United States Environmental Protection FCAO C)w ^T^ A9encv January, 1986 &EPA Research and Development VERIFIED REFERENCE DOSES (RfDs) OF THE U.S. EPA Prepared for THE RISK ASSESSMENT FORUM AND THE RISK ADVISORY GROUP Prepared by THE ADI WORK GROUP OF THE RISK ASSESSMENT FORUM ------- DISCLAIMER Mention of trade names or commercial products does not constitute endorsement or recommendation for use. AVAILABILITY NOTICE For Information contact Dr. Peter Preuss, Acting Director, Office of Health and Environmental Assessment, Office of Research and Development, Washington, DC (202/382-7317). 11 ------- FOREWORD As of May 1, 1985, the Age icy established a group of scientists familiar with the development of reference doses (RfDs) under the direction of Dr. Peter Preuss, Acting Director of the Office of Health and Environmental Assessment of the Office of Research and Development. The purpose of this group 1s to verify existing Agency RfDs and to resolve conflicting values within the Agency. The current procedure to accomplish these tasks 1s a biweekly meeting of scientists from within the Agency. A file 1s created for each chemical that Includes the critical reference, the supporting studies, the U.S. EPA docu- ment that describes the calculation of the RfD, and a two page cover form that summarizes the RfD, the chosen critical toxic effect, the chosen uncertainty factors, and statements concerning the confidence in the data base, the critical study, and the RfD. The jgroup has discussed 144 RfDs. This package reflects the first 65 of these values that were verified. Complete files are available on all RfDs that have been discussed. The files consist of: 1. A cover form (one to several pages) that summarizes Information pertinent to the development of an RfD, such as the chosen effect levels and uncertainty factors, and statements of confi- dence In the RfD, the chosen study and the associated data base 2. The U.S. EPA documentation that supports the RfD 3. The critical study from which the chosen effect level 1s taken and 4. Supporting literature. 111 ------- OUTLINE I. CAS NO. LISTING OF CHEMICALS FOR WHICH RfDs HAVE BEEN VERIFIED II. ALPHABETICAL LISTING OF CHEMICALS FOR WHICH RfDs HAVE BEEN VERIFIED III. COVER FORMS FOR CHEMICALS ------- LIST OF ABBREVIATIONS ACGIH American Conference of Governmental Industrial Hyg1en1sts ADI Acceptable dally Intake AEL Adverse-effect level bw Body weight CAS Chemical Abstract Services CAG Carcinogen Assessment Group cu. m Cubic meter PEL Frank-effect level g Gram l.p. Intraperltoneal kg Kilogram L Liter LOAEL Lowest-observed-adverse-effect level LOEL Lowest-observed-effect level MF Modifying factor mg Milligram MTD Maximum tolerated dose NIOSH National Institute for Occupational Safety and Health NOAEL No-observed-adverse-effect level NOEL No-observed-effect level NTP National Toxicology Program RfD Reference dose s.c. subcutaneous TLV Threshold limit value UF Uncertainty factor ug Mlcrogram ------- CAS No. Listing of Chemicals for Which RfDs Have Been Verified Chemical CAS No. Chemical CAS No. Carbon TetrachloMde CAS: 56-23-5 Cyanides CAS: 57-12-5 Strychnine CAS: 57-24-9 2,3,4,6-Tetrachlorop'henol CAS: 58-90-6 Dlmethoate CAS: 60-51-5 Phenyl Mercuric Acetate CAS: 62-38-4 Carbaryl CAS: 63-25-2 Formic Add CAS: 64-18-6 Hydrogen Cyanide CAS: 74-90-8 Methylene Chloride CAS: 75-09-2 Carbon Dlsulflde CAS: 75-15-0 Cacodyllc Acid CAS: 75-60-5 TMchlorofluorome thane CAS: 75-69-4 D1chlorod1fluoromethane CAS: 75-71-8 l,l,2-Tr1chloro-l,2,2-tr1fluoroethane CAS: 76-13-1 Tetraethyl Lead CAS: 78-00-2 Methyl Ethyl Ketone CAS: 78-93-3 Acrylic Acid CAS: 79-10-9 Pentachloronltrobenzene (PCNB) CAS: 82-68-8 Pentachlorophenol CAS: 87-86-5 Dlnoseb CAS: 88-85-7 MCPA CAS: 94-74-6 2,4-DB CAS: 94-82-6 1,2-D1chlorobenzene CAS: 95-50-1 2,4,5-TMchlorophenol CAS: 95-95-4 Nitrobenzene CAS: 98-95-3 Ethylbenzene CAS: 100-41-4 Toluene CAS: 108-88-3 -1- ------- Chemical CAS No. Chemical CAS No. Chlorobenzene CAS: 108-90-7 Phenol CAS: 108-95-2 Pyrldlne CAS: 110-86-1 Malathlon CAS: 121-75-7 Tetrachloroethylene CAS: 127-18-4 Sodium Cyanide CAS: 143-33-9 Potassium Cyanide CAS: 151-50-8 Llnuron CAS: 330-55-2 Cyanogen Cyanide CAS: 460-19-5 Calcium Cyanide CAS: 502-01-8 Potassium Silver Cyanide CAS: 506-61-6 Silver Cyanide CAS: 506-64-9 Chlorine Cyanide CAS: 506-77-4 Barium Cyanide CAS: 542-62-1 Copper Cyanide CAS: 544-92-3 Nickel Cyanide CAS: 557-19-7 Z1nc Cyanide CAS: 557-21-1 Thallium Acetate CAS: 563-68-8 Mercury Fulminate CAS: 628-86-4 Selenourea CAS: 630-10-4 Thalllc Oxide CAS: 1314-32-5 Cresols CAS: 1319-77-3 Methyl Ethyl Ketone Peroxide CAS: 1338-23-4 Thallium Carbonate CAS: 6533-73-9 Mercury (Inorganic) CAS: 7439-97-6 Barium CAS: 7440-39-2 Thallium Sulfate CAS: 7446-18-16 Fluoride (fluorine) CAS: 7782-41-4 -2- ------- Chemical CAS No. Chemical CAS No. Selenlous Add CAS: 7783-00--8 Hydrogen Sulflde CAS: 7783-06-4 Thallium Chloride CAS: 7791-12-0 Phosphlne CAS: 7803-51-2 Nitrogen Oxide CAS: 10102-43-9 Nitrogen Dioxide CAS: 10102-44-0 Thallium NHrate CAS: 10102-45-1 Thallium Selenlte CAS: 12039-52-0 Aluminum Phosphide CAS: 20859-73-8 -3- ------- Alphabetical Listing of Chemicals for Which RfDs Have Been Verified Chemical Chemical Acrylic Acid Aluminum Phosphide Barium Cyanide Barium Cacodyllc Acid Calcium Cyanide Carbaryl Carbon Dlsulflde Carbon Tetrachlorlde Chlorine Cyanide Chlorobenzene Copper Cyanide Cresols Cyanide (free) Cyanogen 2,4-DB l,2-D1chlorobenzene Dlchlorodlfluoromethane Dlmethoate Dlnoseb Ethylbenzene Fluoride (Fluorine) Formic Add Hydrogen Cyanide Hydrogen Sulflde Unuron Malathlon MCPA Mercury Fulminate Mercury (Inorganic) Methylene Chloride Methyl Ethyl Ketone Methyl Ethyl Ketone Peroxide Nickel Cyanide NUrlc Oxide Nitrobenzene Nitrogen Dioxide Pentachloronltrobenzene (PCNB) Pentachlorophenol Phenol Phenyl Mercuric Acetate Phosphlne -4- ------- Chemical CAS No. Chemical Potassium Cyanide Potassium Silver Cyanide Pyr1d1ne Selenlous Add Selenourea Silver Cyanide Sodium Cyanide Strychnine Tetrachloroethylene 2,3,4,6-Tetrachlorophenol Tetraethyl Lead ThalUc Oxide Thallium Acetate Thallium Carbonate Thallium Chloride Thallium Nitrate Thallium Selenate Thallium Sulfate Toluene Trlchlorofluoromethane 2,4,5-TMchlorophenol l,l,2-Trlchloro-l,2,2-tr1fluoroethane Zinc Cyanide -5- ------- REFERENCE DOSES (RfDs) FOR ORAL EXPOSURE Chemical: Acrylic Acid Carclnogenlclty: None. Systemic ToxIcHy: See below. CAS #: 79-10-7 DePass Endpolnt et al. (1983) Experimental Doses 83 mg/kg/day UF 1000 MF RfD (ADI) 0.08 mg/kg/day NOAEL Rat oral subchronlc study (drinking water) or 6 mg/day for a 70 kg man Reduced body weights 250 mg/kg/day altered organ weights (LOAEL) Endpolnt and Experimental Doses: DePass, L.R., M.D. Woodslde, R.H. Garman and C.S. Hell. 1983. Subchronlc and reproductive toxicology studies on acrylic add 1n drinking water of the rat. Drug Chem. Toxlcol. 6(1): 1-20. In this subchronlc study acrylic add was Incorporated Into the drinking water of rats (15/group/sex) for 3 months at doses of 750, 250, 83 and 0 mg/kg/day. At the high (750 mg/kg) and middle (250 mg/kg) dose levels reduc- tion In body weight and changes In organ weights were observed. These effects coincided with a dose-related reduction 1n food and water consumption. At the 83 mg/kg dose the only effect was a reduction In water consumption. No sig- nificant treatment-related hlstologlcal effects were seen at any dose level. A NOAEL of 83 mg/kg was established In this study. In a short-term Inhalation study (Gage, 1970) no adverse effects were observed 1n eight rats exposed to 80 ppm (about 240 mg/cu. m) acrylic acid, 6 hours/day, 5 days/week for 4 weeks. This exposure Is approximately equivalent mg/kg/day (I.e., 240 mg/cu. m x 0.223 cu. m/day x 6 days x 0.5/1.0 / 0.35 = 14 mg/kg/day). Eight rats 51 mg/kg/day) experienced nose Irritation, lethargy Hlstologlcal and hematologlcal examinations were shorter periods of time resulted In liver, kidney to an oral exposure of 14 hours/24 hours x 5 days/7 exposed at 300 ppm (about and reduced weight gain. normal. Higher doses for and lung damage. Preparation Date: 01/09/86 0420P -1- 01/11/86 ------- Endpolnt and Experimental Doses (cont.): The subchronlc oral study of DePass et al. (1983) appears to be the most appropriate for deriving an ADI, 1n view of the limited data available. Uncertainty Factors (UFs): Using the NOAEL of 83 mg/kg/day and aplylng an uncertainty factor of 1000, (10 to account for subchronlc to chronic conversion, 10 for Intraspedes extrapolation and 10 to protect sensitive Individuals) an ADI of 0.08 mg/kg/ day or 6 mg/day was derived. Modifying Factors (MFs): None. Additional Comments: No oral chronic data are available. Confidence In the RfD: Study: Medium Data Base: Low RfD: Medium The confidence In the study 1s medium because of the number of animals/ dose used, several parameters were studied, and a good dose-severity was obtained. The confidence In the data base 1s low because of the general Jack of supporting studies. The overall confidence In the RfD 1s rated medium to low. Documentation of RfD and Review: ECAO-Clnclnnatl Internal Review, August 1985. U.S. EPA. 1985. Acrylic Add: Review and Evaluation of ADI. Contract No. 68-03-3228. Environmental Criteria and Assessment Office, Cincinnati, OH. Agency RfD Review: First Review: 08/19/85 Second Review: Verification Date: 08/19-/85 U.S. EPA Contact: Primary: C.T. DeRosa FTS/684-7534 or 513/569-7534 Secondary: M.L. Dourson FTS/684-7544 or 513/569-7544 0420P -2- 01/11/86 ------- REFERENCE DOSES (RfDs) FOR ORAL EXPOSURE Chemical: Aluminum Phosphide CarclnogenlcHy: None. Systemic Toxlclty: See below. CAS #: 20859-73-8 Endpolnt Experimental Doses UF MF RfD (ADI) Hackenburg (1972) Rat chronic oral study Body weight and clinical parameters 0.0004 mg/kg/day or 0.03 mg/day for a 70 kg person 0.51 mg/kg of food 100 or 0.025 mg/kg/day (phosphlne) con- verted to 0.043 mg/ kg/day aluminum phosphide (NOAEL) Conversion Factors: Food consumption: 5% bw; molecular weight: A1P/PH3: x 57.95/34.0 thus, 0.51 mg/kg of food x 0.05 kg food/kg bw/day x 57.95/34.0 = 0.043 mg/kg/day Endpolnt and Experimental Doses: Hackenburg, U. 1972. Chronic 1ngest1on by rats of standard diet treated with aluminum phosphide. Toxlcol. Appl. Pharmacol. 