Document pmmR1732gD1X1wJkqpoRJpY8a
fI Health Effects Assessment for 1,1-Dichloroethylene
PB86-134624
U.S. Environmental Protection Agency
September 1984
U.S. DEPARTMENT OF COMMERCE National Technical information Service
ob^56
r
PB86-134624 E PA/540/1-86/051 September 1984
HEALTH EFFECTS ASSESSMENT FOR 1.1-DICHLOROETHYLENE
U.S. Environmental Protection Agency Office of Research and Development
Office of Health and Environmental Assessment Environmental Criteria and Assessment Office
Cincinnati, OH 45268
U.S. Environmental Protection Agency Office of Emergency and Remedial Response Office of Solid Waste and Emergency Response
Washington, DC 20460
REPRODUCED BY
NATIONAL TECHNICAL INFORMATION SERVICE
US DEPARTMENT OF COMMERCE SPRINGEIEID. V* 2Z161
DISCLAIMER This report has been funded wholly or In part by the United States Environmental Protection Agency under Contract No. 68-03-3112 to Syracuse Research Corporation. It has been subject to the Agency's peer and adminis trative review, and It has been approved for publication as an EPA document. Mention of trade names or commercial products does not constitute endorse ment or recommendation for use.
11 b.0
0
PREFACE
This report summarizes and evaluates Information relevant to a prelimi nary Interim assessment of adverse health effects associated with 1,1-dlchloroethylene. All estimates of acceptable Intakes and carcinogenic potency presented In this document should be considered as preliminary and reflect limited resources allocated to this project. Pertinent toxicologic and environmental data were located through on-line literature searches of the Chemical Abstracts, TOXLINE, CANCERLINE and the CHEMFATE/DATALOG data bases. The basic literature searched supporting this document Is current up to September, 1984. Secondary sources of Information have also been relied upon In the preparation of this report and represent large-scale health assessment efforts that entail extensive peer and Agency review. The following Office of Health and Environmental Assessment (OHEA) sources have been extensively utilized:
U.S. EPA. 1980b. Ambient Water Quality Criteria for Dlchloroethylenes. Environmental Criteria and Assessment Office, Cincin nati, OH. EPA 440/5-80-041. NTIS PB 81-117525.
U.S. EPA. 1983b. Health Assessment Document for Vlnylldene Chloride. Environmental Criteria and Assessment Office, Research Triangle Park, NC. EPA 600/8-83-031 A. NTIS PB 84-126762.
The Intent In these assessments Is to suggest acceptable exposure levels whenever sufficient data were available. Values were not derived or larger uncertainty factors were employed when the .variable data were limited In scope tending to generate conservative (l.e., protective) estimates. Never theless, the Interim values presented reflect the relative degree of hazard associated with exposure or risk to the chemlcal(s) addressed.
Whenever possible, two categories of values have been estimated for sys temic toxicants {toxicants for which cancer Is not the endpoint of concern). The first, the AIS or acceptable Intake subchronic, Is an estimate of an exposure level that would not be expected to cause adverse effects when exposure occurs during a limited time Interval (l.e., for an Interval that does not constitute a significant portion of the lifespan). This type of exposure estimate has not been extensively used or rigorously defined, as previous risk assessment efforts have been primarily directed towards exposures from toxicants In ambient air or water where lifetime exposure Is assumed. Animal data used for AIS estimates generally Include exposures with durations of 30-90 days. Subchronic human data are rarely available. Reported exposures are usually from chronic occupational exposure situations or from reports of acute accidental exposure.
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0651'59
The AIC, acceptable Intake chronic. Is similar In concept to the ADI (acceptable dally Intake). It Is an estimate of an exposure level that would not be expected to cause adverse effects when exposure occurs for a significant portion of the lifespan [see U.S. EPA (1980a) for a discussion of this concept]. The AIC Is route specific and estimates acceptable exposure for a given route with the Implicit assumption that exposure by other routes Is Insignificant.
Composite scores (CSs) for noncarcinogens have also been calculated where data permitted. These values are used for ranking reportable quanti ties; the methodology for their development Is explained In U.S. EPA (1983a).
For compounds for which there Is sufficient evidence of carcinogenicity, AIS and AIC values are not derived. For a discussion of risk assessment methodology for carcinogens refer to U.S. EPA (1980a). Since cancer Is a process that Is not characterized by a threshold, anx exposure contributes an Increment of risk. Consequently, derivation of AIS and AIC values would be Inappropriate. For carcinogens, q-|*s have been computed ba: d on oral and Inhalation data If available.
)
1v q65^60
Sk
ABSTRACT In order to place the risk assessment In proper context, the reader Is referred to the preface of this document. The preface outlines limitations applicable to all documents of this series as well as the appropriate use and Interpretation of the quantitative estimates. Evidence for the carcinogenicity of 1,1-dlchloroethylene In animals Is limited. There are essentially no useful human data. A number of oral exposure experiments have yielded negative results, as have Inhalation studies. One Inhalation study showed a significant Increase In the Inci dence of kidney adenocarcinomas In mice exposed to 1,1-dlchloroethylene vapors. Mutagenicity evaluations In numerous _1_n vitro systems have yielded positive results. The U.S. EPA (1983b) has used the kidney adenocarcinoma data In male mice for the computation of a human q-]* for Inhalation exposure to 1,1-dlchloroethylene and derived a q-]* of 1.47xl0-1 (mg/kg bw/day)"1.
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ACKNOWLEDGEMENTS
The Initial draft of this report was prepared by Syracuse Research Corporation under Contract No. 68-03-3112 for EPA's Environmental Criteria and Assessment Office, Cincinnati, OH. Dr. Christopher DeRosa and Karen Blackburn were the Technical Project Monitors and Helen Ball was,the Project Officer. The final documents In this series were prepared for the Office of Emergency and Remedial Response, Washington, DC.
Scientists from the following U.S. EPA offices provided review comments for this document series:
Environmental Criteria and Assessment Office, Cincinnati, OH Carcinogen Assessment Group Office of Air Quality Planning and Standards Office of Solid Waste Office of Toxic Substances Office of Drinking Water Editorial review for the document series was provided by: Judith Olsen and Erma Durden Environmental Criteria and Assessment Office Cincinnati, OH Technical support services for the document series was provided by: Bette Zwayer, Pat Daunt, Karen Mann and Jacky Bohanon Environmental Criteria and Assessment Office Cincinnati, OH
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TABLE OF CONTENTS
Page
1. ENVIRONMENTAL CHEMISTRY AND FATE......................................................................
1
2. ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS ......................
2
2.1. 2.2.
ORAL................................................................................................................. INHALATION....................................................................................................
2 2
3. TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS ...........................................
3
3.1. SUBCHRONIC....................................................................................................
3
3.1.1. 3.1.2.
Oral................................................................................................ Inhalation...................................................................................
3 3
3.2. CHRONIC.............................................................................................................
6
3.2.1. 3.2.2.
Oral................................................................................................ Inhalation...................................................................................
6 8
3.3. TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS..........................
8
3.3.1. 3.3.2.
Oral................................................................................................ Inhalation...................................................................................
8 8
3.4. TOXICANT INTERACTIONS..............................................................................
9
4. CARCINOGENICITY ........................................................................................................ 10
4.1. HUMAN DATA.................................................................................................... , 10
4.1.1. 4.1.2.
Oral................................................................................................ Inhalation...................................................................................
10 10
4.2. BIOASSAYS......................................................................................................... 10
4.2.1. 4.2.2.
Oral................................................................................................ Inhalation...................................................................................
10 10
4.3. 4.4.
OTHER RELEVANT DATA................................................................................... WEIGHT OF EVIDENCE...................................................................................
