Document 6wQekbZ5xEDz4n1N1G3DBBR0g

American industrial hygiene association journal 57 641-649 (19961 louf C.ke*~txc<i ( f\a.y be. I'S^cJ /Vi HvZ ct,4~hxcbed Authors John Jankovic* Frances Drake6 'hzbles. A Screening Method for Occupational Reproductive Health Risk vitcr jnd Health Technical Mipport, Oak Ridge National 1 aPoraton. PO. Roc 2008. Oak Ridge. TN 37831-6292; Midivest Technical, Inc., Oak Ridge. TN 37830 Most currently recognized occupational exposure limits do not consider reproductive toxicological end points consistently when establishing recommended exposure limits in many cases the information is not available, but perhaps as often, existing data is not emoloyed. Further, many manufacturer's material safety data sheets omit reproductive hazard information A method for identifying potential reproductive toxins and screening levels for associated health risks useful for hazard communication and exposure control is presenred.To date, the Registry of Toxic Effects of Chemical Substances lists between 5000 and 6000 chemicals, drugs, and natural substances that show a positive outcome in at least 1 reproductive effects study. This reproductive health risk assessment began with these substances. Using elements of the Environmental Protection Agency's health risk assessment process, the list was reduced to 213 chemicals during the hazard identification step. Occupational reproductive guidelines (ORGs) were developed in the dose-response evaluation step. At the time of this writing, 85% of the chemicals identified in the hazard identification step have had a screening level dose-response assessment completed. Of these, 13% are greater than or equal to a threshold limit value (TLV).The remaining 87% do not have a TLV or ORGs below the TLV.The reproductive toxins list, along with the corresponding dose-response-derived ORGs that have been completed, appears at the end of the text. Keywords: exposure limits, hazard communication, material safety data sheets, reproductive hazards, reproductive toxins method for identifying potential reproduc point, csublishtng/adjusting occupational expo Ative toxins is presented in Figure 1. This sure guidelines, and controlling exposures below method is useful tor hazard communica these levels, the need for a special reproductive tion and in establishing guidelines for ex health program is eliminated. posure control. The objectives are to provide inBased on the current state of health protec formation on potential reproductive hazards thtiaotn legislation and scientific knowledge, such a safety and health professionals can use to estab method is timely and justifiable. The Occupa lish a healthful workplace tor all employees, re tional Safety and Health Administration l OSFLA) gardless of gender, and to protea all workers re requirements for employee hazard communica gardless of reproductive status. By treating repro tion include reproductive roxins in the definition ductive toxicity as any other toxicological end of "health hazard,'": yet according to a 1991 Government Accounting Office report, ' work ers, as well as the general public, remain inade Note: The term "reprodueme' mAsto-dewkymBiHl dfeen. A reproducw* treriewt is one that '`interim wnh rcprtxfcnwe or komI tunaxmng of the nafe or female finm puberty* through Kfaihtood. A devdopmaatamaK pmtacct an rfcct m the offipriflg fton amocp- tmn in pnblTtT TV-f~" maty (It Aaiti rtthr conxpOM(3>anmi abncmataMJ) daont pvmMod (4) ftmamnal dcfcfeocyL'W quately protected from reproductive hazards un der federal regulations. Although material safety data sheets are required for employee health pro tection in the workplace, these sheets generally do not provide