23(1): 147-158. Aluminum phosphide pellets and tablets (Phastoxln) are used as fumlgants for wheat and other grains (D1eter1ch e't al., 1967). Upon exposure to mois- ture In the air, they Immediately decompose to phosphlne gas, with little trace residue of phosphide remaining, which could be lost In handling of the grain. A chronic feeding study of aluminum phosphide-fumigated chow fed to 30 rats/sex was conducted by Hackenburg (1972). The average concentration was 0.51 mg phosph1ne/kg food for a 2-year period. At the end of the treatment period, there were no differences between treated and control rats 1n blood or urine chemistry, hlstologlcal parameters. The phosphlne gas measured In the Hackenburg (1972) study was liberated by decomposition of aluminum phosphide pellets. Acute toxlclty data generated (Sax, 1984) suggest that the phosphide moiety contributes the most to the Preparation Date: 01/06/86 0420P -1- 01/11/86 ------- Endpolnt and Experimental Doses (cont.): acute toxUHy of this compound as opposed to any deleterious effect due to aluminum cation. The steep slope of the dose-response curve of phosphlne gas (KHmmer, 1969) Implies that phosphlne 1s extremely hazardous at doses slightly above a NOEL. Therefore, It 1s appropriate to derive an ADI for aluminum phosphide based' upon the ADI for phosphlne. Uncertainty Factors (UFs): After correcting for the molecular weight of aluminum phosphide relative to that of phosphlne (57.95/34.00). and by application of an uncertainty factor of 100 (10 for Interspedes conversion and 10 for sensitive popula- tion), an ADI for aluminum phosphide of 0.00043 (0.00025 mg/,kg/day phosphlne x 1.70) can be derived. Modifying Factors (MFs): None. Additional Comments: The ACGIH (1984) has recommended a TLV of 0.3 ppm (0.42 mg/cu. m) for phosphlne, based principally upon an ep1dem1olog1cal study by Jones (1964) where workers were exposed Intermittently to about 10 ppm phosphlne gas. Based on this TLV an ADI of 0.0021 mg/kg/day (I.e., 0.42 mg/cu. m x 10 cu. m/day x 5 day/7 day x 0.5/70 kg/10 = 0.0021 mg/kg/day) can be derived. How- ever, an ADI for phosphlne of 0.00025 mg/kg/day based on the 2-year rat study by Hackenburg (1972) (described above) has been derived for providing adequate protection against adverse human health effects. Confidence In the RfD: Study: High Data Base: High RfD: High The confidence 1n the study was rated high because of the moderate number of animals/dose, the extensive methodology employed to assure proper admin- istration of the test compound, and the extensive number of parameters mea- sured. The data base was rated high because the effectiveness and safety of this chemical has been long reported through supporting studies. The overall rating for the RfD 1s, thus, high. 0420P -2- 01/11/86 ------- Documentation of RfD and Review: ECAO-C1nc1nnat1 Internal Review, August 1985. U.S. EPA. 1985. Aluminum Phosphide: Review and Evaluation of ADI. Contract No. 68-03-3228. Environmental Criteria and Assessment Office, Cincinnati, OH. Agency RfD Review: First Review: 08/19/85 Second Review: Verification Date: 08/19/85 U.S. EPA Contact: Primary: C.T. DeRosa FTS/684-7534. or 513/569-7534 Secondary: M.L. Dourson FTS/684-7544 or 513/569-7544 0420P -3- 01/11/86 ------- REFERENCE DOSES (RfDs) FOR ORAL EXPOSURE Chemical: Barium Cyanide Cardnogenlclty: None. Systemic ToxUHy: See below. CAS #: 542-62-1 Endpolnt Experimental Doses UF MF RfD (ADI) Perry et al. (1983) Rat oral chronic study Hypertension 10 ppm barium 1n 100 drinking water (NOAEL) 0.07 mg/kg/day or 5 mg/day for a 70 kg man 100 ppm (LOAEL) estimated as 5.1 mg/kg/day (U.S. EPA, 1985) converted to 7 mg Ba (CN)2 Conversion Factor: Exposure dose was based on U.S. EPA (1985) estimate; molecular weight ratio of Ba(-CN)2/Ba 1s 189/137; thus, 5.1 mg/kg/day x (189/137) = 7 mg/kg/day Endpolnt and Experimental Doses: Perry, H.H., E.F. Perry, M.N. Erlanger effects of chronic barium Ingestlon. stances 1n Environmental Health, Vol. Columbia, MO. p. 155-164. and S.J. Kopp. 1983. Cardiovascular In: Proc. 17th Ann. Conf. Trace Sub- 17. University of Missouri Press, Perry et al. (1983) exposed 10 female rats/group to 0, 1, 10 or 100 ppm barium. 1ji drinking water for up to 16 months. Barium exposure produced no change In growth rate, and no evidence of toxldty was recognized. Limited and preliminary physiologic and biochemical parameters, such as, myocardlal pathophyslology and disturbances In myocardlal metabolism were significantly depressed 1n rats exposed to 100 ppm barium (Perry et al., 1983; Kopp et al., 1985). In addition, rats from this exposure group showed Increased average systolic blood pressure (16 mm Hg average elevation). Preparation Date: 01/09/86 0420P -1- 01/11/86 ------- Endpolnt and Experimental Doses (cont.): A moderate Increase (6 mm Hg) 1n systolic blood pressure was observed In rats exposed to 10 ppm barium; however, the U.S. EPA (1985) determined that the Increase seen after 16 months 1s not large enough to constitute an adverse health effect. Brennlman et al. (1979, 1981) reported a significant Increase In death rate for cardiovascular diseases 1n communities whose water supply contained an average of 7 mg Ba/L, compared with communities whose water supply con- tained an average of 0.1 mg Ba/L. The exposure levels tested 1n these studies did not evaluate a continuous range of exposure to barium and so, although a NOEL may well have been Identified, It 1s Impossible to Identify the highest NOAEL within the framework of their experimental designs. Uncertainty Factors (UFs): The U.S. EPA (1985) justified the use of an uncertainty factor of 100 (10 for Interspecles extrapolation and 10 for sensitive population) to the esti- mated dose of 5.1 mg/kg/day barium on the grounds that the rats 1n Perry et al. (1985) study were exposed to very low levels of all essential metals (specifically calcium). Modifying Factors (MFs): None. Additional Comments: If an ADI for barium cyanide Is based on cyanide (0.02 mg/kg/day CN/6.28, % CN) an ADI of 0.08 mg/kg/day for barium cyanide would result In a dally Intake of 0.06 mg/kg/day of barium. An 'ADI of 0.07 mg/kg/day (0.051 mg/kg/day Ba/0.72, % Ba) for barium cyanide Is somewhat lower than would be derived by analogy to cyanide (0.08 mg/kg/day) and 1s, therefore, recommended to provide adequate protection against adverse health effects. Confidence In the RfD: Study: Medium Data Base: Low RfD: Low The confidence In the study 1s rated medium because three doses were used and a sensitive Indicator (I.e., blood pressure changes) of the critical effect of barium (I.e., cardiac toxlclty) was measured. The confidence 1n the study 1s not rated any higher because of the use of only one sex, and the low 0420P -2- 01/11/86 ------- Confidence In the RfD (cont.): level of essential element exposure that may have predisposed the animals to barium toxldty. The data base 1s rated low because It 1s limited to a few studies. The overall confidence 1n the RfD 1s rated low. Documentation of RfD and Review: Limited peer review and ECAO-Clnclnnatl Internal review, August, 1985. U.S. EPA. 1985. Drinking Water Criteria Document for Barium. Office of Drinking Water, Washington, DC. Agency RfD Review: First Review: 08/05/85 Second Review: Verification Date: 08/05/85 U.S. EPA Contact: Primary: C.T. DeRosa FTS/684-7534 or 513/569-7534 Secondary: M.L. Dourson FTS/684-7544 or 513/569-7544 0420P -3- 01/11/86 ------- REFERENCE DOSES (RfDs) FOR ORAL EXPOSURE Chemical: Barium CAS #: 7440-39-2 CarclnogenlcHy: Systemic Toxldty: See below. Endpolnt Experimental Doses UF MF RfD (ADI) Information to be provided by the Office of Drinking Water Endpolnt and Experimental Doses: Preparation Date: 0420P -1- 01/11/86 ------- Uncertainty Factors (UFs): Modifying Factors (MFs): Additional Comments: Confidence In the RfD: Study: Data Base; RfD: Documentation of RfD and Review: Agency RfD Review: First Review: Second Review: Verification Date: U.S. EPA Contact: Primary: Secondary: FTS/684-75 FTS/684-75 or 513/569-75 or 513/569-75 0420P -2- 01/11/86 ------- REFERENCE DOSES (RfDs) FOR ORAL EXPOSURE Chemical: Cacodyllc Add CAS #: 75-60-5 Carclnogenldty.: None. Systemic ToxIcHy: See below. Endpolnt Experimental Doses UF MF RfD (ADI) Nees (1968) TOO ppm 1n diet as 1000 - 0.01 mg/kg/day NOEL converted to or Rat subchronlc 10 mg/kg/day 0.7 mg for a feeding study 70 kg man (30-90 days) Conversion Factor: Young rat food consumption = 10% bw/day Endpolnt and Experimental Doses: Nees, P.O. 1968. Report on cacodyllc add toxlclty to animals. Wisconsin Alumni Res. Found. EPA Pesticide Petition No. OF0911. In this study weanling rats were fed cacodyllc add as 3, 15, 30 or 100 ppm In the diet for 90 days (estimated 0.3, 1.5, 3 or 10 mg/kg/day). No effects were seen on body weight, food consumption, hematology, organ weight or histology which were attributed to treatment. Therefore, 10 mg/kg repre- sents a free-standing NOEL from this study. Nees et al. (1960) cited In the same pesticide petition (Report on Cacodyllc Add Toxldty to Animals Wisconsin Alumni Res. Found.) reported that feeding 280 mg/kg cacodyllc add to weanling rats for 20 days resulted In testlcular hlstopathologlcal changes, while feeding 140 mg/kg represented a NOEL. While these results provide additional support that the Nees et al. (1968),. feeding levels were Indeed below effect levels and also suggest that the highest NOEL from Nees (1968) may be considerably below the threshold region this study was of Inadequate duration for use In ADI calculation. In addition, doses of 130 mg/kg/day administered to pregnant rats by gastric Intubation resulted 1n Irregular palatine rugae 1n the offspring. Higher doses resulted 1n Increased prenatal death delayed sternal and cerndal ossifi- cation, and depressed fetal weight. These data provide additional supports for not employing the doses from the 20-day study as a basis for ADI estimation. Preparation Date: 01/06/86 0420P -1- 01/11/86 ------- Uncertainty Factors (UFs): The uncertainty factor of 1000 reflects 10 for both Intraspecles and Interspedes variability to the toxlclty of this chemical In lieu of specific data, and 10 for extrapolation of a subchronlc effect level to Us chronic equivalent. Modifying Factors (MFs): None. Additional Comments: None. Confidence 1n the RfO: Study: Low Data Base: Low RfD: Low The low confidence ratings for this study and data base reflect the limited secondary descriptions available at the time of this writing. Low confidence In the RfD follows. Documentation of RfD and Review: ECAO-CIn Internal Review, 1985. U.S. EPA. 1985. Cacodyllc Acid: Review and Evaluation of ADI. Contract No. 68-03-3228. Environmental Criteria and Assessment Office, Cincinnati, OH Agency RfD Review: First Review: 08/05/85 Second Review: Verification Date: 08/05/85 U.S. EPA Contact: Primary: C.T. DeRosa FTS/684-7534 or 513/569-7534 Secondary: H.L. Dourson FTS/684-7544 or 513/569-7544 0420P -2- 01/11/86 ------- REFERENCE DOSES (RfDs) FOR ORAL EXPOSURE Chemical: Calcium Cyanide Carclnogenldty: None. , Systemic Toxlclty: See below. CAS #: 502-01-8 Endpolnt Experimental Doses UF MF RfD (ADI) Howard and Hanzal (1955) Rat chronic oral study Phllbrlck (1979) et al Rat subchronlc to chronic oral bloassay Weight loss, thyroid effects and myelln degeneration 10.8 mg/kg/day CN (NOAEL) converted 19.1 mg/kg/day of calcium cyanide 30.0 mg/kg/day CN (LOAEL) 100 to 0.04 mg/kg/day or 3 mg/day for a 70 kg man Conversion Factor: Molecular weight ratio of Ca(CN)2/2 CN 1s 92/52; thus 10.8 mg/kg/day x 92/52 = 19.1 mg/kg/day Endpolnt and Experimental Doses: Howard, J.H. and R.F. Hanzal. 