13 17
5. REGULATORY STANDARDS AND CRITERIA ................................................................. 18
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TABLE OF CONTENTS (cont.)
Page
6. RISK
ASSESSMENT........................................................................................ T9
6.1. 6.2. 6.3.
ACCEPTABLE INTAKE SUBCHRONIC(AIS) .................................................... ACCEPTABLE INTAKE CHRONIC(AIC)............................................................ CARCINOGENIC POTENCY (q-|*)..................................................................
19 19 19
6.3.1. 6.3.2.
Oral................................................................................................ Inhalation...................................................................................
19 19
7. REFERENCES...................................................................................................................... 20
APPENOIX A: Summary Table for 1,l-D1chloroethylene ........................................ 31
APPENDIX B1: Cancer Data Sheet for Derivation of q-j*................................... 32
APPENDIX B2: Calculation of q-|*................................................................................... 33
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No. 3-1 3- 2
4- 1 4-2 4-3
4-4
LIST OF TABLES
Title
Page
Effect on Experimental Animals of Long Term Inhalation of 1 ,l-01chloroethylene.......................................................................................
4
Pathologic Effects of Long-Term Ingestion of 1,1-Dlchloroethylene Incorporated In the Drinking Water of Sprague-Dawley Rats .......................................................................................
7
Results of Oral Carcinogenicity Bioassays of 1,1-Dlchloroethylene.................................................................................................................
11
Results of Inhalation Carcinogenicity Bioassay of 1,1-Dlchloroethy lene.......................................................................................
12
Distribution of the Different Types of Mammary Tumors After Exposure by Inhalation to 1,1-D1chioroethy1ene In Air After 137 Weeks...................................................................................
14
Distribution of the Different Types of Tumors After Exposure by Inhalation to 1,1-Dlchloroethyulene In Air After 121 Weeks.......................................................................................
15
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ADI AIC AIS BCF bw CAS CS LOEL ppm STEL TLV TWA
LIST OF ABBREVIATIONS
Acceptable dally Intake Acceptable Intake chronic Acceptable Intake subchronic Bioconcentration factor Body weight Chemical Abstract Service Composite score Lowest-observed-effeet level Parts per million Short-term exposure limit Threshold limit value Time-weighted average
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1. ENVIRONMENTAL CHEMISTRY AND FATE
The relevant physical and chemical properties and environmental fate of 1,1-dlchloroethylene (CAS No. 75-35-4), commonly known as vlnylldene chloride, are as follows:
Chemical class: hydrocarbon
Molecular weight:
Vapor pressure:
Water solubility:
Octanol/water partition coefficient:
BCF:
Half-lives In Air: Water:
halogenated al Iphatlc
96.94 (Mabey et al., 1981) 600 mm Hg at 25C (U.S. EPA, 1983b) 2250 mg/1 at 25C (U.S. EPA, 1983b)
69 (estimated) (Mabey et al., 1981) 7 (estimated from the equation of Velth et al., 1979)
2 days (Cuplt-t, 1980) 1-6 days (estimated)
The half-life of 1,1-dlchloroethylene In aquatic media has been esti mated from the reaeration rate ratio of 0.601 and the oxygen reaeration rate constant of 0.19-0.96 day"1 as given by Mabey et al. (1981).
The half-life of 1,1-dlchloroethylene In soil could not be located In the literature available; however, evaporation is expected to be the pre dominant loss mechanism from the soil surface. Based on the octanol/water partition coefficient and aqueous solubility it can be speculated that leaching may play a significant role In determining the fate of this chemi cal In soils. In fact, the detection of this compound In several groundwaters (U.S. EPA, 1983b) Is Indicative of the leachabl1Ity of this compound from soils.
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2. ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL MAMMALS 2.1. ORAL
A number of Investigators have reported the rapid appearance of labeled 1,1 ,-dlchloroethylene In the urine and expired air of rats given an Intragastrlc dose of [14C] 1,1-dlchloroethylene (position of label unspecified) (McKenna et al., 1978; Reichert et al., 1979; Jones and Hathway, 1978). These Investigators concluded that the systemic absorption of 1.1 -d1ch1 oroethylene following Intragastrlc administration Is rapid and fairly complete. 2.2. INHALATION
Andersen et al. (1979) exposed fasted male rats to atmospheres contain ing various concentrations of 1,1-dlchloroethylene In a closed chamber. They observed an Initial rapid phase followed by a slow phase of uptake. The rapid phase was believed to represent whole body equilibrium and was first-order with a rate constant of 2.2 hour'1 (t.j/2=Q.315 hour). The slow phase was believed to represent metabolism.
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3. TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS 3.1. SUBCHRONIC 3.1.1. Oral. Rampy et al. (1977) administered 50, 100 or 200 mg 1,1-dlchloroethylene/s, drinking water to groups of 10 male and 10 female Sprague-Dawley rats for 90 days. There was an Increased Incidence of cyto plasmic vacuolization of hepatocytes In the high dose groups.
Quast et al. (1983) administered capsules containing 1,1-dlchloroethylene In peanut oil (0, 6.25, 12.5 or 25 mg/kg bw/day) to groups of four male and four female beagle dogs for 97 days. No effects were observed on general appearance or demeanor, body weight, food consumption, hematology, clinical chemistry, urinalysis, organ weights, gross pathology or hlstopathology. 3.1.2. Inhalation. Subchronic exposure to 1,1-dlchloroethylene results predominantly In damage to the liver and kidneys (Irish, 1962; Prendergast et al., 1967; Sage, 1970; Rampy et al., 1977). The most thorough of these studies was the study by Prendergast et al. (1967) In which rats, guinea pigs, rabbits, dogs and monkeys were exposed to atmospheric concentrations ranging from 20-395 mg/m3 1,1-dlchloroethylene for up to 90 days (Table 3-1). Intermittent exposure (8 hours/day, 5 days/week, for 6 weeks) to 395 mg/m3 produced no deaths, visible signs of toxicity or hlstopathologlcal changes In any species. At each dose level, the Inhalation chamber typi cally contained 50 rats (Long-Evans or Sprague-Dawley), 15 Hartley guinea pigs, 3 squirrel monkeys, 3 New Zealand rabbits and 2 beagle dogs. The controls consisted of 304 rats, 314 guinea pigs, 57 monkeys, 48 rabbits and 34 dogs. Continuous exposure to concentrations up to 189 mg/m3 produced dose-related mortality In guinea pigs and monkeys, for guinea pigs, mortal ity was significantly Increased over controls In the three highest dose
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TABLE 3-1 Effect on Experimental Animals of Long Term Inhalation of 1,1-Dlchloroethylene*
ConcentratIon 100 ppm
(395*32 mg/m3)
46 ppm (109_*6.2 mg/m3)
26 ppm (101*4.4 mg/m3)
Schedule 30 exposures. 6 hours/day, 5 days/week
90 days, 24 hours/day
90 days. 24 hours/day
Species
Hortallty
rat guinea pig rabbit dog monkey
rat
guinea pig
0/15 0/15 0/3 0/2 0/3
0/15
7/15
dog monkey
0/2 3/9
rat guinea pig
rabbit dog monkey
0/15 3/15
0/3 0/2 2/3
Significant Findings
None None Weight loss In treated animals None Weight loss In treated animals
Animals gained less weight than controls. Hepatic lesions. Renal lesions. Hortallty occurred between day 4 and day 9 of exposure. Slight elevation of liver alkaline phosphatase activity and serum glutamic-pyruvic transaminase activity. Animals lost weight. Hepatic lesions. One dog developed an adrenal cortical adenoma. Hortallty occurred on days 26, 60 and 64. Animals lost weight. Hepatic lesions.
