet reported Adequacy cannot be determined. This study is currently m progress. US EPA, 1993 No inhalation reproductive toxicity studies on phenol were located. Adequate oral studies were not located (ATSDR, 1989. TSCATS, 1992). Reproductive toxicity lesting is currently being required under NPRM (US EPA, 1993) Information on absorption, metabolism, and elimination of inhaled phenol is available for humans and animals (ATSDR. 1989. HEEP. 1987) I REFERENCES ATSDR (Agency for Toxic Substances and Disease Registry) "Toxicological Profile on Phenol " (1989) CKEMTRACK National Toxicology Program Results Report "Results, status and publication information on all NTP chemicals produced from NTP CHEMTRACK system.* July (1993) Dalin, N.M and KristofTersson, R "Physiological effects of a sublethal conceotration of inhaled phenol on the rat." Ann Zool Fennta H 193-199 {I97d). I>e Ceaurriz. J C , Micillino, J C., Bonnet, P.. and Guenier. I P. "Sensory irritation caused by various industrial airborne chemicals." Toxicology Letters 9:137-143 (1981). l>eichmann. W B., Kitzmiller. K.V . and Witherup, B S "Phenol studies VII. Chronic phenol poisoning, with special reference to Ihe effects upon experimental animals of the inhalation of phenol vapor." American Journal ofClinical Pathology M 273-277 (194d). 110 o oo zo -n L-t l-J Z> V -Tl xO Z 05 -t O --i i-* T> Table of Toxicity Data for HAPs (continued) Heller. V C5, and Purse 11, L. "Phenol-contaminated waters and their physiological action." Journal of Pharmacology and Experimental Therapy 63 99-107 (1938) Jones-Price, C. Ledoux, T.A , Reef J.R., Fisher, P W , LanghofT-Paschke, L . Mart, M C., and Kimmel. C A "Teratologic evaluation of phenol {CAS No. 108-95-2) in CD rats Research Triangle Park, NC Research Triangle Institute NT1S PB83247726 (1983a). Jones-Price. C., Ledoux, T A., Reel, J R . LanghofT-Paschke, L . Man; M C, and KimmeLC.A "Teratologic evaluation of phenol (CAS No. 108-95-2) in CD-I mice Laboratory study, September 18. 1980 to January 12. 1981 Research Triangle Park, NC: Research Triangle Institute NTIS PB85I0446I (1983b) Liao. T F , and Oebme, F W "Tissue distribution and plasma protein binding of|uC] phenol in rats Toxicology and Applied Pharmacology 57 220-225 (1981) Meritss. R R "Phenol marasmus " Occupational Medicine. 14 55-56 (1972) NCI, National Cancer Institute "Bioassay of phenol for possible carcinogenicity." Technical Report Series No 203 (1980) Sandage, C "Tolerance criteria for continuous inhalation exposure to toxic material. I. Effects on animals of 90-day exposure to phenol, CC1* and a mixture of indole, skatole, HtS and methyl mercaptan." Wnght-Patterson Air Force Base. OH U S. Air Force systems command, Aeronautical Systems Division, ASD technical report 61 -519 (1961) TSCATS (Toxic Substances Control Act Test Submissions) Database (1992) US EPA. "Acetophenone, phenol, NfN-d imelhyfani line, ethyl acetate, and 2,6-dtmelhylphenol, Proposed test rule, notice of opportunity to initiate negotiations for TSCA Section 4 testing consent agreements" Federal Register 58(223) 61654-61671 November 22 (1993) O O C7 zo Tf 3 X> ~n ZH 0o0 ! '"J J> 11! Chemical Name Diethanolamine Diethanolamine Dkthaool amine Dielhanolamme Diethanolamine Table of Toxicity Rata for HAPs (continued) CAS Number 111 -42-2 II1-42-2 11142-2 111-42-2 111-42-2 Study Type Species Epidemiology Summary Acule toxicity Rats Acute toiklty Sammary Range-finding test Rats Subchronic toxicity Rats Route of Administration Type of Exposure Duration Exposure levels Number studied/ exposure level Inhalalion Vapor or aerosol .Short-term (no further information provided) 200 ppm vapor or 1400 ppm aerosol Not reported Inhalalion Not reported Continuous exposure for 9 days 0 or 25 ppm Not reported Inhalation Not reported A "workday schedule" for 13 weeks 0 or 6 ppm Not reported Response Study Adequacy Comments Reference Respiratory difficulties and some deaths occurred (no further information provided). Increased liver weight, elevated SGOT, increased kidney weight, and elevated BUN were noted Effects included depression of growth rate, increased lung and kidney weights, and some deaths among male rats. No epidemiology data on diethanolamine were located (Clement, 1991a, TSCATS, 