1955. Chronic toxldty for rats of food treated with hydrogen cyanide. Agrlc. Food Chem. 3: 325-329. Since calcium Is present 1n a very high level physiologically, ADIs for CaCN2 can be calculated based on the maximum molar equivalents of cyanide generated 1n adequeous or dilute acid solution. In this 2 yr. dietary study, rats (10/sex/group) were administered food fumigated with HCN. The average dally concentrations were 73 and 183 mg CN/kg diet. From the data reported on food consumption and body weight, dally esti- mated doses were 4.3 mg and 10.8 mg CN/kg bw. The average food CN concentra- tions were estimated based on the author's data for concentration at the be- Preparatlon Date: 01/06/86 0420P -1- 01/11/86 ------- Endpolnt and Experimental Doses (cont.): ginning and end of each food preparation period and by assuming a first order rate of loss for the Intervening period. There were no treatment related effects on growth rate, no gross signs of toxIcHy, and no hlstopathologkal lesions. Studies by PhllbMck et al. (1979) showed decreased weight gain and thyroxln levels and myelln degeneration In rats at 30 mg/kg/day CM. Other chronic studies either gave higher effect levels or used subcutaneous route (Crampton et al., 1979; Lessen, 1971; Herthlng et al., 1960). Human data do not provide adequate Information from which to derive an ADI because effective dose levels of chronically Ingested CN are not documented. Therefore, the study of Howard and Hanzel (1955) provides the highest NOAEL 10.8 mg/kg/day for CN and 1s chosen for the derivation of an ADI for CN of 1.5 mg/day or 0.02 mg/kg/day. Cyanide 1s metabolized extensively 1n the liver, Indicating that the only relevant route of administration for quantitative risk assessment 1n the deri- vation of an oral ADI 1s the oral route of administration. Uncertainty Factors (UFs): According to the U.S. EPA (1985) an uncertainty factor of 100 Is used to derive the ADI (10 for species extrapolation, 10 for sensitive population). Modifying Factors (MFs): A modifying factor of 5 Is used for the apparent tolerance of cyanide when H 1s Ingested with food rather than when administered by gavage or drinking water. Additional Comments: Decreased protein efficiency ratio was produced by dietary cyanide treat- ment of rats during gestation, lactation and postweanlng growth phase 1n the Tewe and.Maner (1981a) experiment: the dose level of cyanide (10.6 mg/kg/day) producing that effect Is slightly lower than the currently accepted NOAEL of 10.8 mg/kg/day (U.S. EPA, 1985). Furthermore, Tewe and Maner (1981b) tested sows. Possible effects observed at about 9.45 mg/kg/day were proliferation of glomerular cells of the kidneys and reduced activity of the thyroid glands In the gilts. However, the number of animals In this experiment was very small. A Japanese study (Amo. 1973) Indicated that 0.05 mg/kg/day of cyanide obtained from drinking water decreased the fertility rate and survival rate 1n the Fl generation and produced 100% mortality In the F2 generation 1n mice. However, 042°p -2- 01/11/86 ------- Additional Comments (cont.): these data are not consistent with the body of available literature. Thus, until additional chronic studies are available, an ADI of 3 mg/day for a 70 kg man Is recommended. Confidence 1n the RfD: Study: Medium Data Base: Medium RfD: Medium The confidence 1n the study 1s medium because adequate records of food consumption and body weight were maintained and animals of both sexes were tested at two doses for 2 years. The data base 1s rated medium because a small but sufficient number of studies support the chosen study. The confi- dence In the RfD follows. Additional chronic/reproductive studies are needed to support a higher level of confidence 1n the RfD. Documentation of RfD and Review: ECAO-C1nc1nnat1 Internal Review, July 1985. U.S. EPA. 1985. Cyanides: Review and Evaluation of ADI. Contract No. 68-03-3228. Environmental Criteria and Assessment Office, Cincinnati, OH. Agency RfD Review: First Review: 08/05/85 Second Review: Verification Date: 08/05/85 U.S. EPA Contact: Primary: C.T. DeRosa FTS/684-7534 or 513/569-7534 Secondary: M.L. Dourson FTS/684-7544 or 513/569-7544 0420P -3- 01/11/86 ------- REFERENCE DOSES (RfDs) FOR ORAL EXPOSURE Chemical: Carbaryl CAS #: 63-25-2 Carclnogenlclty: None. Systemic Toxlcity: See below. Endpolnt Experimental Doses UF MF RfD (ADI) Carpenter et al. 200 ppm of diet 100 - 0.1 mg/kg/day (1961) (9.6 mg/kg/day (NOAEL) Rat chronic feed- 400 ppm of diet 1ng study 15.6 mg/kg/day (LOAEL) Kidney and liver toxlclty Endpolnt and Experimental Doses: Carpenter, C.P., C.W. Well, P.E. Polln, et al. 1961. Mammalian toxldty of 1-naphthayl-N-methylcarbamate (Sevln Insecticide). J. Agrlc. Food Chem. 9: 30-39. Groups of 20 CF-N rats/sex were fed carbaryl at 0, 50, 100, 200 or 400 ppm of diet for 2 years. Food consumption and body weight records were maintained. Interim sacrifices (4-8 animals) from concurrent auxiliary groups were performed at 6, 9 and 12 months for organ weight comparisons and hlstopathologlcal analysis. Hematologlcal analyses were done at semi-regular Intervals throughout the study. Surviving animals were sacrificed at 2 years with gross and hlstopathologlcal examinations performed. The only noteworthy effects .reported were slight hlstopathologlcal changes In the kidneys and liver at the high-dose level. Diffuse cloudy swelling of renal tubules was observed at 1 and 2 years. A statistically significant Increase 1n cloudy swelling of the hepatic cords was also observed after 2 years. Based on body weight and food consumption data, the LOAEL of 400 ppm was equivalent to a dose of 15.6 mg/kg bw/day. The NOAEL established was 9.6 mg/kg bw/day. Preparation Date: 01/09/86 0420P -1 01/11/86 ------- Uncertainty Factors (UFs): UF = lOa x lOh. The UF of TOO Includes uncertainties In Interspecles and Intrahuman variability. Modifying Factors (MFs): None. Additional Comments: Effect and no-effect levels (14 and 7 mg/kg/day, respectively) similar to those found In the critical study were observed for rat body weight reduction and chollnesterase Inhibition 1n a 1 year study. In subchronlc rat studies, higher dose levels (85-200 mg/kg/day) caused kidney toxldty and biochemical changes. Kidney lesions were observed In dogs fed carbaryl,at 5 mg/kg/day for 1 year; however, the effect was not clearly associated with treatment since the lesions appeared In control animals but not In lower dose groups. Carbaryl was teratogenlc for several species with widely varying NOELs. The lowest effect levels of 5-6 mg/kg were observed for dogs, with NOELs of 2-3 mg/kg. Other LOELs were higher than the established chronic LOAEL of 15.6 mg/kg/day. Carbaryl was not teratogenlc for monkeys at 20 mg/kg. The dog studies were judged Inappropriate for human health risk assessment because of differences 1n the metabolism of carbaryl between dogs and humans. Carbaryl has Induced numerical chromosome aberrations (aneuploldy and polyploldy) 1n experimental animals. Carbaryl has not been found to be car- cinogenic, but the data are equivocal. Confidence 1n the RfD: Study: High Data Base: Medium RfD: Medium The critical study was well designed and clearly reported with unequivocal effect levels established. The data base 1s moderately supportive of the nature of the critical effect, 1f somewhat sparse. The principal problem 1s the observation of teratogenlclty In dogs at lower doses. Because the sig- nificance of these data cannot be discounted entirely, confidence In the RfD should be considered medium to low. 0420P -2- 01/11/86 ------- Documentation of RfD and Review: Limited Agency review of 1984 Health and Environmental Effects Profile with the help of two external scientists. U.S. EPA. 1984. Health and Environmental Effects Profile for Carbaryl. Environmental Criteria a/id Assessment Office, Cincinnati, OH. ECAO-CIN-P039. Agency RfO Review: 05/31/85 First Review: Second Review: Verification Date: 05/31/85 U.S. EPA Contact: Primary: M.L. Dourson FTS/684-7544 or 513/569-7544 Secondary: C.T. OeRosa FTS/684-7534 or 513/569-7534 0420P -3- 01/11/86 ------- REFERENCE DOSES (RfDs) FOR ORAL EXPOSURE Chemical: Carbon D1sulf1de Car dnogenl city: None. Systemic Toxlclty: See below. CAS #: 75-15-0 Endpolnt Experimental Doses UF 100 MF RfD (ADI) Hardln et al. (1981) Rabbit Inhalation teratogenic Toxlclty/fetal mal- formations 20 ppm (62.3 mg/ cu. m) (NOEL) con- verted to 11.0 mg/kg/day Price et al. (1984) 25 mg/kg/day (LOAEL) Rabbit oral tera- tology study Fetal resorptlons 0.1 mg/kg/day or 8 mg/day for a 70 kg man Conversion Factors: 6 hour/24 hour, 1.6 cu. m/day breathing rate; 1.13 kg bw and 0.5 absorption rate (I.e., 62.3 mg/cu. m x 6 hour/24 hours x 1.6 cu. m/day / 1.13 kg bw x 0.5 = 11.0 mg/kg/day) Endpolnt and Experimental Doses: Hardln, B.D., G.P. Bond, Nlemelr. 1981. Testing potential. Scand. J. Work M.R. Slkor, F.D. Andrew, R.P. Bellies and R.H. of selected work place chemicals for teratogenic Environ. Health. 7(Suppl. 4): 66-75. The data reported In this study were generated at Litton Blonetlcs, Mary- land (under contract to NIOSH). Rats and rabbits were exposed to 20 ppm or 62.3 mg/cu. m (recommended occupational exposure limit) and 40 ppm or 124.6 mg/cu. m of CS2 during the entire length of the pregnancy period and also 3 weeks prior to breeding to simulate occupational exposure. This report con- taining data on maternal/fetal toxldty and fetal malformations failed to show any adverse effects of CS2 exposure, even at the high dose (124.6 mg/cu. m). Preparation Date: 01/06/86 0420P -1- 01/11/86 ------- Endpolnt and Experimental Doses (cont.): A NCTR/NTP study (Price et al., 1984) observed 25 mg/kg In rabbHs as an AEL (fetal resorptlon). FetotoxUHy and fetal malformations 1n this study were not observed 1n rats at the lowest level (100 mg/kg) of CS2 exposure. Uncertainty Factors (UFs): The 100-fold uncertainty factor reflects 10-fold adjustments for both the expected 1ntra- and Interspedes variability to the toxldty of this compound 1n lieu of chemical-specific data. Note that the usual factor of 10$ (subchronlc to chronic extrapolation 1s not used here sTnce the exposure duration covered the entire critical period for the el1dtat1on of the critical effect. Modifying Factors (MFs): None. Additional Comments: A Bulgarian study (Tabatsova et al., 1983) reported significant fetal mal- formations In rats exposed to a low CS2 dose of 0.03 mg/cu. m over three gen- erations. Based on these data, an ADI would be drastically lower than the ADIs that could be derived from existing guidelines, ep1dem1olog1cal data or other experimental data. Moreover, the Bulgarian study did not present Infor- mation on mode of control exposure, animal diet, selection of F1/F2 breeding pairs and purity of CS2 (hydrogen sulflde, a potent teratogen. Is often found as a contaminant). In a mult1generat1on study, toxic effects of a compound can be confounded by the above factors. The data of Price et al. (1984)"also suggest that the rabbit fetus 1s more sensitive than the rat fetus to CS2-1nduced toxldty. Hardln et al. (1981) observed no effects on fetal development In rats or rabbits following Inhalation exposure to 62.3 or 124.6 mg/cu. m which corresponds to estimated equivalent oral dosages of 5 and 10 mg/kg for rats, and 11 and 22 mg/kg 1n rabbits. The highest NOEL from this study. 22 mg/kg 1n the rabbit, should not be used for an ADI estimate because adverse effects were seen In rabbit fetuses following oral exposure of preg- nant does to 25 mg/kg. Therefore, the highest NOEL which Is below an effect level Is the estimated low dose from the Harden et al. (1981) Inhalation study using rabbits. This dose level, >11 mg/kg, 1s proposed as the basis for ADI derivation. 