None Hortallty occurred between day 3 and day 5 of exposure. Animals lost weight. Animals lost weight. Hortallty occurred between day 3 and day 6 of exposure.
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TABLE 3-1 (cont.)
Concentration
Schedule
Species
Mortality
Significant Findings
16 ppm (61+5.7 mg/m3)
5 ppm (20+2.1 mg/m3)
Control
90 days. 24 hours/day
90 days. 24 hours/day
NR
rat guinea pig dog monkey
rat guinea pig dog monkey
rat guinea pig rabbit dog monkey
0/15 3/15 0/2 0/9
2/45 2/45 0/6 1/21
7/304 2/314 2/48 0/34 1/57
Animals gained less weight than controls Mortality occurred on day 3 and day 4. None Animals lost weight.
Animals gained less weight than controls None Animals lost weight. None
None
`Source: Prendergast et al., 1967 NR = Not reported
SL 065471
groups (61, 101 and 189 mg/m3) and was of borderline significance at the 20 mg/m3 exposure level (p=0.078, 1-talled Fisher exact test). Growth depression was noted In all species at the high dose level. Renal lesions were observed In rats and hepatic lesions and/or enzyme changes were observed In all species at the high dose level; however, no histological lesions were found at concentrations of <101 mg/m3. Depressed weight gain and Increased mortality were observed In some species at all exposure levels. 3.2. CHRONIC 3.2.1. Oral. 1 ,l-01chloroethylene was administered In the drinking water (50, 100 or 200 mg/t) to groups of 48 male and 48 female Sprague-Dawley rats for 2 years (Quast et a 1., 1983; Humlston et al., 1978; Rampy et al., 1977). These water concentrations provided doses of 5-12, 8-20 d 16-40 mg/kg bw/day, respectively. The control groups consisted of 80 maV . and 80 females. 1,1-Dlchloroethylene had no significant effect on general appear ance, body weight, food consumption, water consumption, hematology, urinaly sis, clinical chemistry or organ weights. Gross and hlstopathologlcal exam ination revealed a number of statistically significant lesions (Table 3-2), the most Important of which were hepatocellular fatty changes and periportal hepatoceljular hypertrophy.
The chronic toxicity of 1,1-dlchloroethylene has also been determined In F344/N rats and 86C3F1/N mice. Fifty animals/sex/dose were given 0, 1 or 5 mg/kg bw/day (rats) or 0, 2 or 10 mg/kg bw/day (mice) by gavage, 5 days/week for 2 years (NTP, 1982). Mortality and growth rates were not affected at either dose level In either species. Increased incidences of chronic renal Inflammation were observed In the high dose rats (males, 43/48 vs. 26/50 controls; females, 9/44 vs. 3/49 controls) and liver necrosis In high dose male mice (7/49 vs. 1/46 controls).
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TABLE 3-2
Pathologic Effects of Long-Term Ingestion of 1,1-Olchloroethylene Incorporated In the Drinking Water of Sprague-Dawley Rats*
Effect
50 ppm MF
Dose Level
100 ppm
200 ppm
MFMF
Increased incidence of intra-abdominal fluid or blood in abdominal cavity
Increased Incidence In the total number of rats with hepatocellular fatty change or fatty degeneration
Increased incidence of hepatocellular fatty change with location In lobule not specified
Increased Incidence In periportal hepatocellular fatty change
Increased Incidence of periportal hepatocellular hypertrophy
Increased Incidence of hepatic centrllobular atrophy
Increased Incidence of mammary gland fIbroadenomas/adenofIbromas
/
// /
/ / /
Source: U.S. EPA, 1983b; Humlston et al., 1978 M = male; F = female
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3.2.2. Inhalation. Rampy et al. (1977) and McKenna et al. (1982) reported the results of a Dow Chemical Company 2-year Inhalation study In which groups of 104 male and 104 female Sprague-Dawley rats were exposed to 0, 10 or 40 ppm (0, 39.7 or 158.6 mg/m3) 1,1-dlchloroethylene 6 hours/day, 5 days/week, for 5 weeks, after which the exposures were Increased to 0, 25 or 75 ppm (0, 99.1 or 297.4 mg/m3) for the remainder of the 18-month exposure period (-73 weeks). No dose-related changes were observed In mortality*, body weight, hematology or clinical chemistry. Hepatocellular fatty changes were observed In both sexes at both dose levels. This effect was reversible after treatment was discontinued. Similar hepatic changes have been reported In mice and rats exposed to 55 ppm (218.1 mg/m3) 6 hours/day, 5 days/week for 6-12 months (TWA=38.9 mg/m3) (Lee et al., 1977; Hong et al., 1981). 3.3. TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS 3.3.1. Oral. Nltschke et al. (1980, 1983) administered 1,1-dlchloro ethylene In the drinking water (50, 100 or 200 mg/i.) to Sprague-Dawley rats for 3 generations. Each parental generation consisted of 10 males and 20 females. There were a number of statistically significant effects on reproduction; however, these effects were not dose-related and occurred sporadically throughout the 3 generations. These effects were, therefore, probably not related to exposure to 1,1-dlchloroethylene. At doses of 100 and 200 mg/i, statistically significant Increases In hepatocellular fatty changes were observed In the F^ males and females and the F2 females. 3.3.2. Inhalation. The teratogenicity of Inhaled 1,1-dlchloroethylene has been tested In rats, rabbits and mice (Short et al.. 1977a; Murray et al., 1979). Signs of fetal toxicity, minor skeletal alterations and softtissue alterations were observed at doses that produced maternal toxicity
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and were considered to be feto- and embryotoxlc manifestations of maternal toxicity.,, Maternal toxicity In rats was observed by Short et al. (1977a) at exposure levels as low as 15 ppm. 3.4. TOXICANT INTERACTIONS
The metabolism of dlchloroethylenes Involves the production of reactive epoxide Intermediates that bind covalently to cellular macromolecules (Bonse et al., 1975; Hathway, 1977; McKenna et al., 1978). Compounds such as dlsulflram decrease the covalent binding of 1,1-dlchloroethylene and protect against lethality and hepatotoxlclty (Short et al., 1977b). Pretreatment with Inducers of microsomal enzyme systems also decreased the hepatotoxlclty of 1,1-dlchloroethylene (Reynolds et al., 1975; Jenkins et al., 1972), but Increased mortality (Carlson and Fuller, 1972). Compounds that deplete cellular glutathione Increase the hepatotoxlclty of 1,1-dlchloroethylene (Jaeger et al., 1973a,b, 1974, 1977).
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4. CARCINOGENICITY 4.1. HUMAN DATA 4.1.1. Oral. Pertinent data regarding the oral carcinogenicity of 1,1-dlchloroethylene In humans could not be located In the available literature. 4.1.2. Inhalation. Ott et al. (1976) Investigated the effects of occupa tional exposure to 1,1-dlchloroethylene (<0.2% vinyl chloride) among 138 Dow Chemical Company workers. TWA concentrations were estimated based on job descriptions and Industrial hygiene surveys; the subjects were divided Into groups exposed to <10 ppm (assumed 5 ppm average). 10-24 ppm (assumed 17 ppm average) and >25 ppm (assumed 43 ppm average). There were no statistically significant differences between the exposed groups and controls matched for age and smoking habits; however, the population examined In the study may not be adequate for the detection of cancer. 4.2. BIOASSAYS 4.2.1. Oral. The available data regarding the oral carcinogenicity of 1,1-dlchloroethylene In experimental animals are summarized In Table 4-1. These studies have failed to demonstrate a carcinogenic potential for 1,1-dlchloroethylene In either rats or mice following oral exposure. 4.2.2. Inhalation. The available data on the Inhalation carcinogenicity of 1,1-dlchloroethylene In experimental animals are summarized In Table 4-2. The only studies In which 1,1-dlchloroethylene has produced positive results are those of Maltonl et al. (1977, 1980) In which Sprague-Dawley rats and Swiss mice were used. There were at least 30 animals/sex/dose at the begin ning of the exposure period, with 90-100 animals/sex In the controls. Rats were exposed to atmospheres containing 0, 10, 25, 50, 100 or 150 ppm (0, 39.7, 99.1, 198.3, 396.5 or 594.8 mg/m3) 1.1-dlchloroethylene, 4 hours/ day, 4-5 days/week, for 12 months.