reproductive hazard informa tion.14' Established occupational exposure limits - 1 CMS* A ir. tndiLtriil Hvgiene Association AIHA JOURNAL (57) July 1996 641 C M A 054594 The hazard identification process included the develop ment of the reproductive ravins list that was denved rfom the Registry of Toxic Effects of Chemical Substances iRTECSi database. RTECS, developed bv NIOSH, has toxicity informa tion on approximately 250.000 chemical subsrances. A search of the database for any substance with a positive outcome in at least one reproductive effects study \nelded more than 5500 substances. The list was nar rowed by a search for substances with positive outcomes in hu mans or more than one mam malian species via dermal expo sure, ingestion, or inhalation. The query refined the list to ap proximately 1000 drugs, chemi cals, and natural substances. This list was further reduced to only those substances believed to be important in an occupa tional setting, omitting sub stances used exclusively as drugs or hormones. The final repro- duenve toxins list consists of 213 potennal toxins. These were entered into a FoxPro data base (Table I). Dose-response assessment involved several assumptions. First was the assumption that reproductive effects have thres frequently do not take into eonsideraoon reproductive end points holds.'7' The assumption of a threshold underestimates the nsk for that are clearly below the thresholds established tor other toxic ef a toxin that does not have a threshold. An adjustment for this con fects. 7 cern was made in the case of transplacental carcinogens by the use There is a growing legal imperative tor nondisenminatory gen of an additional uncertainty factor of 10. der-neutral occupational health policy5' that is contrary to tradi The second assumption was that animal data is a reasonable hu tional reproductive health policy, which relies solely on pregnancy man predictor. This is based on the evidence from known human reporting and job reassignment as a means offetal protection. Such developmental toxicity, which in most cases demonstrates that an limited policy falls short of preventing harmful parental exposures imal data are predictive of human developmental effects." .An un that may adversely impact the health of the unborn child or the re certainty factor of 10 was used for animal-to-human extrapolation. productive capacity of adults. For ail of these reasons, this effort is Using a single positive animal study for initial inclusion in the data considered necessary. base is designed to minimize the possibility of missing a true hu man reproductive toxin, i.e., a false negative. Requiring posinvc ef fects in two or more species is an attempt to limit the number of METHODS potential false positives. The third major assumption was that absorption ofdose is com Creation of the reproductive toxins database required idennfication of potential reproductive toxicants, searching the literature plete regardless of the route of entry, and that the toxicity is unaltered.1*' This assumption frequently leads to an overesnmation of tor reproductive no-observed-advetse-effect levels (NOAEL) and the risk at a particular exposure level, and no uncertainty factor is lowest-observcd-adversc-effect levels ILOAEL) tor the reproduc applied for route-to-route extrapolation. Taken in total it is likdv tive toxicants, and determining corresponding occupational repro that these assumptions provide a reasonable margin of safer.