0420P -2- 01/11/86 ------- Confidence In the RfD: Study: High Data Base: Low RfD: Low The confidence In the chosen study 1s high because the exposure encom- passed the critical period, and several species and doses were tested. Confi- dence In the data base Is low because of the unavailability of supporting oral chronic studies. Overall confidence 1n the RfD is low because of uncertainty In the Inter-route conversion model. Until further oral chronic/reproductive studies using U.S. EPA multlgeneratlon protocol are available, a low confi- dence In the RfD 1s recommended. Documentation of RfD and Review: U.S. EPA. 1985. Carbon D1sulf1de: Review and Evaluation of ADI. Contract No. 68-03-3228. Environmental Criteria and Assessment Office, U.S. EPA, Cincinnati, OH. This RfD received an ECAO-C1nc1nnat1 Internal Review during,Hay 1985. Agency RfD Review: First Review: 07/08/85 Second Review: Verification Date: 07/08/85 U.S. EPA Contact: Primary: C.T. DeRosa FTS/684-7534 or 513/569-7534 Secondary: M.L. Dourson FTS/684-7544 or 513/569-7544 0420P -3- 01/11/86 ------- REFERENCE DOSES (RfDs) FOR ORAL EXPOSURE Chemical: Carbon TetrachloMde CAS #: 56-23-5 CardnogenlcHy: Systemic Toxlclty: See below. Endpolnt Experimental Doses UF MF RfD (ADI) Information to be provided by the Office of DMnkfng Water Endpolnt and Experimental Doses: Preparation Date: 0420P -1- 01/11/86 ------- Uncertainty Factors (UFs): Modifying Factors (MFs):~ Additional Comments: Confidence In the RfD: Study: Data Base: RfD: Documentation of RfD and Review: Agency RfD Review: U.S. EPA Contact: First Review: Primary: Second Review: FTS/684-75 or 513/569-75 Verification Date: Secondary: FTS/684-75 or 513/569-75 0420P -2- 01/11/86 ------- REFERENCE DOSES (RfDs) FOR ORAL EXPOSURE Chemical: Chlorine Cyanide (cyanogen chloride) CAS #: 506-77-4 Carclnogenldty: None. Systemic Toxlclty: See below. Endpolnt Experimental Doses Howard and Hanzal 10.8 mq/kq/day CN UF 100 MF 5 RfD (ADI) 0.05 mg/kg/day (1955) Rat chronic oral study PhUbMck et al. (1979) Rat subchronlc to chronic oral bio- assay Height loss and thyroid effects; myelln degeneration (NOAEL), converted to 25.3 mg/kg/day of chlorine cyanide 30 mg/kg/day (LOAEi; or 4 mg/day for a 70 kg man Conversion Factor: Molecular weight C1CN/CN Is 61/26; thus, 10.8 mg/kg/day x 61/26 = 25.3 mg/kg/day Endpolnt and Experimental Doses: Howard, J.W. and R.F. Hanzal. 1955. Chronic toxldty for rats by food treated with hydrogen cyanide. Agrlc. Food Chem. 3: 325-329. Since chloride Is present In very high levels physiologically an ADI of 3.5 mg/day 1s recommended based on the maximum number of molar equivalents (1) of cyanide released 1n aqueous solutions or dilute adds. In this 2 yr. dietary study, rats (10/sex/group) were administered food fumigated with HCN. The average dally concentrations were 73 and 183 mg CN/kg diet. From the data reported on food consumption and body weight, dally estimated doses were 4.3 mg and 10.8 mg CN/kg bw. The average food CN Preparation Date: 01/09/86 0420P -1- 01/11/86 ------- Endpolnt and Experimental Doses (cont.): concentrations were estimated based on the author's data for concentration at the beginning and end of each food preparation period and by assuming a first order rate of loss for the Intervening period. There were no treatment related effects on growth rate, no gross signs of toxlclty, and no histo- pathologlcal lesions. Studies by Philbrlck et al. (1979) showed decreased weight gain and thy- roxln levels and myelln degeneration 1n rats at 30 mg/kg/day CN. Other chronic studies either gave higher effect levels or used subcutaneous route (Crampton et al., 1979; Lessen, 1971; Herthlng et al., 1960). Human data do not provide adequate Information from which to derive an ADI.because effective dose levels of chronically Ingested CN are not documented. Therefore, the study of Howard and Hanzel (1955) provides the highest NOAEL 10.8 mg/kg/day for CN and 1s chosen for the derivation of an ADI for CN of 1.5 mg/day or 0.02 mg/kg/day. Cyanide 1s metabolized extensively 1n the liver, Indicating that the only relevant route of administration for quantitative risk assessment In the deri- vation of an oral ADI Is the oral route of administration. ' Uncertainty Factors (UFs): According to the U.S. EPA (1985) an uncertainty factor of 100 is used to derive the ADI (10 for species extrapolation, 10 for sensitive population). Modifying Factors (MFs): A modifying factor of 5 1s used for apparent tolerance of cyanide when It Is Ingested with food rather than when administered by gavage or drloklng water. Additional Comments: Decreased protein efficiency ratio was produced by dietary cyanide treat- ment of .rats during gestation, lactation and postweanlng growth phase in the Tewe and Haner (1981a) experiment: the dose level of cyanide (10.6 mg/kg/day) producing that effect is slightly lower than the currently accepted NOAEL of 10.8 mg/kg/day (U.S. EPA, 1985). Furthermore, Tewe and Maner (1981b) tested sows. Possible effects observed at about 9.45 mg/kg/day were proliferation of glomerular cells of the kidneys and reduced activity of the thyroid glands 1n the gilts. However, the number of animals In this experiment was very small. A Japanese study (Amo, 1973) Indicated that 0.05 mg/kg/day of cyanide obtained from drinking water decreased the fertility rate and survival rate in the Fl generation and produced 100% mortality in the F2 generation In mice. However, 0420P -2- 01/11/86 ------- Additional Comments (cont.): these until kg man 1s data are not consistent with the body of available literature. Thus, additional chronic studies are available, an ADI of 3.5 mg/day for a 70 recommended. Confidence In the RfD: Study: Medium Data Base: Medium RfD: Medium The confidence 1n the study 1s medium because adequate records of food consumption and body weight were maintained and animals of both sexes were tested at two doses for 2 years. The data base Is rated medium because a small but sufficient number .of studies support the chosen study. The .confi- dence In the RfD follows. Additional chronic/reproductive studies are needed to support a higher level of confidence 1n the RfD. Documentation of RfD and Review: U.S. EPA. 1985. Cyanides: Review and Evaluation of ADI. Contract No. 68-03-3228. Environmental Criteria and Assessment Office,. Cincinnati, OH. ECAO-C1nc1nnat1 Internal Review, July 1985. Agency RfD Review: First Review: 08/05/85 Second Review: Verification Date: 08/05/85 U.S. EPA Contact: Primary: C.T. DeRosa FTS/684-7534 or 513/569-7534 Secondary: M.L. Dourson FTS/684-7544 or 513/569-7544 0420P -3- 01/11/86 ------- REFERENCE DOSES (RfDs) FOR ORAL EXPOSURE Chemical: Chlorobenzene CAS #: 108-90-7 Cardnogenlclty: Systemic Toxldty: See below. Endpolnt Experimental Doses UF MF RfD (ADI Last minute Information prevented the release of these values. Endpolnt and Experimental Doses: Preparation Date: 0420P -1- 01/11/86 ------- Uncertainty Factors (UFs): Modifying Factors (MFs): Additional Comments: Confidence In the RfD: Study: Data Base: RfD: Documentation of RfD and Review: Agency RfD Review: U.S. EPA Contact: First Review: Primary: Second Review: FTS/684-75 or 513/569-75 Verification Date: Secondary: FTS/684-75 or 513/569-75 0420P -2- 01/11/86 ------- REFERENCE DOSES (RfOs) FOR ORAL EXPOSURE Chemical: Copper Cyanide Carclnogenlclty: None. Systemic Toxlclty: See below. CAS #: 544-92-3 Endpolnt Experimental Doses UF MF RfD (ADI) Howard and Hanzal (1955) Rat chronic oral study PhUbrlck et al. (1979) Rat subchronlc to chronic oral bio- assay Weight loss, thyroid effects and myelln degeneration 10.8 mg CN/kg/day (NOAEL) converted to 37.2 mg C.u(CN)2/kg/ day 30 mg/kg/day CN (LOAEL) 100 0.07 mg/kg/day or 5 rog/day for a 70 kg man Conversion Factors: Molecular weight: Cu(CN)2/CN 1s 89.5/26; thus, 10.8 mg CN kg x (89.5/26) = 37.2 mg/kg/day) Endpolnt and Experimental Doses: Howard,. J.W. and R.F Hanzal. 1955. Chronic toxlclty to rats of food treated with hydrogen cyanide. Agrlc. Food Chem. 3: 325-329. Copper cyanide has not been tested for toxlclty. Copper cyanide can exist as cuprlc cyanide or cuprous cyanide. Cuprlc cyanide Is extremely unstable and dissociates to form cyanide and a cuprous cyanide complex. An ADI can be derived for cuprlc cyanide based on the molar equivalents of free cyanide only since cuprous cyanide (CuCN) Is not soluble In water or dilute add. An ADI calculated based on molar equivalents (1) of free CN would be 5.20 mg/day. Preparation Date: 01/09/86 0420P -1- 01/11/86 ------- Endpolnt and Experimental Doses (cont.): In this 2-year dietary study, rats (10/sex/group) were administered food fumigated with HCN. The average dally concentrations were 73 and 183 mg CN/kg diet. From the data reported on food consumption and body weight, dally esti- mated doses were 4.3 mg and 10.8 mg CN/kg bw. The average food CN concentra- tions were estimated based on the author's data for concentration at the beginning and end of each food preparation period and by assuming a first order rate of loss for the Intervening period. There were no treatment related effects on growth rate, no gross signs of toxldty. and no hlsto- pathologlcal -lesions. Studies by PhllbMck et al. (1979) showed decreased weight gain and thy- roxln levels and myelln degeneration 1n rats at 30 mg/kg/day CN. Other chronic studies either gave higher effect levels or used subcutaneous route (Crampton et al., 1979; Lessen. 1971; Herthlng et al., 1960). Human data do not provide adequate Information from which to derive an ADI because effective dose levels of chronically Ingested CN are not documented. Therefore, the study of Howard and Hanzel (1955) provides the highest NOAEL. 10.8 mg/kg/day for CN and Is chosen for the derivation of an ADI for CN of,1.5 mg/day or 0.02 mg/kg/day. Cyanide Is metabolized extensively 1n the liver, Indicating that the only relevant route of administration for quantitative risk assessment 1n the deri- vation of an oral ADI Is the oral route of administration. Uncertainty Factors (UFs): According to the U.S. EPA (1985) an uncertainty factor of 100 Is used to derive the ADI (10 for species extrapolation, 10 for sensitive population). Modifying Factors (MFs): A modifying factor of 5 Is used for' apparent tolerance of cyanide when It 1s Ingested with food than when administered by gavage or drinking water. Additional Comments: Decreased protein efficiency ratio was produced by dietary cyanide treat- ment of rats during gestation, lactation and postweanlng growth phase In the Tewe and Maner (1981a) experiment: the dose level of cyanide (10.6 mg/kg/day) producing that effect is slightly lower than the currently accepted NOAEL of 10.8 mg/kg/day (U.S. EPA, 1985). Furthermore, Tewe and Maner (1981b) tested sows. Possible effects observed at about 9.45 mg/kg/day were proliferation of glomerular cells of the kidneys and reduced activity of the thyroid glands In the gilts. However, the number of animals 1n this experiment was very small. 0420P -2- 01/11/86 ------- Additional Comments (cont.): A Japanese study (Amo, 1973) Indicated that 0.05 mg/kg/day of cyanide obtained from drinking water decreased the fertility rate and survival rate In the Fl generation and produced 100% mortality In the F2 generation 1n mice. However, these data are not consistent with the body of available literature. Thus, until additional chronic studies are available, an ADI of 5.2 mg/day for a 70 kg man Is recommended. Confidence In the RfD: Study: Medium Data Base: Low RfD: Low The confidence In the study Is medium because adequate records of food consumption and body weight were maintained and animals of both sexes were tested at two doses for 2 years. The data base Is rated low because this chemical has not been tested. The confidence 1n the RfD 1s low because It Is based on analogy. Chronic/reproductive studies are needed to support a higher level of confidence In the RfD. Documentation of RfD and Review: U.S. EPA. 1985. Cyanides: Review and Evaluation of ADI. Contract No. 68-03-3228. Environmental Criteria and Assessment Office, Cincinnati, OH. ECAO-C1nc1nnat1 Internal Review, July 1985. Agency RfD Review: First Review: 08/05/85 Second Review: Verification Date: 08/05/85 U.S. EPA Contact: Primary: C.T. DeRosa FTS/684-7534 or 513/569-7534 Secondary: M.L. Dourson FTS/684-7544 or 513/569-7544 0420P -3- 01/11/86 ------- REFERENCE DOSES (RfDs) FOR ORAL EXPOSURE Chemical: Cresols Carclnogenldty: None. Systemic Toxldty: See below. CAS #: 1319-77-3 Endpolnt Experimental Doses UF MF RfD (ADI) NIOSH (1978) Occupational expo- sure criterion TLV = 10 mg/cu. m 10 mg/cu. m TLV con- verted to 0.51 mg/ kg/day Conversion Factors; 0.05 mg/kg or 4 mg/day for a 70 kg man 10 mg/cu. m x 10 cu. m/day x 0.5 absorption factor x 5 days/7 days / 70 kg = 0.51 mg/kg/day Endpolnt and Experimental Doses: NIOSH (National Institute of Occupational Safety and Health) for a Recommended Standard...Occupational Exposure to Cresol. CDC, Cincinnati, OH. DHEW (NIOSH) Publ. No. 78-133. 