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TABLE 4-1 Results of Oral Carcinogenicity Bioassays of 1,1-Dlchloroethylene*
Species
Dose
Route of Administration
Total Duration of Observation
(weeks)
F Indlngs
Reference
SpragueDawley rats
SpragueDawley rats
Fischer 344 rats
B6C3F1 mice
SpragueDawley rats
20. 10, 5, 0.5 mg/kg for 12 months
50, 100, 200 ppm In drinking water
5 ml/kg of a 1000 or 200 ppm solution
10 ml/kg of a 1000 or 200 ppm solution
0.5, 5, 10. 20 mg/kg/day
gavage, dally
Ingestion
gavage, 5 days/ueek gavage, 5 days/week gavage, 5 days/week
147 104 103 103 52-59
Mo statistically significant Increase
No statistically significant increase
No statistically significant Increase
No statistically significant Increase
No brain tumors
Haltonl et al., 1977 Quast et al., 1983 NIP, 1982
NTP, 1982
Haltonl et al.. 1982
*$ource: U.S. EPA, 1983b
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TADtf 4-2 Results of Inhalation Carcinogenicity Bioassays of l,l-D1chloroeihylene
Spec tes
Sprague-Dawley rats
Swiss alee
Dose
10. 25, SO, 100, ISO ppa, 4-5 days/week for 12 aonlhs
10, 25 ppa, 4-5 days/ week for 12 aonths
Chinese hamsters Utstar rats
Sprague-Dawley rats CD-I atce
25 ppa, 4-5 days/week for 12 aonths
200 ppa for 5 aonths, followed by 100 ppa for 6 aonths, 5 days/ week
100, 75 ppa, 5 days/ week for 12 aonths
55 ppa, 5 days/week
CD rats
Sprague-Dawley rats CD alee
CD rats
Sprague-Dawley rats
55 ppa, 5 days/week for 12 aonths
25, 75 ppa for 24 aonths
55 ppa, 5 days/week 1, 3 or 6 aonths
55 ppa, 5 days/week 1, 3, 6 or 10 aonths
10, 25, 50, 100, 150 ppa
`Source: U.S. IPA, 1983b
Route of Administration
Inhalation, 4 hours/day
Inhalation, 4 hours/day
Inhalation, 4 hours/day Inhalation, 4 hours/day
Inhalation, 4 hours/day Inhalation, 6 hours/day Inhalation, 6 hours/day Inhalation
Inhalation, 6 hours/day tnhalatIon, 6 hours/day Inhalation, 4-5 days/week
Total Duration of Observation 137 weeks
121 weeks
157 weeks llfeltae
lifetime 12 aonths 12 aonths 104 weeks 13. 15 or 18 aonths 13, 15, 10 or 22 aonths 52 weeks
fIndtngs
Statistically significant Increase In total aaaaary tumors, but not carcinomas alone, only at 10 and 100 ppm; no dose response
Kidney carcinomas at 25 ppa tn males (none In controls!
Statistically significant Increase In mammary carcinomas In females; no dose response
Ho statistically significant Increase
Ho statistically significant Increase
Ho statistically significant Increase
Ho statistically significant Increase
Ho statistically significant Increase
Ho statistically significant Increase
Ho statistically significant Increase
Ho statistically significant Increase
Ho brain tumors
Reference
Hallonl et al., 19)1, 1900
Ha Hon 1 et al., 197), I960
Hal ton1 el al.. 197), 19B0 Viola and Caputo, 19)7
Viola and Caputo, 19)7 lee et al., 19 78
lee el al., 1978
McKenna et al., 1982 Hong el al., 1981
Hong et al., 1981
Hal ton! et al., 1982
SL 065478
The results of these studies are summarized In Tables 4-3 and 4-4. There were Indications that 1,1-dlchloroethylene Induced mammary tumors In both rats and mice; however, there was no clear dose-response relationship and these tumors could not positively be attributed to exposure to 1,1-dlchloroethylene. The only tumors that the authors considered related to the treatment were kidney adenocarcinomas In male mice. 4.3. OTHER RELEVANT DATA
1.1- Dlchloroethylene has been tested for yeast and bacterial mutagenic ity In the Ames assay, the liquid suspension assay, the host-mediated assay and exposure of bacteria to atmospheres containing 1,1-dlchloroethylene, both with and without mammalian metabolic activating systems (Bartsch et al., 1975, 1979; Malavellle et al., 1977; Simmon et al., 1977, 1979; Simmon, 1978; Baden et al., 1976, 1977 , 1978; Waskell, 1978; Grelm et al., 1975; Cerna and Kypenova, 1977; Laumbach et al., 1977; Bartsch, 1976; Barbln et al., 1978; Bonse et al., 1975). 1 ,1-Dlchloroethylene Is mutagenic to Esche richia coll. Salmonella typhlmurlum. Bacillis subtllls and Saccharomyces cerevlslae. In the presence, but not the absence, of a mammalian metabolic activating system.
1.1- Dichloroethylene vapors have been demonstrated to be mutagenic to the plant, Tradescantla. following a 24-hour exposure to concentrations as low as 22 ppm (87.2 mg/m9); however, a 6-hour exposure to 1288 ppm (5107 mg/m9) did not produce a mutagenic effect {Van't Hof and Schalrer, 1982). In contrast, negative results have been obtained In assays using cultured mammalian cells (Drevon and Kurokl, 1979) and In dominant lethal assays In mice (Andersen and Jenkins, 1977) and rats (Short et al., 1977c).
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mu 4 3
Distribution of Ihe Different Types of Hawnary Tumors After Exposure by Inhalation to 1,1-Dlchloroethylene In Air After 137 Weeksa'b
Group Concen Ho. trations
Animals (Soraque Oawlev rats, lb Weeks Old at Start)
Ho. al Corrected**1
Sex Start
Humber
X
Average Latency
lime* (weeks)
No. of Tumors/ Tumor-
Bear tng Animals
*9 Ho.