-. ductive guidelines (ORG). Aspects of the Environmental Protec- Thtdose-response evaluation began with an examination ofcur uon Agencv's (EPA's) procedure for risk assessment were used for rent occupational exposure guides for established limits reported as hazard identificanon and dose-response assessment as applied in protective of reproductive health. If an exposure limit inclusive of the National Institute for Occupational Safety and Health reproductive health was found, it was adopted as the ORG for that (NIOSH) glycol ether criteria document. 6' ORGs were calculated substance and entered into the database. The references for occu using the uncertainty factor method.'71 pational limits included the American Conference of Governmental CMA 054595 Reproductive Toxin Guidelines* Chemical Name CasMe. 2,4-DDD 2.4,S-T 2,4,S*T, N-butyl ester 2,4-0 2,4-D butyl ester 2.4-D, isooctyl ester2-MePA Acetaldehyde Acetic acid, indolylAcetonitrile Acrolein AcrylamideQ Aflatoxin-B Alcohol, 2-ethylhexyl Alcohol, ethyl- Alcohol, methyl Aldnn Allyl chloride Aluminum-chlorideAmmonicotinamide Aminopteridine Amitrole Amudane Aroclor 1016 ^^^oclor 1254 ^^Proclor 1260 Arsenic (elmtl/organic) Atrazine BAPN BAPN Fumarate Baygon Benomyl Benzene Benzene, (epoxy ethyl)Benzimidazolecarbamic BenzolA (pyrene ^Bispheriof A Boric adid Butadiene, 1,3Butyl alcohol, tertButyromtrile, Cacodylic acid Cadmium Cadmium chloride Captan Carbaryl Carbofuran Carbon dioxide Carbon disulfide Carbon monoxide Cartap Chlorhydrin ^^hlorine dioxide ^Btloroamphenicol ^Chlorobenzene Chloroform Chloromethyl mercury 53-T9-0 93-76-5 93-79-8 94-75-7 94-80-4 25168-26-7 70657-70-4 75-07-0 87-51-4 75-05-8 107-02-8 79-06-1 1162-65-8 104-76-7 64-17-5 67-56-1 309-00-2 107-05-1 7446-70-0 329-89-5 54-62-6 61-82-5 126-07-8 12674-11-2 11097-69-1 11096-82-5 7440-38-2 1912-24-9 151-18-8 2079-89-2 114-26-1 17804-35-2 71-43-2 96-09-3 10605-21-7 50-32-8 80-05-7 10043-35-3 106-99-0 75-65-0 10232-92-5 75-60-5 7440-43-9 10108-64-2 133-06-2 63-25-2 1563-66-2 124-38-9 75-15-0 630-08-0 15263-52-2 96-24-2 10049-04-4 56-75-7 108-90-7 67-66-3 115-09-3 one* incomplete 0.18 mg/m' 0.18 mg/m1 1.50 mg/1%1 6.0 mg/m1 ' incomplete 7.06 mg/m1 14.4 mg/m1 6 mg/m1 22.7 mg/m1 0.12 mg/m1 0.03 mg/m1 incomplete 97.7 mg/m1 1880 mg/m1 262 mg/m1 0.012 mg/m1 3 mg/m1 0.36 mg/m1 0.02 mg/m1 1.2 pg/m1 0.2 mg/m1 0.75 mg/m1 1.4 pg/m1 1.4 pg/m1 1.4 pg/m1 05 pg/m1 2,1 mg/m1 0.68 mg/m3 0.68 mg/m1 03 mg/m1 0.30 pg/m1 0,05 mg/m3 0.78 mg/m1 incomplete 0.175 pg/m1 Cp.3 mcj/mO 1.5 mg/m1 0.26 mg/m1 106 mg/m1 incomplete 0.18 mg/m1 2 pg/m1 2 pg/m1 0.75 mg/m1 5 mg/m1 0.03 mg/m1 1800 mg/m1 8.4 mg/m1 14 mg/m1 incomplete incomplete 0.28 mg/m1 12 mg/m1 46 mg/m1 2.6 mg/m1 LOD Uf 100 100 100 100 100 100 100 100 100 NA 100 NA NA 1000 NA 100 1000 100 NA 1000 30 30 30 1000 100 1000 1000 NA 1000 1000 100 NA 1000 100 1000 100 1000 NA NA 100 NA 100 10 100 NA NA 100 NA 100 NA Endpoint1 R R R D 0 D D D D NA D NA NA D NA R D D NA D D 0 D D R D D NA R D 0 TC D R D D 0 NA NA 0 NA R D/R D D/R D D NA D NA CMA 054596 cr NA NA NA NA NA NA NA NA NA 220 NA NA NA 3.4 NA NA NA NA NA NA 3.3 3.3 3.3 4.7 NA NA NA NA NA 1.4 NA 1 NA NA 400 NA NA 8 NA NA NA NA NA NA NA NA NA NA 200 NA continued Chemical Name Coal-derived complex Cyclohexanone Cyclohexylamine Cyclophosphamide Cydophosphoramide DDT Diaminotoluene, 2, 4Diazinon Dibenzofuran, Dibromochloropropane Dichlorobenzene, p-O Dichlorvos Dicumarol Dieldrin Diethylene glycol Diethylstilbesterol Oifolatan Dimethoate Dimethyl-2-thiourea, Dimethylben2anthracene Dimethylformamide Dimethylurea, 1,3Dinocap Dinoseb C^joctylphthalateJ) DPPlT'--------- Disulfiram EGDME EGEE EGMBE EGME EGME, diEGMEA EGMEEA EGPE End rin Enflurane ____ pichlorhydrin Ergocalciferoi Ethyl methane sulfonate Ethylene dibromide Ethylene glycol Ethylene glycol diethyl Ethylene oxide Ethylene thiourea Ferbam Firemaster BP-6 Folpet Formamide Fungaflor Furlfuramide Gallium-arsenide