1978. Criteria U.S. DHEW, PHS, NIOSH's recommendation Is based on a review and assessment of the avail- able literature primarily the subchronlc Inhalation studies of Uzhdavlne et al. (1972). Uzhdavlne et al. (1972) exposed rats and guinea pigs to 0-cresol at a concentration of 9.0 (plus or minus 0.9) mg/cu. m. No effect was seen 1n guinea pigs. In rats, the authors reported various hematopo1et1c effects, respiratory tract Irritation and sclerosis of lungs. Uzhdavlne et al. (1972) also reported humans exposed to 6 mg/cu. m (duration unspecified) cresol experienced nasopharynegeal Irritation. No adequate chronic or subchronlc data exist to base an ADI. Environ lists an ADI of 0.113 mg/kg/day based on ACGIH (1980) TLV of 22 mg/cu. m. The NIOSH (1978) criterion based on a far more complete, detailed and critical review of the available literature than Is the ACGIH TLV. Other studies support the findings (effects) reported In the Uzhdavlne et al. (1972) study cited by NIOSH. Consequently, the NIOSH (1978) criterion 1s a more prudent basis for an ADI of 0.051 mg/kg/day to protect against adverse health effects. Preparation Date: 01/09/86 0420P -1- 01/11/86 ------- Uncertainty Factors (UFs): The 10-fold uncertainty factor represents the expected Intrahuman varl ability to the toxldty of this chemical In lieu of chemical-specific data. Modifying Factors (MFs): None. Additional Comments: No chronic toxldty studies were conducted and the subchronlc data was poorly characterized and documented. Until further oral chronic, subchronlc or reproductive data Is available, a low confidence 1n the RfD 1s recom- mended. An additional factor of 10 was not deemed necessary due to the fact the various hematopoletlc effects observed In rats were considered slight and reversible. No effects wre seen 1n guinea pigs and no hlstopathologlcal effects were reported 1n either species. Confidence 1n the RfD: Study: Low Data Base: Low RfD: Low The confidence 1n both the procedure to estimate an oral RfD by a TLV and the resulting RfD 1s low since this method 1s only used when sufficient oral and Inhalation toxldty data do not exist. Documentation of RfD and Review: U.S. EPA. 1985. Cresol: Review and Evaluation of ADI. Contract No. 68-03-3228. Environmental Criteria and Assessment Office, Cincinnati, OH. U.S. EPA. 1985. Health and Environmental Effects Profile for Cresols. Environmental Criteria and Assessment Office, Cincinnati. OH. ECAO-CIN-P138. The Health and Environmental Effects Profile has received an Agency-wide review with the help of two external scientists. Agency RfD Review: F1rs.t Review: 07/08/85 Second Review: Verification Date: 07/08/85 U.S. EPA Contact: Primary: C.T. DeRosa FTS/684-7534 or 513/569-7534 Secondary: M.L. Dourson FTS/684-7544 or 513/569-7544 0420P -2- 01/11/86 ------- REFERENCE DOSES (RfDs) FOR ORAL EXPOSURE Chemical: Cyanide (free) Cardnogenldty: None. Systemic Toxldty: See below. CAS #: 57-12-15 Endpolnt Experimental Doses UF MF RfD (ADI; Howard and Hanzal (1955) Rat oral chronic study Ph1lbr1ck et al. (1979) Rat oral subchronlc to chronic study Primary myelln degeneration and decreased thyroxln levels 10.8 mg/kg/day CN (NOAEL) 30 mg/kg/day CN (LOAEL) 100 0.02 mg/kg/day or 2 mg/day for a 70 kg man Endpolnt and Experimental Doses: Howard, J.W. and R.F. Hanzal. 1955. Chronic toxldty to rats of food treated with hydrogen cyanide. AgMc. Food Chem. 3: 325-329. Hydrogen cyanide Is soluble 1n water and dilute acid (which Includes the gastric environment) and 1s readily hydrolysed to 1 molar equivalent of CN and 1 molar equivalent of hydrogen (Hartung, 1982). In this 2-year dietary study, rats (10/sex/group) were administered food fumigated with HCN. The average dally concentrations were 73 and 183 mg CN/kg diet. From the data reported on food consumption and body weight, dally esti- mated doses were 4.3 mg and 10.8 mg CN/kg bw. The average food CN concentra- tions were estimated based on the author's data for concentration at the beginning and end of each food preparation period and by assuming a first Preparation Date: 01/09/86 0420P -1- 01/11/86 ------- Endpolnt and Experimental Doses (cont.): order rate of loss for the Intervening period. There were no treatment related effects on growth rate, no gross signs of toxlclty, and no hlstopatho- loglcal lesions. Studies by Phllbrlck et al. (1979) showed decreased weight gain and thyroxln levels and myelln degeneration 1n rats at 30 mg/kg/day CN. Other chronic studies either gave higher effect levels or used subcutaneous route (Crampton et al., 1979; Lessen, 1971; Herthlng et al., 1960). Human data do not provide adequate Information from which to derive an ADI because effective dose levels of chronically Ingested CN are not documented. Therefore, the study of Howard and Hanzel (1955) provides the highest NOAEL 10.8 mg/kg/day for CN and 1s chosen for the derivation of an ADI for CN of 1.5 mg/day or 0.02 mg/kg/day. Cyanide Is metabolized extensively In the liver. Indicating that the only relevant route of administration for quantitative risk assessment 1n the deri- vation of an oral ADI 1s the oral route of administration. Uncertainty Factors (UFs): According to the U.S. EPA (1985) an uncertainty factor of 100 Is used to derive the ADI (10 for species extrapolation, 10 for sensitive population). Modifying Factors (MFs): A modifying factor of 5 1s used for apparent tolerance of cyanide when It 1s Ingested with food than when administered by gavage or drinking water. Additional Comments: Decreased protein efficiency ratio was produced by dietary cyanide treat- ment of rats during gestation, lactation and postweanlng growth phase In the Tewe and Maner (1981a) experiment: the dose level of cyanide (10.6 mg/kg/day) producing that effect Is slightly lower than the currently accepted NOAEL of 10.8 mg/Jcg/day (U.S. EPA, 1985). Furthermore, Tewe and Maner (1981b) tested sows. Possible effects observ.ed at about 9.45 mg/kg/day were proliferation of glomerular cells of the kidneys and reduced activity of the thyroid glands In the gilts. However, the number of animals In this experiment was very small. A Japanese study (Amo, 1973) Indicated that 0.05 mg/kg/day of cyanide obtained from drinking water decreased the fertility rate and survival rate In the Fl generation and produced 100% mortality 1n the F2 generation In mice. However, these data are not consistent with the body of available literature. Thus, until additional chronic studies are available, an ADI of 1.5 mg/day for a 70 kg man Is recommended. 0420P -2- 01/11/86 ------- Confidence in the RfD: Study: Medium Data Base: Medium RfD: Medium The confidence 1n the study 1s medium because adequate records of food consumption and body weight were maintained and animals of both sexes were tested at two doses for 2 years. The data base 1s rated medium because a small but sufficient number of studies support the chosen study. The confi- dence In the RfD follows. Additional chronic/reproductive studies are needed to support a higher level of confidence 1n the RfD. Documentation of RfD and Review: U.S. EPA. 1984. Health Effects Assessment for Cyanides. Environmental Cri- teria and Assessment Office, Cincinnati, OH. ECAO-CIN-H011. U.S. EPA. 1985. Drinking Water Criteria Document for Cyanides. Office of Drinking Water, Washington, DC. The ODW criteria document and OERR health effects assessment have both had an extensive Agency-wide and limited external review. Agency RfD Review: First Review: 08/05/85 Second Review: Verification Date: 08/05/85 U.S. EPA Contact: Primary: C.T. DeRosa fTS/684-7534 or 513/569-7534 Secondary: M.L. Dourson FTS/684-7544 or 513/569-7544 0420P -3- 01/11/86 ------- REFERENCE DOSES (RfDs) FOR'ORAL EXPOSURE Chemical: Cyanogen Cardnogenldty: None. Systemic Toxlclty: See below. CAS #: 460-19-5 Endpolnt Experimental Doses UF MF 5 -RfO (ADI) Howard and Hanzal (1955) Rat chronic oral study Phllbrlck et al. (1979) Rat subchronlc to chronic oral bio- assay Weight loss and thy- roid effects; myelln degeneration 10.8 mg/kg day CN (NOAEL) converted to 21.6 mg/kg/day of cyanogen 100 0.04 mg/kg/day or 3 .mg/day for a 70 kg man 30 mg/kg/day (LOAEL) CN Conversion Factors: Molecular weight of C2N2/CN 1s 52/26; thus 10.8 mg/kg/day x 52/26 = 21.6 mg/kg/day. Endpolnt and Experimental Doses: Howard, J.W. and R.F. Hanzal. with hydrogen cyanide. Agrlc. 1955. Chronic toxIcHy to Food Chem. 3: 325-329. rats of food treated Cyanogen does not completely dissociate Into free CN In water or dilute acetic solution. However, without an evaluation of the toxlclty of the parent compound, an ADI based on molecular equivalents (1) CN would be 3 mg/day. In this 2-year dietary study, rats (10/sex/group) were administered food fumigated with HCN. The average dally concentrations were 73 and 183 mg CN/kg diet. From the data reported on food consumption and body weight, dally estl- Preparatlon Date: 01/09/86 0420P -1- 01/11/86 ------- Endpolnt and Experimental Doses (cont.): mated doses were 4.3 mg and 10.8 mg CN/kg bw. The average food CN concentra- tions were estimated based on the author's data for concentration at the beginning and end of each food preparation period and by assuming a first order rate of loss for the Intervening period. There were no treatment related effects on growth rate, no gross signs of toxldty, and no hlstopatho- loglcal lesions. Studies by Phllbrlck et al. (1979) showed decreased weight gain and thyroxln levels and myelln degeneration In rats at 30 mg/kg/day CN. Other chronic studies either gave higher effect levels or used subcutaneous route (Crampton et al., 1979; Lessell, 1971; Herthlng et al., I960.). Human data do not provide adequate Information from which to derive an ADI because effective dose levels of chronically Ingested CN are not documented. Therefore, the study of Howard and Hanzel (1955) provides the highest NOAEL 10.8 mg/kg/day for CN and 1s chosen for the derivation of an ADI for CN of 1.5 mg/day or 0.02 mg/kg/day. Cyanide Is metabolized extensively In the liver, Indicating that the only relevant route of administration for quantitative risk assessment In the deri- vation of an oral ADI Is the oral route of administration. Uncertainty Factors (UFs): According to the U.S. EPA (1985) an uncertainty factor of 100 Is used to derive the ADI (10 for species extrapolation, 10 for sensitive population). Modifying Factors (MFs): An additional 5 1s used for apparent tolerance of cyanide when It Is Ingested with food than when administered by gavage or drinking water. Additional Comments: Decreased protein efficiency ratio was produced by dietary cyanide treat- ment of rats during gestation, lactation and postweanlng growth phase 1n the Tewe and Maner (1981a) experiment: the dose level of cyanide (10.6 mg/kg/day) producing that effect 1s slightly lower than the currently accepted NOAEL of 10.8 mg/kg/day (U.S. EPA, 1985). Furthermore, Tewe and Maner (1981b) tested