Histologically Examined Hlstotypec
fibrous and f Ibroadenous
Average Latency
Time* % (weeks)
tare I nous
Average Latency
Time* No. X (weeks)
I
150 ppm
H
60
bO 13.3
F bO bO 73.3
H/F 120 120 43.3
97*14 82*3 82*3
1.0 100.0 b
1.5
97.7
38*
1.4
98.1
44
75.0 88.4
Bb.3
109*8 83*3 8b *3
1 12.5 9 20.9 10 19. b
2b 78*8 73*8
11 100 ppm
H r H/f
30 30 bO
30 lb.7 104*9
30 83.3
82*4
bO 50.0
85*4
1.0 100.0 5
100.0
1.7
92.0
21*
91.3
l.b
93.3
2b
92.8
104*9 83*5 87*4
00
0
3 13.0 102*10
3 10.7 102*10
111 50 ppm
H 30 f 30 H/F bO
30 23.3 10b *5
30 7b.7
79*4
bO 50.0
8b*4
1.9 100.0 7
100.0
1.9
95. b
21*
95.4
1.7
9b. 7
28
96.5
10b *5 82*4 88*4
00
0
1 4.5 bB
1 3.4 b8
IV 25 ppm
H 30 f 30
H/f bO
28
14.3
103*10
1.0 100.0 4
100.0
103*10
00
0
30 70.0
8b *4
l.b
95.2
20*
100.0
87*4
4 20.0
82*10
58 43.1
88*4
1.5
9b.0
24
100.0
90*4
4 lb.7
82*10
V 10 ppm
H 30 f 30 H/f bO
29 10.3 30 93.3 59 52.5
81*23 83*4 81*4
1.0 100.0 3
100.0
l.b
85.7
24*
100.0
1.5
87.1
27
100.0
81*23 85*4 85*4
00 5 20.8 5 18.5
0 90*14 90*14
VI
no treat-
H
100
81 12. b 115*b
mpnt
f 100
99 bl.b
87*2
(controls) H/f
200
18b
38.7
91*3
1.0
100.0
11
1.5
91.8
44
1.4
93.0
55
100.0 78.6 82.1
115*6 88*3 93*3
O0 lb 28. b lb 23.9
0 95*5 95*5
^Source: Haltont et al., 1990 Exposure was for 4 hours/day. 4-5 days/week for 5? weeks cTwo or More tours of the sane and/or different types (fibroadenomas, carcinomas, sarcomas, carcinosarcomas) may be present In the sane animals.
A carcinoma was found In one male In Ihe 150 ppm group, and no animals were observed to have sarcomas.
dlIve animals after 10 weeks, when the first tumor |a leukemia) was observed. elhe percentages refer to the corrected numbers. *Average age at Ihe onset of the first mammary tumor per animal, detected at the periodic control or at autopsy,
gihe percentages refer to total numbers of animals bearing mammary tumors. hThe percentages refer to total numbers of animats bearing mammary tumors, histologically examined. *Stal1st leally significant Increase compared to control by chi-square test (p<0.05). Comparisons are made between numbers with tumors/correcled numbers.
SL 6548o
TABLE 4 4 Distribution of the Different types of Tumors After Exposure by Inhalation to 1,1-Dlchloroethylene In Air After 121 Meeks*>b
Groups No.
Treatment
ConcentratIons
Length
nnimais iswtss Ice 16 weeks old [(Groups I.11.III.IV, V.V1) and 9 weeks old (Groups IV bis,
VII at startl
Sex No. at Start
______ Kidney Adenocarcinomas
Corrected Numbere No.
Average Latency
Time' X (weeks)
An 1mIs with Tumors c
_________ Haanarv lumors__________
Corrected Numbere No.
Average Latency
T1mee X (weeks)
d _______ Pulmonary Adenomas
Corrected Numbere No.
Average Latency
Time' X (weeks)
1
200 ppm
2 days
11
100 ppm
2 days
111
SO ppm
1 week
IV
?S ppm
52 weeks
IV bis 25 ppm
52 weeks
V
10 ppm
52 weeks
VI no
NA
treatment
(controls)
H f H/f
H f H/F
H 1 H/f
H F H/F
H f H/F
H F H/F
H F H/f
60 1 0 0 0 6 0 0 0 60 28 0 0 0 53 1 1.9 87 120 29 0 0 0 59 1 1.7 87
5
00
0
46 1 2.2 51
53 1 1.9 51
30 12 0 0 0 21 0 0 0
18
2 11.1
62.7
30
13 0 0 0
20
3 10.7
46.3
26
2 1.7 53.2
60 25 0 0 0 49 3 6.1 46.5 44 4 9.1 58.4
30 17 1 5.9 64 27 0 0 0
26 1 3.0 62
30
14 0 0 0
20
2 7.1 39.13
21
3 11.1
00.8
60
31 1 3.2 64
55
2 3.6 39.13
53
4 7.5 75.7
30
21 39 14.3 71 .5 29
00
0
28
7' 25.0
73.6
30
26 0 0 0
30
4h 13.3
68.11
29
7> 24.1
05.6
60
47 3 6.4 71 *5 59
4 6.0 68.11
57
14 24.6
30.4
120
98 259 25.5 75*2 117
1 0.0 46
113
16' 14.2
17.3
120
112 1 0.9 77
110
l2h 10.2
69.4
118
11' 9.3
70.6
240
210 26 12.4 75.2 235
13 5.5 67.4
231
21 11.7
71.3
30 25 0 0 0 30 0 0 0
20
11' 39.3
71.5
30
26 0 0
-
30
6h 20.0
63.5
30
3' 16.0
60.4
60
51 0 0 0
60
6 10.0
63.5
58
14 24.1
70.4
100 56 0 0 0 92 1 1.1 25
80 3 3.7 66.7
100 73 0 0 0 97 2 2.1 49.7 92 4 4.3 56.7
200
129 0 0 0
109
3 1.6 41.9
172
7 4.1 60.4
SL 065481
TABLE 44 (coni.)
Groups No.
_____ Treatment
Conceittratlons
Length
Animats (Swiss mice It weeks old ((Groups 1,11,III,IV V.V1) and 9 weeks old (Groups IK bis,
VII at start!
Sex Ho. at Start
Kidney AdenocarcInoMs
Corrected Humber' Ho.
Average Latency
lime' X (weeks)
Animats with Tumors HanMrv lumorsc
Corrected Humber' HO.
Average Latency
Time' X (weeks)
Pulmonary AdenoMsd
Corrected Humber' Ho.
Average Latency
lime* X (weeks)
Vll no
HA
treatment
(controls)
H
90 70 0 0 0 80 0 0 0
73 3 4.1 56.11
F
90 85 0 0 0 88 0 0 0
86 2 2.3 75.12
H/f
180 155 0 0 0 168 1 0.6 83
159 5 3.1 64.8
'Source: Ha Hon l et at., 1980
Exposure was for 4 hours/day, 4-5 days/week for 52 weeks cATT mammary tumors In females were histologically diagnosed as carcinomas, cr dso^e pulmonary adenomas were cellular atyplas.
'Alive animats when the first tumor was observed: kidney adenocarcinoma, 55 weeks; manmary tumor, 27 weeks; pulmonary adenoma, 36 weeks. The percentages refer to the corrected numbers.
Average time from the start of the experiment to the detection (at the periodic control or at autopsy). 9p<0.01, combined 25 ppm (28/119) males vs. control Mies (0/196) by chi-square test. Based on corrected numbers. hp<0.01 combined control males (6/153) vs. TO ppm Mies (11/28) and vs. combined 25 ppm Mies (29/294). Also, combined control feMles (6/178) vs. 10 ppm
females (3/30) and vs. combined 25 ppm feMles (18/147) 'p<0.01 combined control feMles (3/1B5) vs. TO ppm feMles (6/30) and vs. combined 25 ppm feMles (16/148). Based on corrected numbers.
NA j Not applicable
SV
4.4. WEIGHT OF EVIDENCE IARC (1982) has evaluated the evidence for carcinogenicity of 1,1-dl-
chloroethylene and concluded that the evidence for carcinogenicity In humans Is "Inadequate," the evidence for carcinogenicity In animals Is "limited," and the evidence for activity In short-term tests Is "sufficient." Applying the criteria for weight of evidence proposed by the Carcinogen Assessment Group of the U.S. EPA (Federal Register, 1984) 1,1-dlchloroethylene Is most appropriately classified In Group C - Possible Human Carcinogen.
-17-
SL 065483
5. REGULATORY STANDARDS AND CRITERIA
The ACGIH (1980) has established a TLV of 5 ppm (-20 mg/m3) and a STEL of 20 ppm (~80 mg/m3), which are believed low enough to prevent overt toxicity In exposed workers.