1992, TOXLINE, 6/93). Inadequate. Exposure levels, number of test animals, exposure duration identification of no-cflect-level were not reported This is an abstract Hartung el al. 1970 Adequate acute inhalation toxicity data on diethanolamine were not located (Clement, 1991a. TSCATS, 1992. TOXLINE, 6/95) Inadequate Protocol information critical to assessing die study is not reported (for example, number of test animals, other exposure levels, if any) This is an abstract. Hartung et al., 1970 Inadequate Protocol information critical to assessing the study is not reported (for example, number of test animals, other exposure levels, if any). This is an abstract. Hartung el >1. 1970 112 r> o3 zo T1 Tt vD z-t coo -i U! T> Chemical Name U Diethanolamine Dielhanotammc Diethanolamine Dielhanol amine Dielhaitofamine Diethanolamine o o zT--A] o o >-* o \) >> z H--i 00 O Table of Toxicity Data for HAPs (continued) CAS Number 111-42-2 HI-42-2 It 1-42-2 111-42-2 1 r 1-42-2 1II-42-2 Study Type Subchronic loxicity Species Rats, guinea pigs, and dogs Rome of Administration Type of Exposure Duration Inhalation Vapor 6 hours/day, 5 days/week for 9 weeks Subchronic toxicity Rais, guinea pigs, and dogs Inhalation Vapor Continuously for 90 days Subchroaic toxicity - Summary Chronic toxkity Summary Skm painting assay Not reported Topical Carcinogenicity - Summary Not reported Not reported Exposure levels Number studied/ exposure level Response Study Adequacy Comments Reference 0 or 0.5 ppm 0 or 0 26 ppm Not reported 10 rats, 6 guinea pigs, 3 dogs/ exposure group, all males 10 rats, 5 guinea pigs, 2 dogs/sex/ exposure group, all males Not reported No signs of toxicity were noted. Histopathological examination of a wide variety of tissues including sections of the cerebrum, cerebellum, and eye showed no lesions. No toxicity was observed in guinea pigs or dogs; equivocal histological evidence of slight lung effects in rats. Results are not available yet This study is inadequate because duration of exposure was less lhan 90 days The concentration test was likely ihe highest vapor concentration obtainable. Purity 99%; most endpoints were evaluated. Eastman Kodak Company, 1989 This study is inadequate since high aerosol exposure may occur The concentration test was likely the highest vapor concentration obtainable Purity was not reported; most endpoints were evaluated Eastman Kodak Company, 1989 Additional testing could he required on subchronic inhalation toxicity of inhaled diethanolamine. Oral subchronic toxicity testing has been completed by NTP (CHEMTRACK, 7/93). No data on the chronic inhalation toxicity of diethanolamine were located (Clement, 1991a; TSCATS, 1992; TOXLTNE, 3/93). This test is in progress presently, The histopalhology portion of the study is under review. NTP, no dale No data on the carcinogenicity of diethanolamine wen located (Clement, 1991a, TSCATS, 1992, CHEMTRACK, 7/93). Studies by die oral (dietary) and derma) routes have been initiated by NT?; the subchronic studv is complete (NT? Report 120). Chemical Name Diethanolamine Cbelhanoiamtne Diethanolamine Table of ToKicily Dala for IIAPs (continued) CAS Number II1-42-2 IIH2-2 Ml-42-2 Study Type Neurotoxicity Species Rats Neurotox icity - Sa mm ary Chemofl7 Kavlock post natal mouse screening test Mice Route of Administration Type ofExposurc Oral Drinking water Duration 11 weeks Exposure levels Number studied/ exposure level 0. 0 16.0 32 063. 1 25, 2 5, and 5 0 mg/mL (doses were 2ft28ft mg/kg Tot males and 15240 mg/Vg for females) 10/sex/cxposure level Oral Garage Daily on gestation days 6-15 0 and 450 mgfleg/day 50 mated females/group Response Study Adequacy Demyeltnalion of brain and spinal cord at 2 5 and 5 0 mg/mL This was a subchronic toxicity study showing neuroloxic effects Comments Reference Purity was not reported, this study identified a NOAEL of 1 25 and a LOAELof 2 5 for neurotoxicity Battel le Columbus | Lab. 1989 | No maternal toxicity, despite exposure to the predicted LD,,,. Developmental toxicity occurred {decreased neonatal survival, p=0 001, increased gestation length, p<0 01) and neonatal weight gain. p 4 0.001) Available evidence for diethanolamine suggests a potential for neurotoxicity (TSCATS, 1992) However, the