rGIvcidol.J) Glycol ether Gossypol Halothane Hexachlorobenzene Cat No. None 108-94-1 108-91-8 50-18-0 51-18-0 50-29-3 95-80-7 333-41-5 57117-31-4 96-12-8 106-46-7 62-73-7 66-76-2 60-57-1 111-96-6 56-53-1 2425-06-1 60-51-5 534-13-4 57-97-6 68-12-2 96-31-1 39300-45-3 88-85-7 117-81-7 74-31-7 97-77-8 110-71-4 110-80-5 111-76-2 109-86-4 111-77-3 110-49-6 111-15-9 2807-30-9 72-20-8 13838-16-9 106-89-8 50-14-6 62-50-0 106-93-4 107-21-1 629-14-1 75-21-8 96-45-7 14484-64-1 59536-65-1 133-07-3 75-12-7 35554-44-0 3688-53-7 1303-00-0 556-52-5 111-46-6 303-45-7 151-67-7 118-74-1 0HG* 3 mg/m3 100 mg/m3 4,3 mg/m3 6 pg/m3 incomplete 0.01 -g/m3 0.11 mg/m3 1,08 pg/m3 incomplete 4 pg/m3 60 mg/m3 0.03 mg/m3 0.01 mg/m3 0.012 mg/m3 0.75 mg/m3 2 ng/m3 incomplete 036 mg/m3 incomplete 0.1 mg/m3 135 mg/m3 120 mg/m1 0.03 mg/m3 0.01 mg/m3 3 mg/m3 0.08 mg/m3 0.06 mg/m3 0.18 mg/m3 1.8 mg/m3 3.6 mg/m3 0.3 mg/m3 9 mg/m3 0.5 mg/m3 2.7 mg/m3 25.6 mg/m3 0.012 mg/m3 incomplete 1 pg/rrr 0.03 mg/m3 8 pg/m3 26 mg/m3 incomplete 1.8 mg/m3 0.30 mg/m3 6.84 mg/m3 1.4 pg/m3 6 mg/m3 5,22 mg/m3 0.60 mg/m3 1.8 mg/m3 incomplete i^5!09 mq/mQ 75 mg/m3 0.02 mg/m3 0.16 mg/m3 . 0.025 mg/m3 644 AIHA JOURNAL (57) fuly 1996 UF 1000 NA 25 1000 1000 1000 1000 1000 NA 1000 10 1000 1000 NA 100 10000 100 100 1000 1000 100 1000 100 1000 100 100 100 100 NA 100 100 1000 NA NA 10000 100 100 NA 100 100 30 10 100 100 10000 1000 10 100 1000 NA Endpoint1 D NA R D/R R R D R NA D D R D TC D R D D D D R D D D D D D D D D D R NA D/R R R R D D D D D R 0 R R 0 R D NA CMA 054597 CR 6300 NA NA NA 3 300 NA 7, NA NA NA 3, NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA 5.6 NA 600 10 NA NA NA NA NA NA NA NA NA NA 40 continued TABLE!, Reproductive Toxin Guidelines4 (continued) Chemical Name CasNe. OM* Hexachlorphene Hexane Hexanedione, 2,5Hydrazine Hydroxymethyl mercury Iodine Isocyanate, MethylKanechlor 500 Kepone Lead Lead acetate Lead, tetraethyl Lewisite Lindane Maneb Melamine, hexamethylMercury (II) chloride Mercury (II) oxide Mercury and compounds Methanesulfonic acid, Methotrexate Methoxychlor Methoxyflurane Methyl benzimidazole ^Blethyi chloride t~"\ ^Wfoethyl ethyl ketone) Methyl mercury Methyl metiram f Methylenechloride ^ Methylformamide, NMethylpyrrolidone, NMIBK Mintezol Mi rex Molybdenum Morpholine Mustard gas Nickel (II) chloride Nickel and compunds Nickel carbonyl Nicotine Nitrofen Nitrofurazone Nitrogen dioxide Nitrosamine. diethylNitrosamine, dimethylNitrosomethylurea Nitrotoluene. oNitrous oxide Oxygen Perchloroethylene Petroleum naphtha ^B|henol ^Phenylalanine nitrogen Phenylmercuric acetate Phosmet Phosphate, trimethyl- 70-30-4 110-54-3 110-13-4 302-01-2 1184-57-2 7553-56-2 624-83-9 61788-33-8 143-50-0 7439-92-1 301-04-2 78-00-2 541-25-3 58-89-9 12427-38-2 645-05-6 7487-94-7 21908-53-2 7439-97-6 66-27-3 59-05-2 72-43-5 76-38-0 1065-21-7 74-87-3 78-93-3 22967-92-6 8064-35-5 75-09-2 123-39-7 872-50-4 108-10-2 148-79-8 2385-85-5 7439-98-7 24602-86-6 505-60-2 7718-54-9 7440-02-0 13463-39-3 54-11-5 1836-75-5 59-87-0 10102-44-0 55-18-5 62-75-9 684-93-5 88-72-2 10024-97-2 7782-44-7 127-18-4 64742-95-6 108-95-2 148-82-3 62-38-4 732-11-6 512-56-1 0.6 mg/nr1 176 mg/m3 incomplete 0.006 mg/m3 LOD incomplete 0.002 mg/m3 1.4 pg/m3 incomplete 0.01 mg/m3 0.01 mg/m3 0.01 mg/m3 0.5 pg/m3 0.003 mg/m3 3 mg/m3 incomplete 0.01 mg/m3 0.01 mg/m3 0.01 mg/m3 incomplete 0.15 mg/m3 3.01 mg/m3 8.1 mg/m3 incomplete 4.65 mg/m3 590 mg/m3 LOD incomplete C2.4 mg/m3 _) 5.4 mg/mJ 0.91 mg/m3 205 mg/m3 0.6 mg/m3 incomplete incomplete incomplete 0.003 mg/m3 0.01 mg/m3 0.01 mg/m3 0.01 mg/m3 0.01 pg/m3 10 pg/m3 0.09 mg/m3 0.18 mg/m3 7 ng/m3 0.02 |ig/m3 0.4 pg/m3 incomplete 90 mg/m3 ppOj 148 mm Hg 11.87 mg/m3 12 mg/m3 3.6 mg/m3 incomplete