The U.S. EPA (1980b) has estimated that an ambient water concentration of 0.33 \iq/l would result In excess carcinogenic potency over a lifetime exposure. Both NI0SH and 0SHA consider 1,1-dlchloroethylene to be a potential carcinogen and have established an exposure limit of 1.0 ppm (-4 mg/m3) as a TWA or 5 ppm (-20 mg/m3) as a 15-minute celling (ACGIH, 1980).
-18-
SL 065484
6. RISK ASSESSMENT
6.1. ACCEPTABLE INTAKE SUBCHRONIC (AIS)
1,1-Dichloroethylene Is a chemical associated with cancer In animals and
for which data are sufficient for computing a
It Is, therefore, in
appropriate to calculate an oral or Inhalation AIS for 1,1-dichloroethylene.
6.2. ACCEPTABLE INTAKE CHRONIC (AIC)
1,1-Dichloroethylene Is a chemical associated with cancer In animals and
for which data are sufficient for computing a q.j*. It Is, therefore, In
appropriate to calculate an oral or Inhalation AIC for 1,1-dichloroethylene.
6.3. CARCINOGENIC POTENCY (q *)
6.3.1. Oral. No data were located In the available literature that Indi
cated a carcinogenic potential for orally administered 1,1-dlchloroethylene.
Therefore, no q^* could be derived.
6.3.2. Inhalation. Only one study was located In the available litera
ture that Indicated a carcinogenic response to Inhaled 1,1-dichloroethylene
(Maltonl, et al., 1977, 1980). In this study, groups of at least 30 Swiss
mice/sex/dose were exposed to 0, 39.7 or 99.1 mg 1,1-dlchloroethylene/m3,
4 hours/day, 4-5 days/week, for 12 months. Kidney adenocarcinomas were
observed In 28/119 male mice In the high dose groups as compared with 0/126
control male mice. The U.S. EPA (1983b) has analyzed these data and derived
a q^* of 1.47xl0-1 (mg/kg bw/day)'1. The data base from which this
q.|* Is calculated Is presented In Appendix B. This assessment uses the
same study as U.S. EPA (1980b); however, when the water quality document was
developed, only Interim results of this study were available, hence the
difference In estimates.
-19-
SL 065485
7. REFERENCES
ACGIH (American Conference of Governmental Industrial Hygienists). 1980. Documentation of the Threshold Limit Values, 4th ed. (Includes Supplemental Documentation, 1981, 1982, 1983). Cincinnati, OH.
Andersen, M.E. and L.J. Jenkins, Jr. 1977 . Oral toxicity of 1,1-dlchloroethylene in the rat: Effects of sex, age and fasting. Environ. Health Perspect. 21: 157-163. (Cited In U.S. EPA, 1983b)
Andersen, M.E., M.L. Gargas, R.A. Jones and L.J. Jenkins, Jr. 1979. The use of Inhalation techniques to assess the kinetic constants of 1,1-dlchloroethylene metabolism. Toxicol. Appl. Pharmacol. 47(2): 395-409. (Cited In U.S. EPA, 1983b)
Baden, J.M., M. Brlnkenhoff, R.S. Wharton, B.A. Hitt, V.F. Simmon and R.I. Mazze. 1976. Mutagenicity of volatile anesthetics: Halothane. Anesthesio logy. 45(3): 311-318. (Cited In U.S. EPA, 1983b)
Jaden, J.M., M. Kelley, R.S. Wharton, B.A. Hitt, '
Simmon and R.I. Mazze.
1977. Mutagenicity of halogenated ether anesthe.-*s. Anesthesiology. 46:
346-350. (Cited In U.S. EPA, 1983b)
Baden, J.M., M. Kelley, V.F. Simmon, S.A. Rice and R.I. Mazze. 1978. Fluroxene mutagenicity. Mutat. Res. 58: 183-191. (Cited In U.S. EPA, 1983b)
-20-
06546 ST-
Barbln, A., G. Planche, A. Crolsy, C. Malavellle and H. Bartsch. 1978. Detection of electrophilic metabolites of halogenated olefins with 4-(4-nltrobenzyl) pyridine or with Salmonella typhlmurium. Mutat. Res. 53: 150. (Cited In U.S. EPA, 1983b)
Bartsch, H. 1976. Mutagenicity tests In chemical carcinogenesis. In: Environmental Pollution and Carcinogenic Risk, IARC Scientific Publications No. 13. INSERM Symposia Series. IARC, Lyon, France. Vol. 52, p. 229-240. (Cited In U.S. EPA, 1983b)
Bartsch, H., C. Malavellle, R. Montesano and L. Tomatls. 1975. Tissue mediated mutagenicity of vlnylldene chloride and 2-chlorobutadlene In Sal monella typhlmurium. Nature (London). 225(5510): 641-643. (Cited In U.S. EPA. 1983b)
Bartsch, H., C. Malavellle, A. Barbln and G. Planche. 1979. Mutagenic and alkylating metabolites of haloethylenes, chlorobutadlenes and dlchlorobutenes produced by rodent or human liver tissues. Evidence for oxlrane formation by P-450 linked microsomal oxygenase. Arch. Toxicol. 41: 249-277. (Cited In U.S. EPA, 1983b)
Bonse, G., T. Urban, D. Reichert and D. Henschler. 1975. Chemical reactiv ity, metabolic oxlrane formation and biological reactivity of chlorinated ethylenes In the Isolated perfused rat liver preparation, Blochem. Pharmacol. 24: 1829-1834. (Cited In U.S. EPA, 1983b)
-21-
SL 065487
Carlson, G.P. and G.C. Fuller. 1972. Interaction of modifiers of hepatic microsomal drug metabolism and the Inhalation toxicity of 1,1-dlchloroethylene. Res. Commun. Chem. Pathol. Pharmacol. 4(3): 553-560. (Cited In U.S. EPA, 1983b)
Cerna, M. and H, Kypenova. 1977. Mutagenic activity of chloroethylenes analyzed by screening system tests. Mutat. Res. 46(3): 214-215. (Cited In U.S. EPAf. 1983b)
Cup 111r L.T. 1980. Fate of Toxic and Hazardous Materials In the Air Envi ronment. U.S. EPA, Environmental Sciences Research Laboratory, ORD, Re ?arch Triangle Park, NC. EPA 600/3-80-084. NTIS PB 80-221948.
Drevon, C. and T. Kurokl. 1979. Mutagenicity of vinyl chloride, vlnylldene chloride and chloroprene In V79 Chlnese-hamster cells. Mutat. Res. 67(20): 173-182. (Cited In U.S. EPA, 1983b)
Federal Register. 1984. Environmental Protection Agency. guidelines for carcinogenic risk assessment. 49 FR 46294-46299.
Proposed
Gage, J.C. 1970. The subacute Inhalation toxicity of 109 Industrial chem icals. Br. 0. Ind. Med. 27(1): 1-18. (Cited In U.S. EPA. 1983b)
Grelm, H., G. Bonse, Z. Radwan, 0. Reichert and 0. Henschler. 1975. Muta genicity 1_n vitro and potential carcinogenicity of chlorinated ethylenes as a function of metabolic oxlrane formation. Blochem. Pharmacol. 24(21): 2013-2017. (Cited In U.S. EPA, 1983b)
-22-
SL 065488
Hathway, D.E. 1977. Comparative mammalian metabolism of vinyl chloride and vlnylldeae chloride In relation to oncogenic potential. Environ. Health Perspect. 21: 55-59. (Cited In U.S. EPA, 1983b)
Hong, C.8., J.M. Winston, L.P. Thornburg, C.C. Lee and J.S. Woods. 1981. Follow-up study on the carcinogenicity of vinyl chloride and vlnylldene chloride In rats and mice. Tumor Incidence and mortality subsequent to exposure. J. Toxicol. Environ. Health. 7: 909-924. (Cited In U.S. EPA, 1983b)
Humlston, C.G., J.F. Quast, c.E. Wade, J. Ballard, J.E. Beyer and R.W Llsowe. 1978. Results of a two-year toxicity and oncogenicity study with vlnylldene chloride Incorporated In the drinking water of rats. MCA Report No. VCD 1.3-Tox-0rl-Dow. Toxicology Research Laboratory Health and Environ mental Research, Dow Chemical USA, Midland, MI. (Cited In U.S. EPA, 1983b)
IARC (International Agency for Research on Cancer). 1982. Results and conclusions. In; Chemicals, Industrial Processes and Industries Associated with Cancer In Humans. IARC Monographs on the Evaluation of the Carcino genic Risk of Chemicals to Humans. WHO, IARC, Lyon, France. Vol. 1-29 {Supp1 4).