sows. Possible effects observed at about 9.45 mg/kg/day were proliferation of glomerular cells of the kidneys and reduced activity of the thyroid glands In the gilts. However, the number of animals In this experiment was very small. A Japanese study (Amo, 1973) Indicated that 0.05 mg/kg/day of cyanide obtained from drinking water decreased the fertility rate and survival rate In the Fl generation and produced 100% mortality in the F2 generation in mice. However, 0420P -2- 01/11/86 ------- Additional Comments (cont.): these data are not consistent with the body of available literature. Thus, until additional chronic studies are available, an ADI of 3.0 mg/day for a 70 kg man 1s recommended. Confidence In the RfD: Study: Medium Data Base: Low RfD: Low The confidence In the study 1s medium because adequate records of food consumption and body weight were maintained and animals of both sexes were tested at two doses for 2 years. The data base 1s rated low because this chemical has not been tested. The confidence 1n the RfD Is low because It 1s based on analogy. Chronic/reproductive studies are needed to support a higher level of confidence 1n the RfD. Documentation of RfD and Review: ECAO-C1nc1nnat1 Internal Review, July 1985. U.S. EPA. 1985. Cyanides: Review and Evaluation of ADI. Contract No. 68-03-3228. Environmental Criteria and Assessment Office, Cincinnati, OH. Agency RfD Review: First Review: 08/05/85 Second Review: Verification Date: 08/05/85 U.S. EPA Contact: Primary: C.T. DeRosa FTS/684-7534 or 513/569-7534 Secondary: M.L. Dourson FTS/684-7544 or 513/569-7544 0420P -3- 01/11/86 ------- REFERENCE DOSES (RfDs) FOR ORAL EXPOSURE Chemical: 2,4-DB CAS #: 94-82-6 CarclnogenlcHy: None. Systemic Toxlclty: See below. Endpolnt Experimental Doses UF HF RfD (ADI) CBI 8 mg/kg/day (NOAEL) 1000 - 0.008 mg/kg/day Dog subchronlc oral 25 mg/kg/day (LOAEL) bloassay Internal hemorrhage, mortallty Endpolnt and Experimental Doses: CBI (Confidential Business Information) Four beagle dogs/sex/group were fed 2,4-DB at dose levels of 0, 2.5, 8.0, 25 or 80 mg/kg bw/day for 90 days. The two higher doses produced frank effects Including death, hemorrhage throughout the body and aspermatogenesls within 3-9 weeks of treatment. Slightly Increased 11 ver-to-body weight ratios were observed at both lower dose levels, but no gross or microscopic pathology was evident. Uncertainty Factors (UFs): The uncertainty factor of 1000 reflects 10 for both Intraspecles and Interspecles variability to the toxlclty of this chemical In lieu of specific data, and 10 for extrapolation of a subchronlc effect level to Its chronic equivalent. Preparation Date: 01/09/86 °420P -1- 01/11/86 ------- Modifying Factors (MFs): None. Additional Comments: A subchronlc rat study (CBI) showed somewhat higher effect and no-effect levels than were observed 1n the dog study. Severe kidney and liver damage was observed at 1000 ppm 2,4-DB In the diet (80-100 mg/kg bw/day). A NOEL of about 25-30 mg/kg/day was established. 2,4-DB does not appear to be teratogenlc, but the data are very limited. Structurally related compounds (2,4-D and 2,4,5-T) are teratogenlc. No data on carclnogenldty are available. 2,4-DB has not been shown to be mutagenlc. Confidence In the RfD: Study: Medium Data Base: Low RfD: Low Confidence In the critical study Is medium because of the moderate number of animals and large number of dose groups employed, but not high, because some data are lacking. Confidence In the data base 1s low, because of the. general lack of data, but tends toward medium because one moderately sup- portive study Is available. Confidence in the RfD 1s low because of the weak data base. Documentation of RfD and Review: The ADI In the 1984 Health and Environmental Effects Profile has had a limited Agency review with the help of two external scientists. U.S. EPA. 1984. Health and Environmental Effects Profile for 2,4-DB. Envi- ronmental Criteria and Assessment Office, Cincinnati, OH. ECAO-CIN-P060AP. Agency .RfD Review: First Review: 05/31/85 Second Review: 06/19/85 Verification Date: 06/19/85 U.S. EPA Contact: Primary: M.L. Dourson FTS/684-7544 or 513/569-7544 Secondary: C.T. DeRosa FTS/684-7534 or 513/569-7534 0420P -2- 01/11/86 ------- REFERENCE DOSES (RfDs) FOR ORAL EXPOSURE Chemical: 1,2-D1chlorobenzene CAS #: 95-50-1 Cardnogenlclty: Systemic Toxlclty: See below. Endpolnt Experimental Doses UF MF RfD (ADI) Last minute Information prevented the release of these values. Endpolnt and Experimental Doses: Preparation Date: 0420P -]- 01/11/86 ------- Uncertainty Factors (UFs): Modifying Factors (MFs): Additional Comments: Confidence In the RfD: Study; Data Base: RfD: Documentation of RfO and Review: Agency RfO Review: U.S. EPA Contact: First Review: Primary: Second Review: FTS/684-75 or 513/569-75 Verification Date: Secondary: FTS/684-75 or 513/569-75 0420P -2- 01/11/86 ------- REFERENCE DOSES (RfOs) FOR ORAL EXPOSURE Chemical: Dlchlorofluoromethane CAS #: 75-71-8 Cardnogenldty: None. Systemic ToxIcHy: See below. e6eťoŤoŤeoo*BťŤoťŤ'"''eo6Doi>efto.BBeooŤeaooo6Ť<'Oo*ooce*o<'ť*'Ť>00ťŤťeťť*0"ť"*ťťť"Ťťo Endpolnt Experimental Doses UF MF RfD (ADI) Sherman (1974) 15 mg/kg/day (NOEL) 100 - 0.2 mg/kg/day or Rat chronic oral 10' mg/day for a study 70 kg man Reduced body weight 150 mg/kg/day (LOAEL) Endpolnt and Experimental Doses: Sherman, H. 1974. Long-term feeding studies In rats and dogs with dlchloro- dlfluoromethane (Freon 12 Food Freezant). Haskell Laboratory for Toxicology and Industrial Medicine Report No. 24-74. The study reported by the Haskell Laboratory (Sherman et al., 1974) Involved 2-year feeding studies In which dogs and rats received 300 ppm or 3000 ppm of d1chlorod1fluoromethane. This report contained data on clinical biochemical, urine analytical, hematologlcal or hlstopathologlcal evalua- tions. Additionally, carcinogenic and three-generation reproductive studies were conducted In rats. Except for decreased weight gain in rats (about 20/4 In females) which received 3000 ppm (150 mg/kg/day) dlchlorodlfluoromethane In the diet, no other adverse effects were attributable to this compound In either rats or dogs. The Haskell Laboratory study reported above Is sufficiently complete to derive an ADI for adequate protection against adverse human health effects. The high dose (3000 ppm or 150 mg/kg/day) caused decreased body weights In rats and thus considered as a LOAEL; whereas the low dose (300 ppm or 15 mg/kg/day) 1n rats produced no adverse effects attributable to the oral administration of dlchlorodlfluoromethane (Freon 12). Preparation Date: 01/06/86 0420P -1- 01/11/86 ------- Uncertainty Factors (UFs): The NOEL from the 2-year rat study (15 mg/kg/day) and an uncertainty factor of 100 (10 for species extrapolation and 10 for sensitive Individuals) were used to derive the ADI of 0.2 mg/kg/day or 10 mg/day for a 70 kg human being. Modifying Factors (MFs): None. Additional Comments: None. Confidence In the RfD: Study: High Data Base: Low RfD: High The Haskell Laboratory study Is a chronic oral study In two species which Incorporated extensive clinical and toxlcologlcal parameters. Therefore, a high level of confidence 1n study Is appropriate. Confidence 1n the data base Is low because of the lack of other data. Confidence In the RfD follows at high to medium. Documentation of RfD and Review: This document has undergone a limited Agency review. U.S. EPA. 1982. Errata: Halomethanes' Ambient Water Quality Criteria Docu- ment for the Protection of Human Health. Environmental Criteria and Assess- ment Office. Cincinnati, OH. ECAO-CIN-D023. Agency RfD Review: First Review: 07/08/85 Second Review: 07/22/85 Verification Date: 07/22/85 U.S. EPA Contact: Primary: C.T. DeRosa FTS/684-7534 or 513/569-7534 Secondary: M.L. Dourson FTS/684-7544 or 513/569-7544 0420P -2- 01/11/86 ------- REFERENCE DOSES (RfDs) FOR ORAL EXPOSURE Chemical: Dlmethoate CAS #: 60-51-5 Carclnogenldty: None. Systemic Toxlclty: See below. Endpolnt Experimental Doses UF MF RfD (ADI) Edson et al. (1967) NOEL: 0.2 mg/kg/day 10 - 0.02 mg/kg/day Short-term feeding LOAEL: 0.4 mg/kg/day study In humans Decreases 1.n chol- Inesterase (ChE) activity Endpolnt and Experimental Doses: Edson, E.F., K.H. Jones and W.A. Watson. 1967. Safety of dlmethoate Insecti- cide. Br. J. Med. 4: 554-555. Thr1ty-s1x male and female adult volunteers without occupational exposure to organophosphate Insecticides were arranged In groups and given repeated doses of dlmethoate. The dlmethoate was administered as a flavoured aqueous solution. Venous blood samples were taken twice before and once or twice/week after dlmethoate dosage started. ChE 1n whole blood was measured and Us depression taken as the critical first response to dlmethoate. Activity In red cells and plasma were also determined separately. The study was under close medical supervision, and Inquiry was also made for any effects other than ChE depression, though none was detected. The results show that no significant change occurred with 0.068 or 0.202 mg/kg/day. ChE values at 0.434 mg/kg/day began to show a slow downward trend by day 20, and this continued to the end of the test at 57 days. Higher doses showed the same effects at an earlier stage, and a somewhat faster rate. The rate and extent of red cell ChE depression closely paralleled those of whole- blood ChE. No localized gastrointestinal or other clinical effects occurred In any group. Preparation Date: 01/09/86 0420P -1- 01/11/86 ------- Uncertainty Factors (UFs): The uncertainty factor of 10 accounts for the expected Interhuman vari- ability to the toxlclty of this chemical In Heu of specific data. An addi- tional uncertainty factor of 10-fold to adjust the results found after short- term to chronic exposures Is not considered necessary here because the criti- cal toxic effect, chollriesterase Inhibition 1s Immediate and occurs regardless of exposure duration. Modifying Factors (MFs): None. Additional Comments: None. Confidence 1n the RfD: Study: High Data Base: High RfD: High The study Is given a confidence rating of high because 1t was conducted In humans with a fair amount of subjects at each of five doses. Chollnesterase Inhibition, the critical toxic effect was measured. The supporting animal data base 1s given a confidence rating of high because It Is extensive and yields similar RfD values. High confidence In the RfD follows. Documentation of RfD and Review: The ADI has been through the Registration Standard process of the OPP. Gessert, R.A. 1982. Memorandum to P. Parsons. Dlmethoate Registration Standard; Toxicology Assessment. Office of Pesticide Programs, U.S. EPA, Washington, DC, August 31. Agency RfD Review: First Review: 07/08/85 Second Review: 07/22/85 Verification Date: 07/22/85 U.S. EPA Contact: Primary: R. Engler FTS/537-7490 or 202/557-7490 Secondary: M.I. Dourson FTS/684-7544 or 513/569-7544 0420P -2- 01/11/86 ------- REFERENCE DOSES (RfDs) FOR ORAL EXPOSURE Chemical: Dlnoseb CAS #: 88-85-7 Carclnogenlclty: Limited data are negative. Systemic Toxldty: See below. Endpolnt Experimental Doses UF MF RfD (ADI) CBI NOEL: None 1000 - 0.001 mg/kg/day Rat chronic oral LOAEL: 1 mg/kg/day bloassay Decreased body and thyroid weights Endpolnt and Experimental Doses: CBI (Confidential Business Information) Sixty rats/sex/group were fed diets containing dlnoseb at 0, 1, 3 or 10 mg/kg bw/day for up to 104 weeks. Ten animals/sex were sacrificed at 1 year for Interim results. Clinical signs of toxldty attributed to dlnoseb were evident 1n all treated