LOD 0.01 mg/m3 0.60 mg/m3 Uf 100 NA 1000 NA 1000 30 1000 1000 1000 1000 1000 NA NA NA NA 100 10 100 100 NA NA 100 10 1000 NA 100 Endpoint' D NA D NA D D D D D D R D NA NA NA D R D R NA NA R D D NA D CR NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA 14 NA NA NA NA 1000 100 100 100 100 100 1000 10 NA NA 10000 NA NA 100 100 100 NA 1000 1000 R R R R D D R R TC TC TC NA D R D D NA D R CMA 054598 NA NA 8 NA NA NA NA NA 1 1 NA NA NA 20 NA NA NA NA NA continued TABLLl. Reproductive Toxin Guidelines* (continued) Oitmicif Nam* Cos Ho. OK* UF Endpoint' CR Phthalate, dibutyl- 84-74-2 0.72 mg/m3 1000 D NA Piperonyl butoxide 51-03-6 0.90 mg/m3 1000 R NA Polybrominated biphenyl 67774-32-7 1.4 pg/m3 30 D NA Polychlorinated biphenyl 1336-36-3 1.4 qg/m3 30 0 3.3 Potassium iodide 7681-11-0 1.0 mg/m3 NA NA NA Propionic acid, 120-36-5 incomplete Resorcinol methyl ether 150-19-6 incomplete Ronnel 299-84-3 0.08 mg/m3 1000 0 NA Sodium arsemte 7784-46-5 0.01 mg/m3 NA NA 100 Sodium chlorite 7758-19-2 6.84 mg/m3 1000 D NA Sodium fluoride 7681-49-4 2.5 mg/m3 NA NA NA Sodium iodide 7681-82-5 1 mg/m3 NA NA NA Sodium nitrite 7632-00-0 incomplete Sodium selenate 13410-01-0 incomplete Sodium selenite 10102-18-8 incomplete C Styrene -- TTJO-42-5 85 mq/m3 "'y NA D 0.3 Sulfur dioxide ~~ 7446-09-5 2.3 mg/m* 100 D NA TCDD 1746-01-6 incomplete TEG 112-27-6 338 mg/m3 100 D NA TEGDiME 112-49-2 75 mg/m3 10 D NA Tetraglyme 143-24-8 3.6 mg/m3 NA NA NA Tetrahydrofuran 109-99-9 590 mg/m3 NA D NA Thiadiazole, 26907-37-9 4 pg/rn3 100 D NA Thiourea 62-56-6 6 mg/m3 1000 D NA Thiram 137-26-8 0.16 mg/m3 1000 D NA Toluene 108-88-3 9.6 mg/m3 10 D NA Toluenediamine, o- 95-80-7 1.8 mg/m3 100 D NA Toluenesulfonamide, o- 88-19-7 2.4 mg/m3 100 D NA Toxaphene 8001-35-2 0.02 mg/mJ 1000 D 20 Tributyl tin oxide 56-35-9 incomplete Trichlorfon 52-68-6 0.48 mg/m3 100 0 NA Trichloroethylene 79-01-6 5.5 mg/m3 100 0 NA Tridiphane 58138-08-2 0.02 mg/m3 500 R NA Triethylenemelamine 51-18-3 60 ng/m3 10000 R NA T riethy lenetetramine 112-24-3 2.9 mg/m3 . 10 D NA Trifluralin 1582-09-8 3 mg/m3 1000 D NA Urethane 51-79-6 6 mg/m3 1000 D NA / Vinyl chloride 753JT3-------------- 4 ug/nvX NA TC 1 Vinylidene chloride 75-35-4 14 mq/m3 ) 10 D NA Warfarin 81-81-2 10pg/mJ 10 D NA Xylene, o-, m-, p- 1330-20-7 1.5 mg/m3 10 D NA Zinc sulfate 7733-02-0 2 mg/m3 1000 D NA * These exposure guidelines have been derived from a screening level of risk assessment and should not be construed as unequivocally safe exposure limits. 9 ORGs represent 8 hour time-weighted averages unless otherwise noted. c D = Developmental: R = reproductive: TC - transplacental carcinogen: CR * cancer nsk/10,000; UF " uncertainty factor; = TLV believed to be adequate to protect reproductive health; LOD - limit of detection Industrial Hygienists' Documentation of Threshold Limit Values, OSHA substance-specific standards permissible exposure limits, I PELs), the German Maximum Concentrations in the Workplace0 (MAKs), and NIOSH recommended exposure limits (RLs). If an exposure limit was not found, the literature was searched for a NOAEL or LOAEL with a reproductive end point. The search for information on the NOAEL/LOAEL consisted of studies from peer-reviewed literature found in the following databases: Hazardous Substances Database,1'" TOXLINE,"01 NIOSHTIC. REPROTOX,ljl and IRIS.131 Human data were preferred for the NOAEL/LOAEL, but in the majority of cases quantitative human exposure data were not available. If human data were not found, NOAELs/LOAELs obtained from animal studies were used, typically employing the most sensitive end point from the most sensitive mammalian species. If inhalanon data were unavailable, ingestion studies or dermal