available study was not designed specifically to determine neurotoxicity; thus, more neurotoxicity studies could be required Tor diethanolamine This is an adequate screening test, but is not adequate to evaluate developmental toxicity since malformations were not studied The ChemoffT Kavlock preliminary screen score was 19, which represents high priority for testing in a conventional developmental toxicity lest. This is an acceptable screening lest; compound identity was confirmed by gats chromatography using a flame ionization detector NIOSH, 1987 r> o z> zo ~n i-t `-j a \> Tt & z 00 --I o --I !J1 1 Id C0NFTDFNTTA1 \) ^0 CO o Chemical Nume Diethanolamine I Diethanolamine jj Diethanolamine Diethanolamine Diethanolamine 1 Table of Toxicity Data for HAPs (continued) CAS Number 111-42-2 Study TypeSpecies Route of Administration Cheroofl? Kavlock preliminary developmental toxicity Mice Oral 1IM2-2 Developmental toxicity - Seminary *11 -42-2 Subchronic toxicity Rats Oral 111-42-2 Reproductive toxicity - Summary 111-42-1 Pharmacokinetics * Summary Number studied/ Type of ExposureDurationExposure levelsexposure levelResponseStudy AdequacyCommentsReference Gavage Drinking water Daily on gestation days 6-1S 450 mg/kg/day 34/expostire level 13 weeks 0,0 16,0,32. 0 63. 1.25,2 5, and 5 0 mg/mL (doses were 28288 mg/kg for males and 15240 mg/kg for females) 10/sexfexposure level No maternal toxicity Developmental toxicity was noted (decreased number of viable litters, percent survival of pups, and weight gained by pups) This is an adequate screening test, but is not adequate to evaluate developmental toxicity since malformations were not studied This maybe a report on the NIOSH, 1987, lest, but if so, some information was lacking in (his presentation. Purity was not reported (purest grade commercially available); only one exposure level used; did not measure many parameters of developmental toxicity. Union Carbide Corp., 1990 Additional testing con Id be required on the developmental toxicity of diethanolamine Developmenlal screening tests completed by NIOSH suggest the siibsttmce is a developmental toxicant, and results place it Hi a hi gh-priority category for testing Atrophy of the prostate at 5.0 mg/mL; atrophy of seminal vesicle, hypospermia m the epididymis, and spermatic arrest m the testis at 2.5 and 5.0 mg/mL. This was a subchronk toxicity study which identified reproductive effects. Purity was not reported; this study identifies a NOAEL of 1.25 mgfoiL and aLOAEL of 2.50 mg/mL for reproductive effects in males. Batteik Columbus Lab, 19*9 Available evidence for diethanolamine suggests a potential for reproductive toxicity m males (TSCATS. 1992). However, the available study was no! designed specifically lo determine reproductive toxicity, thus, more reproductive toxicity studies could be retpiired for diethanolamine The only pharmacokinetics study located for diethanolamine used intravenous administration in dogs (TSCATS. 1992). 115 Table of Toxicity Data for HAPs (continued) REFERENCES Battellc Columbus Lab "Diethanolamine Subchronic dosed water and dermal studies in F344 rats and B6C3F1 mice -- Final report for prechronic dosed water study ofdiethanolamine lit Fischer 344 rats." TSCA FYT submission OTSI189-0721, microfiche number OTS0000721. Washington. DC OPPT, US EPA (1989) CHEMTRACK National Toxicology Program Results Report "Results, status and publication information on all NTP chemicals produced from NTP CHEMTRACK system." July (1993) Clement. "Draff inhalation reference dose for diethanolamine (1 11-42-2)." Prepared by Clement Associates, Inc. for Environmental Criteria and Assessment Office (1991 a). Eastman Kodak Company. "Subacute inhalation toxicity ofdiethanolamine and bimat imbiba/rt (485K)." TSCA 8D submission 86-890000205, microfiche number OTSOS16742. Washington, DC OPPT, US EPA (1989). Hartimg, R., Rigas, L K , and Cornish, H.H. "Acute and chronic toxicity of diethanolamine." Toxicology and Applied Pharmacology. 