Irish, D.D. 1962. Aliphatic halogenated hydrocarbons.
Patty's
Industrial Hygiene and Toxicology, 2nd ed., Vol. 2, F.A. Patty, Ed. John
Wiley and Sons, Inc., NY. p. 1305-1308. (Cited In U.S. EPA, 1983b)
-23-
SL 065489
Jaeger, R.J., R.B. Conolly and S.O. Murphy. 1973a. Diurnal variation of hepatic glutathione concentration and Its correlation with 1,1-dlchloroethylene Inhalation toxicity In rats. Res. Commun. Chem. Pathol. Pharmacol. 6(2): 465-471. (Cited In U.S. [PA, 1983b)
Jaeger, R.J., M.J. Trabulus and S.D. Murphy. 1973b. Biochemical effects of 1,1-dlchloroethylene In rats. Dissociation of Its hepatotoxlclty from a llpoperoxldatlve mechanism. Toxicol. Appl. Pharmacol. 24(3): 457-467. (Cited In U.S. EPA, 1983b)
Jaeger, R.J., R.B. Conolly and S.D. Murphy. 1974. Effect of 18-hour fast and glutathione depletion on 1,1-dlchloroethylene-lnduced hepatoxlclty and lethality In rats. Exp. Mol. Pathol. 20(2): 187-198. (Cited In U.S. EPA, 1983b)
Jaeger, R.J., S. Szabo and L.J. Coffman. 1977. 1 ,1 -Dlchloroethylene hepa totoxlclty: Effect of altered thyroid function and evidence for the subcellular site of Injury. J. Toxicol. Environ. Health. 3(3): 545-555. (Cited In U.S. EPA. 1983b)
Jenkins, L.J., Jr., M.J. Trabulus and S.D. Murphy. 1972. Biochemical effects of 1,1-dlchloroethylene In rats. Comparison with carbon tetrachlor ide and W1,2-dlchloroethylene. Toxicol. Appl. Pharmacol. 23(3): 501-510. (Cited In U.S. EPA, 1983b)
-24-
06^90 Sl*
Jones, B.K. and D.E. Hathway. 1978. The biological fate of vlnylldene chloride In rats. Chem. Biol. Interact. 20(1): 27-41. (Cited In U.S. EPA, 1983b.)
Laumbach, A.D., S. lee, J. Wong and U.N. Strelps. 1977. Studies on the mutagenicity of vinyl chloride metabolites and related chemicals. Prev. Detect. Cancer Proc. Int. Symp. 1: 155-170. (Cited In U.S. EPA, 1983b)
Lee, C.C., J.C. Bhandarl, J.M. Winston, et al. 1977. Inhalation toxicity of vinyl chloride and vlnylldene chloride. Health Perspect. 21: 25-32. (Cited In U.S. EPA, 1983b)
Lee, C.C., J.C. Bhandarl, J.M. Winston, W.B. House, R.L. Dixon and J.S. Woods. 1978. Carcinogenicity of vinyl chloride and vlnylldene chloride. J. Toxicol. Environ. Health. 4(1): 15-30. (Cited In U.S. EPA, 1983b)
Mabey, I^R., J.H. Smith, R.T. Podoll, et al. 1981. Aquatic Fate Process
Data for Organic Priority Pollutants. U.S. EPA, Monitoring and Data Support
Division, Office of Water Regulations and Standards, Washington, DC. 440/4-81-014.
EPA
Malavellle, C., G. Planche and H. Bartsch. 1977. Factors for efficiency of the Salmonella mlcrosome mutagenicity assay. Chem. Biol. Interact. 17(2): 129-136. (Cited In U.S. EPA, 1983)
-25-
SL 06549J
Maltoni, C., G. Cottl, L. Morisi and P. Chleco. 1977. Carcinogenicity bioassays of vlnylldene chloride. Research plan and early results. Med. Lav. 68(4): 241-262. (Cited In U.S. EPA, 1983b)
Maltoni, C., G. Cottl, L. Morisi and P. Chleco. 1980. Toxicity and Car cinogenicity Bioassay of VinylIdlne Chloride II. Chronic Toxicity and Carcinogenicity Report of Institute of Oncology and Tumor Center. Bologna, Italy. (Cited In U.S. EPA, 1983b)
Maltoni, C., A. Clllbertl and D. Carrettl. 1982. Experimental contribu tions 1q Identifying brain potential carcinogens In the petrochemical Industry. Ann. NY Acad. Scl. 381: 216-249. (Cited In U.S. EPA, 1983b)
McKenna, M.J., 3.A. Zemple, E.O. Madrid, W.H. Braun and P.3. Gehrlng. 1978. Metabolism and pharmacokinetic profile of vlnylldene chloride In rats following oral administration. Toxicol. Appl. Pharmacol. 45(3): 821-835. (Cited In U.S. EPA, 1983b)
McKenna, M.3., J.F. Quast, H.O. Yakel, M.F. Balmer and L.W. Rampy. 1982. Vlnylldene Chloride: A Chronic Inhalation Toxicity and Oncogenicity Study In Rats. Toxicology Research Laboratory, Health and Environmental Sciences, Dow Chemical USA, Midland, MI. (Cited In U.S. EPA, 1983b)
Murray, F., K. Nltschke, L. Rampy and B. Schwetz. 1979. Embryotoxldty and fetotoxlclty of Inhaled or Ingested vlnylldene chloride In rats and rabbits. Toxicol. Appl. Pharmacol. 48: 189-202. (Cited In U.S. EPA, 1983b)
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SL 065492
Nltschke, K.D., B.A. Schwetz, C.G. Humlston, et al. 1980. A Multiple Generation Reproduction Study In Rats Maintained on Drinking Water Contain ing Vlnylldene Chloride. Toxicology Research Laboratory, Health and Envi ronmental Research, Dow Chemical USA, Midland, MI. (Cited In U.S. EPA, 1983b)
Nltschke, K.D., F.A. Smith, J.F. Quast, J.M. Norris and B.A. Schwetz. 1983. A three-generation rat reproductive toxicity study of vlnylldene chloride In the drinking water. Fundam. Appl, Toxicol. 3: 75-79. (Cited In U.S. EPA, 1983b)
NTP (National Cancer Instltute/Natlonal Toxicology Program). 1982. NTP Technical Report on the Carcinogenesis Bioassay of Vlnylldene Chloride In F344/N Rats and B6C3F1/M1ce (Gavage Study). NPT No. 80-82. NIH Publ. No. 82-1784. NTP, Research Triangle Park, NC and Bethesda, MD. U.S. DHHS, PHS, National Institute of Health. (Cited In U.S. EPA, 1983b)
Ott, M.G., W.A. Flshbeck, J.C. Townsend and E.J. Schneider. 1976. A health study of employees exposed to vlnylldene chloride. 3. Occup. Med. 18(11): 735-738. (Cited In U.S. EPA, 1983b)
Prendergast, J.A., R.A. Jones, L.J. Jenkins, Jr. and J. Siegel. 1967. Effects on experimental animals of long-term Inhalation of trichloroethy lene, carbon tetrachloride, 1,1,1-trlchloroethane, dlchlorodlfluoromethane and 1,1-dlchloroethylene. Toxicol. Appl. Pharmacol. 10(2): 270-289.