groups (hunched posture and urine staining of coat). A statistically significant and dose-related reduction In body weight gain was observed at 3 and 10 mg/kg/day. This effect was evident within the first year of treatment, and occurred despite Increased food consumption. Decreased mean relative absolute thyroid weights In all treated males and decreased relative thyroid weights 1n mid-dose males were observed at the 104-week terminal kill. No consistent dose-related effects were observed for hematology, selected blood chemistries or urlnalysls values. IIl.vicky and Caslda (1969) suggested that the mechanism of toxldty for dlnoseb Involved an elevated metabolic rate associated with uncoupling of oxldatlve phosphorylatlon. The observation of decreased growth rate with Increased food consumption, concurrent with decreased thyroid weight Is con- sistent with this hypothesis. Preparation Date: 01/06/86 0420P -1- 01/11/86 ------- Uncertainty Factors (UFs): The uncertainty factor of 1000 reflects 10 for both Intra- and Inter- species variability to the toxlclty of this chemical In lieu of specific data, and 10 for extrapolation from a LOAEL to It hypothesized NOAEL. Modifying Factors (MFs): None. Additional Comments: Body weight losses due to dlnoseb treatment have also been reported for rats treated at 9.1 mg/kg/day for 11 weeks and at 10 mg/kg/day for 6 months. A 90-day dog study showed reversible heart and liver effects at 5.3 mg/kg/day with a NOEL of 3 rag/kg/day. Dlnoseb was not carcinogenic 1n one rat study, and has not been found to be rautagenlc. Dlnoseb was teratogenlc by l.p. and s.c. administration to mice, but not by the oral route. Male reproductive toxlclty was observed for rats fed dlnoseb at 15.6 mg/kg/day for 11 weeks. Confidence 1n the RfD: Study: High Data Base: Medium RfD: Medium The confidence 1n the chosen study 1s high because of the large number of animals/sex 1n three dose groups, the large number of parameters measured, and because of the Interim kill. The data base Is rated medium because the sup- porting studies are only subchronlc 1n duration. Confidence 1n the RfD Is not higher than medium because a NOAEL was not established. Documentation of RfD and Review: The ADJ. In the 1984 Health and Environmental Effects Profile has received limited Agency review with the help of two scientists. U.S. EPA. 1984. Health and Environmental Effects Profile for Dlnoseb. Environmental Criteria and Assessment Office, Cincinnati, OH. ECAO-CIN-PO-87AP. 0420P -2- 01/11/86 ------- Agency RfD Review: First Review: 07/08/85 Second Review: 07/22/85 Verification Date: 07/22/85 U.S. EPA Contact: Primary: M.L. Dourson FTS/684-7544 or 513/569-7544 Secondary: C.T. DeRosa FTS/684-7534 or 513/569-7534 0420P -3- 01/11/86 ------- REFERENCE DOSES (RfDs) FOR ORAL EXPOSURE Chemical: Ethylbenzene CAS #: 100-41-4 CarclnogenlcHy: None. Systemic Toxlclty: See below. Endpolnt Experimental Doses UF MF RfD (ADI) Wolf et al. (1956) 136 mg/kg/day (NOEL); 1000 - 0.1 mg/kg/day 408 mg/kg/day (LOAEL) Rat subchronlc to chronic oral bio- assay Liver and kidney toxlclty Conversion Factor: 5 days/7 days; thus, 136 mg/kg/ day x 5 days/7 days =97.1 mg/kg/day Endpolnt and Experimental Doses: Wolf, H.A., V.K. Rowe, D.D. McColHster, R.L. HolUngsworth and F. Oyen. 1956. lexicological studies of certain alkylated benzenes and benzene. Arch. Ind. Health. 14: 387-398. The chosen study Is a rat 182-day oral bloassay where ethylbenzene was given 5 days/week at doses of 13.6, 136, 408 or 680 mg/kg/day In olive oil gavage. There were 10 albino female rats/dose group with 20 controls. The criteria considered In Judging the toxic effects on the test animals were growth, mortality, appearance and behavior, hematologlcal findings, terminal-concentration of urea nitrogen 1n the blood, final average organ and body weights, hlstopathologlcal findings, and bone marrow counts. The LOAEL of 408 mg/kg/day 1s associated with hlstopathologlcal changes In liver and kidney. Preparation Date: 01/09/86 0420P -1- 01/11/86 ------- Uncertainty Factors (UFs): The uncertainty factor of 1000 reflects 10 for both Intraspecles and Interspecles variability to the toxldty of this chemical In Heu of specific data, and 10 for extrapolation of a subchronlc effect level to Us chronic equivalent. Modifying Factors (MFs): None. Additional Comments: None. Confidence In the RfD: Study: Low Data Base: Low RfD: Low Confidence In the chosen study 1s low because rats of only one sex were tested and the experiment was not of chronic duration. Confidence 1n the supporting data base Is low because other oral toxldty data are not found. A low confidence In the RfD follows. Documentation of RfD and Review: A recent ORD document reaffirms the ADI from the ODW criteria document. -Both documents have extensive Agency review with the help of selected outside scientists review. An Identical ADI was publicly reviewed during the 1980 Ambient Water Quality Criteria series. U.S. EPA. 1980. Ambient Water Quality Criteria for Ethylbenzene. Environ- mental .Criteria and Assessment Office, Cincinnati, OH. EPA 440/5-80-048. U.S. EPA. 1985. Drinking Water Criteria Document for Ethylbenzene. Office of Drinking Water, Washington, DC. (Public review draft) U.S. EPA. 1985. Health Effects Assessment for Ethylbenzene. Environmental Criteria and Assessment Office, Cincinnati, OH. ECAO-CIN-H008. 0420P -2- 01/11/86 ------- Agency RfD Review: First Review: 05/20/85 Second Review: Verification Date: 05/20/85 U.S. EPA Contact: Primary: M.L. Dourson FTS/684-7544 or 513/569-7544 Secondary: C.T. DeRosa FTS/684-7534 or 513/569-7534 0420P -3- 01/11/86 ------- REFERENCE DOSES (RfDs) FOR ORAL EXPOSURE Chemical: Fluoride Cardnogenlclty: None. Systemic Toxlclty: See below. CAS #: 7782-41-4 Endpolnt Experimental Doses UF MF RfD (ADI) Hodge (1950) Cited In: Underwood (1977) Children epidemic- logical study Dental mottling 1 ppm (NOAEL con- verted to 0.05 mg/ kg/day 2 ppm (LOAEL) Coverslon Factor: 1 mg/L child = 0.05 mg/kg/day 0,05-0.2 mg/ kg/day or 1 mg/day for a 20 kg child excess fluoride Intake over background (NOAEL) x 1 L/day / 20 kg Endpolnt and Experimental Doses: Hodge, H.C. 1950. The concentration of fluorides In drinking water to give the point of minimum carles with maximum safety. J. Am. Dent. Assoc. 40: 436. Cited In: Underwood, E.J. 1977. Trace Elements In Human and Animal Nutrition. Academic Press, NY. Fluoride related compounds are used In the prevention of dental carles. Extensive human epldem1olog1cal studies with large populations have been carried out over the last 40 years. The NOAEL (1 ppm) and LOAEL (2 ppm) In drinking water are defined within a narrow dose range. Underwood (1977) Is the secondary reference cited for RfD (ADI) basis. Hodge (1950) 1s the primary reference dted 1n Underwood (1977). Hodge (1950) studied children consuming fluoride In their drinking water. Fluoride levels of 0-14 ppm were Investigated. Dental mottling was the parameter of Interest. Fluoride levels of 2-10 ppm produced a linear dose response curve (Increasing mottling with Increasing dose). Fluoride levels of 0.1-1.0 ppm produced no observable effect. An assumption of 20 kg bw for children was used as the children studied were 12-14 years old. Preparation Date: 01/06/86 0420P -1- 01/11/86 ------- Uncertainty Factors (UFs): Uncertainty factors were not deemed necessary since the NOAEL Is that of the critical toxic effect (I.e., dental fluorosls) In a sensitive population of humans (I.e., children for a length of exposure that encompasses both the critical toxic effect and the sensitive population. Modifying Factors (MFs): None. Additional Comments: A range of RfD of 0.05-0.2 mg/kg/day Is given. The upper limit Is based on the Surgeon General's statement that no adverse medical effects occur at excess fluoride exposures of 4 ppm of drinking water or less (I.e., 4 mg/L x 1 L/day / 20 kg = 0.2 mg/kg/day). Confidence, 1n the RfD: Study: Medium Data Base: High RfD: High Confidence 1n the study Is medium because the exposures represent excess fluoride Intake and not total doses. Confidence In the data base Is high because of the large number of _studies conducted 1n children all support the chosen NOAEL. Confidence In the RfD Is high because little uncertainty remains In the toxlclty data base. Documentation of RfD and Review: ECAO-C1nc1nnat1 Internal Review, July 1985. U.S. EPA. 1985. FlouMne: Review and Evaluation of ADI. Contract No. 68-03-3228. Environmental Criteria and Assessment Office, Cincinnati, OH. Agency RfD Review: First Review: 08/05/85 Second Review: Verification Date: 08/05/85 U.S. EPA Contact: Primary: C.T. DeRosa FTS/684-7534 or 513/569-7534 Secondary: M.L. Dourson FTS/684-7544 or 513/569-7544 0420P -2- 01/11/86 ------- REFERENCE DOSES (RfOs) FOR ORAL EXPOSURE Chemical: Formic Add CarclnogenlcHy: None. Systemic Toxldty: See below. CAS #: 64-18-6 Endpolnt Experimental Doses UF MF RfD (ADI Malorny (1969) Rat oral chronic study 200 mg/kg/day (NOAEL) 0.2* drinking water 100 2 mg/kg/day or 140 mg/day for a 70 kg man Solmann (1921) Rat oral subchronlc bloassay Body weight 0.5% drinking water (LOAEL) Endpolnt and Experimental Doses: Malorny. G. 1969. Acute and chronic toxldty of formic add and formate. Z. Ernachrungswlss. 9: 332-339. Formic add Is a normal component of human tissues and foods and is Important In Intermediary metabolism. Ingested formic add 1s rapidly metabolized and excreted (Malorny, 1969). The best Information on which to base an ADI Is the study of Malorny (1969) In which no adverse effects were observed 1n several generations (5) of rats that consumed 150-200 mg/kg/day (author's estimated range) of formic add. None of the other Information available suggests that toxic effects would occur at lower levels. Solmann (1921) reported a series of studies 1n which rats received 0.25X formic acid In drinking water (mean dosage of 160 mg/kg) for 15 week without showing any effects on growth or food and water consumption. Solmann (1921) also reported a study 1n which men consumed sodium formate 1n doses of 10 g/day (150 mg/kg/day) for some time without any harmful effects. On the other hand, formate doses of 2-3 g several times dally has been reported to cause nausea and albumlnurla In men (von Oettlngen, 1969). Preparation Date: 01/09/86 0420P -1- 01/11/86 ------- Endpolnt and Experimental Doses (cont.): The TLV for formic add vapor In the atmosphere Is 5 ppm (ACGIH, 1984), the same as the OSHA standard (CFR, 1981). Formic add 1s "generally recog- nized as safe" as a synthetic flavoring substance and an Indirect food sub- stance (Guest et al., 1982). Uncertainty Factors (UFs): Based on the Information available, the NOEL of 200 mg/kg/day (Malorny, 1969) can be divided by an uncertainty factor of 100 (10. for Intraspedes extrapolation and 10 for sensitive population) to derive an ADI of 2 mg/kg/day for protection against adverse human health effects. Modifying Factors (MFs): None. Additional Comments: None. Confidence In the RfD: Study: Medium Data Base: Medium RfD: Medium The study Is given a medium confidence because of the extensive length of testing (I.e., 5 generations), several parameters were measured. The data base 1s rated medium because several studies are available that support the choice of NOAEL. A medium rating 1n the'RfD follows. Documentation of RfD and Review: ECAO-C1nc1nnat1 Internal Review, August 1985. U.S. EPA. 1985. Formic Add: Review and Evaluation of ADI. Contract No. 68-03-3228. Environmental Criteria and Assessment Office, Cincinnati, OH. 0420P -2- 01/11/86 ------- Agency RfD Review: First Review: 08/19/85 Second Review: Verification Date: 08/19/85 U.S. EPA Contact: Primary: C.T. DeRosa FTS/684-7534 or 513/569-7534 Secondary: M.L. Dourson FTS/684-7544 or 513/569-7544 0420P -3- 01/11/86 ------- REFERENCE DOSES (RfDs) FOR ORAL EXPOSURE Chemical: Hydrogen Cyanide Carctnogeniclty: None. - Systemic Toxlclty: See below. CAS #: 74-90-8 Endpolnt Experimental Doses UF MF 5 RfD (ADI) Howard and Hanzal (1955) Rat oral chronic study Phtlbrick et al. (1979) Rat subchronlc to chronic oral bio- assay Decreased body and thyroid weights and rayelln degeneration 10,8 rag/kg/day CN (NOAEL) 100 30 rag/kg/day (LOAEL) CN 0,02 mg/kg/day or 2 mg/day for a 70 kg man Conversion 27/26; thus HCN Factor: Molecular 10.8 mg/kg/day CN x weight of HCN/CN is 27/26 =11.2 rag/kg/day Endpolnt and Experimental Doses: Howard, J.H. and R.F Hanzal. 