17:308 (1970) NIOSH "Screening of priority chemicals for reproductive hazards - Monoethanolaminc (CAS. No. 141-43-5): Diethanolamine (CAS. No 111-42-2); Triethanolamine (CAS. No 102-71-6)" Prepared for National Institute for Occupational Safety and Health (NIOSH) NTIS Document No. PB89139067(1987) NTP (Nkmal Toxicology Program). "NTP Technical Report on Toxicity Studies of Diethanolamine (CAS No. L11 -42-2) Administered Topically ami in Drinking Water to F344/N Rats." Technical Report Series 820 (1992). TOXLiNE. National Library of Medicine Online Database. (1993). TSCATS (Toxic Substances Control Act Test Submissions) Database (1992). Union Carbide Corporation. "Screening of priority chemicals for reproductive hazards find report Monoethanolamine, diethanolamine, triethanolamine with cover letter." TSCA 8D submission Old Doc ID 86-900000423, microfiche number OTS0526003. Washington, DC: OPPT, US EPA (1990). n ou 1zT--j1 o --* \oJ z---t --i J> oo oSJ U6 <1 rc *- CC Kz O' li es c V o c zcc Table of Toxicity Data for HAPs (continued) Chemical Name 1,2,4-Trichlorobenzene 1 ,2,4-Trichlorobenzcoe 1 4,4-Trichforobcrizcne 1,2,4-Trictdorobenzcne l ,2,4'Trichlorobenzene 1,2,4-TrichJorobenzene CAS Number 120-82-1 120-82-1 120-12-] 120-82-1 120-82-1 120-82-1 Study Type Species Epidemiology - Summary Route of Administration Type of Exposure Acute toxicity RKS inhalation Vapor Acute tuiicity - Summary Subchronic toxicity Rats Inhalation Vapor Subchronic toxicity Ruts Inhalation Vapor Subchrwue toiicity - Summary Duration 4 hours, then observed for 14 days 7 hours/day, 5 days/week for 44 days 6 hours/day, 5 days/week for 3 months Exposure levels Number studied/ exposure level 418 ppm 6 males 0,30, or 100 ppm 20 males/exposure group 0,3, and 10 ppm 10-26/sex/ exposure group Response No mortality; lacrimation, salivation, pink cars, labored breathing, and discoordinatiort were observed; body weights decreased 16%, then recovered normally. Increased urinary excretion of porphyrin at 30 and 100 ppm, no gross Of histologic effects. Increased urinary exaeiion of porphyrin at 10 ppm. Study Adequacy Comments Reference No epidemiological studies were located (HAD, 1915, HEA, 1987, TSCATS, 1992). This ts an inadequate acute toxicity study because only males were used arid only one concentration was tested. No LCW could be calculated. E.I. DuPont de Nemours, 1982 DaU on the acute intostation toxicity of 1,2,4-ttricMorobcnzeee were inadequate (HAD, 19 85; HEA, I9S7;TSCATS, 1992). This study is limited since only male lest animals were used. This study identified a LOAEL of 30 ppna; however, the authors indicated that the observed effect might not be toxic. Rodba, 1981 A limited number ofparameters were examined. This study identified a LOAEL of JO ppm; however, the authors indicated that the observed effect might not be toxic. Watanabc et al, 1978 Subchronic inhalation toxicity studies were kx,ated; however, an unequivocal LOAEL was identified (HAD, 1985; HEA, 19*7, TSCATS, 1992). 117 Table of Toxicity Data for H A Ps (continued) Chemical NimeCAS Number l ,2,4-Trichlorobenzene 120-H2-1 1,2,4-TrkMorabenzene I2CM2-1 Study TypeSpecies Chronic toxicity Rats Chronic toxicity Rabbits Route of Administration Number studied11 Type of Exposure_______ DurationExposure levelsexposure levelResponseStudy AdequacyComments Reference Inhalation Vapor Inhalation Vapor Continuous exposure for 26 weeks 0,25,50* and 100 ppm 30 males/group Continuous exposure for 26 weeks 0* 25,50* and 100 ppm 16 males/group No effects were noted on survival, body weight* ophthalmic condition, hematological or serum biochemistry, pulmonary function or operant behavior. HistopathologicaJ examination revealed transient mild hepatomegaly and vacuolation in liver parenchymal cells, and hyaline degeneration in the renal cortex in alt test groups at 4 and 13 weeks ofexposure. These changes were not apparent at 26 weeks of exposure. No effects were noted on survival, body weight, ophthalmic condition, henudologicat or serum biochemistry, pulmonary function, operant Inadequate. Only male test animals were used. Inadequate. Only male test animals were used. The increase in size and vacuolation of the cytoplasm of hepatocytes may reflect an increase in the amount of endoplasmic reticulum needed to increase detoxifying enzymes. Coate e( al., 1977 It is not known whether transient changes such as those found in rats occurred here, since interim sacrifices Coate eld , 1977 r> o CJ zo Tj I -> O *0 n vD Z CO HO H vO 1> 118