studies were used. The NOAEL or LOAEL was converted to a value for hu mans using the calculations employed by NIOSH'6' and IRIS, i.e., scaling the NOAEL or LOAEL to a human equivalent aj * aiua tnnpNii isti t,,iv iqox, CMA 054599 Jose and dividing by a combined uncertainty factor, including a ^10 tor vanabilitv m human susccpnbilirv. For inhalation data the absorbed animal dose was determined using the average animal bodv weights and inhalation rates described in EPA's Toxicology Handbook. H' Absorbed animal dose (inhalation) tor reproductive end points; img kg'dav) = NOAEL (mg/m3) inhalation rate (m Vdav) exposed hours X xr animal body weight i kg; 24 hours The absorbed animal dose was converted to an equivalent hu man concentration bv assuming a 60-kg body weight (average fe male weight1' i and a 10-rm inhalation rate tor an 8-hour workda\ The average female body weight was used, as it results in a more conservative ORG. Equivalent exposure tor humans: The lifetime cancer risk was included to provide a companson berween the reproductive guideline and the cancer nsk at that level. For substances listed by the World Health Orgamzauon;o as transplacental carcinogens in animals, the ORG was established based on the exposure corresponding to an occupational lifetime nsk of l in 10,000 when an EPA slope factor was available. This nsk was chosen to represent a level equated with the nsk of mor tahtv from work in the retail clothing sector.15 If a slope factor w as unavailable, the ORG was calculated using the uncertainty factor method with an added uncertainty factor of 10 for the nonthreshold possibility extant with transplacental carcinogenesis. Unit risk per pg/m3 _ slope factor per mg/kg/dav x 10 mVdav body weight (60 kg) x 1000 pg/mg , 3 (10-4) x (70vrs.) pg/m = ------------------------- -----------------z (40 vrs) x unit nsk per pg/m i mg/m' absorbed dose for animals i mg/kg/day) x 60 kg 10 m3/dav When oral or dermal animal data was used, it was converted to an equivalent human airborne concentration by assuming a 60-kg bodv weight and a 10-rm inhalation rate. Equivalent exposure tor humans (oral and dermal): . ,J 60 kg (mg/m = mg/kg/dav x -----s---- 5 5 6 10 m /day The equivalent exposure for humans was then divided by an un certainty factor to obtain the ORG: _ equivalent exposure for humans uncertaintv factor An example of a reproductive toxins database record is depicted in Figure 2. Fields includes chemical name, CAS number, update code, class of chemical compound, animal species with positive re productive studies, ORG, UF, end point, and the cancer risk asso ciated with the ORG (if an EPA unit risk was available). A memo field containing descriptive information on human and animal repreductive/developmental data along with the information used tor establishing the ORG (including the uncertainty factors) was also included. Substances may be added, selected for a screening assessment, or deleted from the database on the basis of new in formation. A copy of the database including the ORG list and the descrip tive memo field is available by sending two floppy disks and a selfaddressed envelope to the authors. The multiplicative uncertainty factors1''1 included 10 for most sensitive human. 