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Quast, J.F., C.G. Humlston, C.E. Wade, et al. 1983. A chronic toxicity and oncogenicity study In rats and subchronic toxicity study In dogs on Ingested vlnylldene chloride.. Fund. Appl. Toxicol. 3(1): 55-62. (Cited In U.S. EPA, 1983b)
Rampy, L.W., J.F. Quast, C.G. Humlston, M.F. Balmer and B.A. Schwetz. 1977. Interim results of two-year toxicological studies In rats of vlnylldene chloride Incorporated In the drinking water or administered by repeated Inhalation. Environ. Health Perspect. 21: 33-43. (Cited In U.S. EPA, 1983b)
Reichert, D., H.W. Werner, M. Metzler and Q. Henschler. 1979. Molecular mechanism of 1,1-dlchloroethylene toxicity: Excreted metabolites reveal different pathways of reactive Intermediates. Arch. Toxicol. 42(3): 159-169. (Cited In U.S. EPA, 1983b)
Reynolds, E.S., M.T. Moslen, S. Szabo, R.J. Jaeger and S.D. Murphy. 1975. Hepatotoxlclty of vinyl chloride and 1,1-dlchloroethylene: Role of mixed function oxidase system. Am. J. Pathol. 81: 219. (Cited In U.S. EPA, 1983b)
Short, R.D., Jr., J.L. Minor, J.M. Winston, B. Ferguson and T. Unger. 1977a. Toxicity Studies of Selected Chemicals. Task II. The Developmental Toxicity of Vlnylldene Chloride Inhaled by Rats and Mice During Gestation. Prepared by Midwest Research Institute, Kansas City, MO, under Contract 68-01-3242. U.S. EPA, Office of Toxic Substances, Washington, OC. EPA 560/6-77-022. (Cited In U.S. EPA, 1983b)
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SL 065494
Short, R.D., J.M. Winston, J.L. Minor, C.D. Hong, J. Selfter and C.C. Lee. 1977b. Toxicity of vlnylldene chloride In mice and rats and Its alterations by various treatments. J. Toxicol. Environ. Health. 3(5-6): 913-921, (Cited In U.S. EPA, 1983b)
Short, R.D., J.L. Minor, J.M. Winston and C.C. Lee. 1977c. A dominant lethal study In male rats after repeated exposures to vinyl chloride or vlnylldene chloride. J. Toxicol. Environ. Health. 3: 5-6. (Cited In U.S. EPA, 1983b)
Simmon, V.F. 1978. Structural correlations of carcinogenic and mutagenic alkyl halides. |n: Structural Correlations between Carcinogenicity and Mutagenicity, DHEW (ISS-FDA) Publication No. 78-1046, p. 163-171. (Cited In U.S. EPA, 1983b)
Simmon, V.F., K. Kauhanen and R.C. Tardlff. 1977. Mutagenic activity of chemicals Identified In drinking water. In: Progress in Genetic Toxicology. (Cited In U.S. EPA, 1983b)
Simmon, V.F., H.S. Rosenkranz, E. Zelger and L.A. Poirier. 1979. Mutagenic activity of chemical carcinogens and related compounds In the Intraperltoneal host-mediated assay. J. Natl. Cancer Inst. 62: 911-918. (Cited In U.S. EPA, 1983b)
U.S. EPA. 1980a. Guidelines and Methodology Used In the Preparation of Health Effects Assessment Chapters of the Consent Decree Water Quality Criteria. Federal Register. 45:79347-79357.
-29-
SL 065495
U.S. EPA. 1980b. Ambient Water Quality Criteria for Dlchloroethylenes. Environmental Criteria and Assessment Office, Cincinnati, OH. EPA 440/5-80-041. NTIS PB 81-117525.
U.S. EPA. 1983a. Methodology and Guidelines for Reportable Quantity Deter minations Based on Chronic Toxicity Data. Prepared by the Environmental Criteria and Assessment Office, Cincinnati, OH, OHEA for the Office of Solid Waste and Emergency Response, Washington, OC.
U.S. EPA. 1983b. Health Assessment Document for Vlnylldene Chloride. Environmental Criteria and Assessment Office, Research Triangle Park, NC. EPA 600/8-83-031A. NTIS PB 84-126762.
Van't Hof, J. and L.A. Schalrer. 1982. Tradescantla assay systems for gaseous mutagens. A report of the-U.S. Environmental Protection Agency Gene Tox Program. Mutat. Res. 99(3): 303-315. (Cited In U.S. EPA, 1983b)
Velth, G.D., D.L. OeFoe and B.V. Bergstedt. 1979. Measuring and estimating the bioconcentration factors of chemicals In fish. J. Fish Res. Board Can. 36: 1040-1048.
Viola, P.L. and A. Caputo. 1977. Carcinogenicity studies on vlnylldene chloride. Environ. Health Perspect. 21: 45-47. (Cited In U.S. EPA, 1983b)
Waskell, L. 1978. Study of the mutagenicity of anesthetics and their metabolites. Mutat. Res. 57: 141-153. (Cited In U.S. EPA, 1983b)
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APPENDIX A Summary Table for 1,1-Dlchloroethylene
Species
Inhalation
AIS
AIC
Carcinogenic potency
mouse
Oral
AIS
AIC
Carcinogenic potency
NO = Not derived
Experimental Dose/Exposure
39.7 or 99.1 mg/ma
Effect
kidney adenocarcinomas
91*
ND ND
1.47x10"1 (mg/kg bw/day)1
ND ND ND
Reference
Maltonl et al., 1977, 1980; U.S. EPA, 1983b
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APPENDIX B1 Cancer Data Sheet for Derivation of q-|*
Compound: 1,1-dlchloroethylene Reference: Maltonl et al., 1980 Species, Strain, Sex: mice, Swiss, male Body weight: 0.03 kg (assumed) Length of exposure (le) = 52 weeks Length of experiment (Le) = 104 weeks Lifespan of animal (L) = 104 weeks Tumor site and type: kidney, adenocarcinoma Route, vehicle: Inhalation
Experimental Doses or Exposures (ppm)
0
10
25 .
Transformed Dose+ (ppm)
0
0.54
1.35
Incidence No. Responding/No. Tested
or Examined
0/126
0/25
28/119
+Total dose period = 1/2 total lifetime Unadjusted q-|* from study * 1.7xl0-1 (ppm)-1 Human q-j*=1.47xl0-1 (mg/kg/day)-1 (see Appendix B2)
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* *
APPENDIX B2 Calculation for q^*
Lifetime risk of cancer associated with 1 ppm, p: -0.17
p=1 -e For 1,1-dlchloroethylene: 1 wg/m3 = 0.25 ppm by the formula
C (mg/m3) = C (ppm) x MW (molecular weight ~of chemical) * 24.45 (moles/1 of air)
Lifetime risk of cancer associated with 1 mg/m3, p:
1_e-(0.17)(0.25) P=
4.2x10-2
(mg/kg/day) 1 = 70 kg x 4.2 x 10"2 * 20 mVday 1 mg/m3 * 0.147
where:
70 - assumed body weight of humans In kg
20 = human Inhalation rate In m3/day.
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