10 tor animal to human extrapolation, 10 for use of a LOAEL, 10 for inadequate study design and a possible modi fying factor of 0.1 for a high animal dose (>1000 mg/kg/day),'171 and 0,1 for an animal study with effects seen only at maternally toxic doses. The modifying factor for studies reporting develop mental effects only at maternally toxic doses was included since "ad\ ersc effects on development that occur only with maternal toxicity mav not indicate a specific hazard to the conceptus" and thus are not as great a concern.1111 The uncertainty factors (UF) applied in each ORG determmaoon are included in the list at the end of this article. For carcinogens with slope factors published by EPA,1191 an up per bound estimate of the cancer risk expected over a lifetime of occupational exposure at the ORG was determined using the fol lowing calculations. Unit risk per pg/m3 = slope factor per mg/kg/day x inhalation rate (10 m3/day) body weight (60 kg) x 1000 pg/mg Lifetime cancer nsk = exposure ar ORG (pg/m3) x 40 vrs X unit risk per pg/m3 70 yrs Discussion The purpose of this study was to provide a frame of reference tor reproductive health protection in the workplace regardless of gen der or reproductive status. The safety of the workplace depends on hazard identification followed by exposure control below an estab lished limit, and these limits should protea workers from all adverse effects, including reproductive effects. While ORGs do not represent consensus standards or limits, they are based on reproductive end points. ORGs can be used to flag potential reproductive toxicity concerns for workers at the levels listed. As stated earlier, where a TLV is believed to be protective of reproductive effects, it is used as the ORG. The assumption that other nonreproductive effects are automatically safeguarded at a particular ORG or TLV is not jusofied. As a case in point, consider carcinogens. Of 28 substances for which cancer nsk could be estimated, 84% (26/31) of the corre sponding ORGs equated to a cancer nsk in excess of 1 in 10,000; some consider risk above this level unacceptable. The study has generated a database consisting of 213 poten tial reproductive toxins. The majority of the substances have as sociated ORGs based on animal reproductive NOAELs or LOAELs. As expeaed, there are differences between the ORGs and existing TLVs. At this time 85% (180/213) of the dose/re sponse determinations have been completed; of these, 47% (85/180) do not have established TLVs. For substances with TLVs, 25% (24/95) have established limits equal to or lower C M A 054000 j CAS NO: 67-56-1 Ud; 9509 ! Chemtype: ACDMST Species: Rat Mus ORG: 262 mg/m3 UF: NA--TLV believed to be protective i CA-RISK/1E4: NA ENDPOINT: D PROFILE: METHYL ALCOHOL PHYSICAL DATA: MW: 32.04; Physical state: liquid: VP: i 96 mm Hg at 20C. I OCCUPATIONAL STANDARDS: ACGIH 262 mg/m3; NIOSH 260 mg/m3: MAK 260 mg/m3. Group D. | "Classification in a pregnancy group is not yet possible." | PPE: Material is toxic via skin absorption. Therefore, skin contact must be prohibited or else the ORG is invalidated. Butyl Rubber and Saranex are best PPE materials. Natural Rubber. Nitrile Rubber, PVAL, and PVC are not recommended. ANIMAL DATA: Rogers, et al.. reported two studies in mice with inhalation doses of MeOH at 5000 and 10,000 ppm (study 1) and 2000 and 5000 ppm (study 2) for 7 hours a day on days 6 through 16 of gestation. In both studies the 5000 ppm exposure produced exencephaly in one-third of the fetuses. At 2000 ppm. 1 of 220 fetuses had exencephaly. Controls had no incidence of exencephaly in the offspring. (Rogers, Toxicologist, 11(l):344, 1991). In a more recent study, Rogers exposed mice to 1000, 2000, 5000, 7500, 10,000, or 15,000 ppm methanol for 7 hrs/day on days 6-15 of gestation. The NOAEL for developmental toxicity was reported at 1000 ppm (1310 mg/m3). A dose-related increase in cervical ribs was significant at the 2000 ppm level. Increased exencephaly and cleft palate were reported at 5000 ppm, and increased embryo/fetai death at 7500 ppm (Rogers, et al.. Teratology. Mar; 47(3), pp: 175-88. 1993). Rais have been found to be less sensitive than mice to the developmental effects of methanol, with effects seen only at 10,000 ppm and above (Rogers, Toxicologist. Mar: 13(1). pp:13. 1993). ORG RECOMMENDATION: Using the NOAEL of 1000 ppm (1310 mg/m3), the ORG is 458.5 mj/m when an uncertainty factor of 10 is applied (10 for most sensitive human. 10 for animal extrapolation, and 0.1 as a modifying factor for the high dose). Since the calculated ORG is above the TLV, the TLV of 262 mg/m3 is accepted as the ORG as protective of reproductive effects. FIGURE 2. Example ofa database r*terd than the calculated ORG and were assumed adequate tor protec tion of reproductive effects, leaving 75% that have established limits grearer than the ORG. Overall, 87% (156/180) of the sub stances identified by the dosc/response portion of this assess ment method have inadequate reproductive exposure limits. As expected, animal data make up the majorin' of the available toxi cological information, although 9% (17/180) of the ORGs are based on human data. Several limitations to this method must be recognized. The two major categories of limitations are lack or information on specific chemicals and inadequate mechanistic models useful in extrapolating from animals to humans. The identification process of potential reproductive toxins is limited by the amount of currently available toxicological data on repro ductive effects. If, during the literature search, insufficient data is found on the reproductive effects of a substance, this is reported in the memo field. RTECS is used as a primarv data source due to its comprehensive inclusion of positive data. However. RTECS docs not report negative studies, which limits the documentation available for a weight of evidence approach to substance selection or elimination. Another problem frequently encountered is the difficulty in finding certain citations, especially foreign citations Less frequently encountered, but just as limiting, a citation is lo cated that does not include a dose level from which to calculate an ORG. The ORGs presented are based on the most sensitise (lowest) reproductive NOAEL/LOAEL discovered using the sources referenced earlier, A reasonable effort was made to locate the best available information. Beyond this no claim or s eracitv is made. The majority of the available reproductive data used in es tablishing human inhalation ORGs is from oral studies in ani mals. The difficulties with extrapolation between species and routes of exposure arc frequently discussed in the literature. In the absence of human data or mechanistic models the usual al ternative is to appiy uncertainty factors for the various assump tions inherent in the assessment. Conclusion This study presents information on reprodueme exposureguides on which to base hazard assessment and make in formed decisions on the need for exposure control. In most cases, the ORGs have been derived from a screening level of risk assessment and should not be construed as uncquivocallv safeexposure limits. It is hoped that thev will serve as a catalyst and forum for further debate resulting in refinements that will en hance occupational health without being unnecessarily burden some. REFERENCES 1. Office of Technology Assessment Task Force: Reproductive Health Hazards tn the Workplace. Philadelphia, PA: J.B. Lippincurt Co., 1988. pp 6, 55. 2. "Labor," Code ofFederal Regulations Title 29, Pt. 1910.1200 1989 pp 354-355. 3. United States General Accounting Office: Reproductive and Develop mental Toxicants. Regulator* Actions Provide Uncertain Protection (GAO/PEMD-92-3). Washington DC, October 1991. pp. 2-3 4. Paul, M. and S. 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