1955, Chronic toxicity to rats of food treated with hydrogen cyanide. Agric. Food Chen. 3: 325-329. Since hydrogen is present in very high levels physiologically an ADI of 1.5 mg/day is recoonended based on cyanide content. In this 2-year dietary study, rats (10/sex/group) were administered food fumigated with HCN. The average daily concentrations were 73 and 183 mg CN/kg diet. Froa ttie data reported on food consumption and body weight, daily esti- mated doses were 4.3 mg and 10.8 mg CN/kg bw. The average food CN concentra- tions were estimated based on the author's data for concentration at the Preparation Date: 01/06/86 Q42QP -1- 01/11/86 ------- Endpolnt and Experimental Doses (cont.): beginning and end of each food preparation period and by assuming a first order rate of loss for the Intervening period. There were no treatment related effects on growth rate, no gross signs of toxldty, and no hlstopatho- loglcal lesions. Studies by PhUbrlck et al. (1979) showed decreased weight gain and thyroxln levels and myelln degeneration In rats at 30 mg/kg/day CN. Other chronic studies either gave higher effect levels or used subcutaneous route (Crampton et al., 1979; Lessen, 1971; Herthlng et al., I960). Human data do not provide adequate Information from which to derive an ADI because effective dose levels of chronically Ingested CN are not documented. Therefore, the study of Howard and Hanzel (1955) provides the highest NOAEL 10.8 mg/kg/day for CN and 1s chosen for the derivation of an ADI for CN of 1.5 mg/day or 0.02 mg/kg/day. Cyanide Is metabolized extensively In the liver. Indicating that the only relevant route of administration for quantitative risk assessment In the deri- vation of "an oral -ADI 1s the oral route of administration. Uncertainty Factors (UFs): According to the U.S. EPA (1985) an uncertainty factor of 100 1s used to derive the ADI (10 for species extrapolation, 10 for sensitive population). Modifying Factors (MFs): A modifying factor of 5 1s used for apparent tolerance of cyanide when It 1s Ingested with food than when administered by gavage or drinking water. Additional Comments: Decreased protein efficiency ratio was produced by dietary cyanide treat- ment of rats during gestation, lactation and postweanlng growth phase In the Tewe and Haner (1981a) experiment: the dose level of cyanide (10.6 mg/kg/day) producing that effect 1s slightly lower than the currently accepted NOAEL of 10.8 mg/kg/day (U.S. EPA, 1985). Furthermore, Tewe and Maner (1981b) tested sows. Possible effects observed at about 9.45 mg/kg/day were proliferation of glomerular cells of the kidneys and reduced activity of the thyroid glands In the gilts. However, the number of animals 1n this experiment was very small. A Japanese study (Amo, 1973) Indicated that 0.05 mg/kg/day of cyanide obtained from drinking water decreased the fertility rate and survival rate 1n the Fl generation and produced 100% mortality In the F2 generation In mice. However, these data are not consistent with the body of available literature. Thus, 0420P -2- 01/11/86 ------- Additional Comments (cont.): until additional chronic studies are available, an ADI of 2 mg/day for a 70 kg man 1s recommended. Additional chronic/reproductive studies are needed to support a higher level of confidence In the RfD. Confidence 1n the RfD: Study: Medium Data Base: Medium RfD: Medium The confidence In the study 1s medium because adequate records of food consumption and body weight were maintained and animals of both sexes were tested at two doses for 2 years. The data base Is rated medium because a small but sufficient number of studies support the chosen study. The confi- dence In the RfD follows. Additional chronic/reproductive studies are needed to support a higher level of confidence 1n the RfD. Documentation of RfD and Review: U.S. EPA. 1984. Health Effects Assessment for Cyanides. Environmental Cri- teria and Assessment Office, Cincinnati, OH. ECAO-CIN-H01.1. U.S. EPA. 1985. Drinking Water Criteria Document for Cyanides. Office of Drinking Water, Washington, DC. The Drinking Water Criteria document and the Health Effects Assessment document have undergone an extensive Agency and limited external review. Agency RfD Review: First Review: 08/05/85 Second Review: Verification Date: 08/05/85 U.S. EPA Contact: Primary: C.T. DeRosa FTS/684-7534 or 513/569-7534 Secondary: M.L. Dourson FTS/684-7544 or 513/569-7544 0420P -3- 01/11/86 ------- REFERENCE DOSES (RfDs) FOR ORAL EXPOSURE Chemical: Hydrogen Sulflde CAS #: 7783-06-4 Cardnogenldty: None. Systemic ToxIcHy: See below. Endpolnt Experimental Doses UF MF RfD (ADI) Watterau et al. 3.1 mg/kg/day (NOAEL) 1000 - 0.003 mg/kg/day (1964-1965) or 0.2 mg/kg/day for P1g oral toxicHy a 70 kg man study (subchronlc) GI disturbance 15 mg/kg/day (LOAEL) Dose Conversion: 0.200 kg of diet/day x 1210 mg H2S/kg of diet / 78 kg bw = 3.1 mg/kg bw/day Endpolnt and Experimental Doses: Watterau, H., H. Ockert and U.G. Knape. 1964-1965. In: ToxIcHy of Hydrogen Sulflde 1n Animal Feeding. Survey of the literature. (Westermann et al., 1975. Landwlrtsch. Forsch. 28: 70-80) Data regarding chronlc/subchronlc toxldty of H2S was limited and H2S Is not scheduled for cardnogenlcHy testing by the NTP (1985). The oral toxl- clty data (Watterau et al., 1964-1965) may be used to calculate an ADI. Although lacking 1n some detail, Watterau et al. (1964-1965) suggest that adult pigs showed digestive disorders when their diet was replaced by a high percentage of dried greens containing H2S at an approximate Intake of 15 mg/kg/day. This effect was not reproduced 1n a second experiment. This dose may be .considered a LOAEL. Watterau et al. (1964-1965) also tested pigs for 105 days at three lower doses. An Intermediate dose of approximately 3.1 mg/kg/day (determined from Information given 1n the critical study) was associated with no changes In body weight gain when compared to control. Preparation Date: 01/10/86 0420P -1- 01/11/86 ------- Uncertainty Factors (UFs): The uncertainty facotr of 1000 represents 10 for Interspedes extrapola- tion, 10 for sensitive population and 10 for subchronlc exposure. An ADI of 0.003 mg/kg/day may be recommended for adequate protection against adverse human health effects. Modifying Factors (MFs): None. Additional Comments: Based on ep1dem1olog1cal data (Poda, 1966) the ACGIH (1980) has recom- mended a TLV-TWA of 10 ppm (13.9 mg/cu. m) for hydrogen sulflde. However, citing evidence of eye Injury, headaches, nausea and Insomnia after exposure to H2S at low concentrations for several hours, NIOSH (1977) adopted a celling occupational exposure limit of 10 ppm with a I0-m1nute maximum exposure to this concentration. More rigorous ep1dem1olog1cal evidence, however, Is limited. Until further chronic/reproductive data available, a low confidence In the RfD 1s recommended. Confidence 1n the RfD: Study: Low Data Base: Low RfD: Low The confidence In the study 1s rated low because the number of animals/ dose group was unspecified and the study was designed to test for only minimal toxic responses. The supporting oral toxldty data base Is rated low because 1t does not exist. Low confidence In the RfD follows. Documentation of RfD and Review: ECAO-C1nc1nnat1 Interanl Review, August 1985. U.S. EPA. 1985. Hydrogen Sulflde: Review and Evaluation of ADI. Contract No. 68-03-3228, Environmental Criteria and Assessment Office, Cincinnati, OH. Agency RfD Review: First Review: 08/19/85 Second Review: Verification Date: 08/19/85 U.S. EPA Contact: Primary: C.T. DeRosa FTS/684-7534 or 513/569-7534 Secondary: M.L. Dourson FTS/684-7544 or 513/569-7544 0420P -2- 01/11/86 ------- REFERENCE DOSES (RfDs) FOR ORAL EXPOSURE Chemical: Llnuron CAS #: 330-55-2 CardnogenlcHy: Systemic Toxlclty: See below. Endpolnt Experimental Doses UF MF RfD (ADI) Information to be provided by the Office of Pesticide Programs Endpolnt and Experimental Doses: Preparation Date: °420P -1- 01/11/86 ------- Uncertainty Factors (UFs): Modifying Factors (MFs)r Additional Comments: Confidence In the RfD: Study: Data Base: RfD: Documentation of RfD and Review: Agency flfD Review: U.S. EPA Contact: First Review: Primary: Second Review: FTS/684-75 or 513/569-75 Verification Date: Secondary: FTS/684-75 or 513/569-75 0420P -2- 01/11/86 ------- REFERENCE DOSES (RfDs) FOR ORAL EXPOSURE Chemical: Malathlon CAS #: 121-75-7 Cardnogenlclty: None. Systemic Toxlclty: See below. oťaaoeŤ6Ťťťť*Ť6ť*ťi>ŤŤŤoťo"'>e*0ťBS*eoo>B8S'oe*'''"0*oe"ce"0"0''**e*'*''*Se""S''B**et** Endpolnt Experimental Doses UF MF RfD (ADI) *.ftťŤŤťŤeť*ťŤťť6"*"ťŤŤťŤťťŤtooIť"*eeoc'l80000C*eeeo''*"eOS**<'*ee****"*"****e**** Rider et al. (1959); 0.23 mg/kg/day 10 - 0.02 mg/kg/day Moeller and Rider (NOEL); (1962) - Human subchronlc 0.34 mg/kg/day oral bloassay (LOEL) Chollnesterase Inhibition Endpolnt and Experimental Doses: Rider, J.A., H.C. Hoeller, J. Swader and R.G. Devereaux. 1959. A study of the antlchollnesterase properties of EPN and malathlon 1n human volunteers. CUn. Res. 1: 81. Moeller, H.C. and S.A. Rider. 1962. Plasma and red blood cell Chollnesterase activity as Indications of the threshold of Incipient toxldty of ethyl-p- nltrophenylthlonobenzenephosphonate (EPN) and malathlon In human being. Toxlcol. Appl. Pharmacol. 4: 123-130. Malathlon was administered by gelatin capsules to groups of five healthy male volunteers ranging 1n age from 23-63 years at doses of either 8 mg/day for 32 days, 16 mg/day for 47 days or 24 mg/day for 56 days. Chollnesterase activity, was determined twice weekly before, during and after administration of the chemical. The Intermediate dose was a NOEL. The high-dose was associated with a depression In plasma and RCB Chollnesterase activity with no clinically manifested side effects. The choice of human study for derivation of the ADI 1s well supported by animal studies. Although the clinical study appears to have been well Preparation Date: 01/09/86 0421P -1. 01/11/86 ------- Endpolnt and Experimental Doses (cont.): conducted with five male volunteers In each of three dose groups, the duration of the study Is rather short (32-56 days), Investigators only looked for one type of effect and body weights were not given. Uncertainty Factors (UFs): The 10-fo.ld factor accounts for the expected Interhuman variability to the toxldty of this chemical In lieu of specific data. Note that the usual factor of 10S to estimate a chronic effect level from a .subchronlc effect level 1s not considered necessary here because the critical toxic effect (I.e., chollnesterase Inhibition) 1s thought to be Independent of exposure duration. Modifying Factors (HFs): None. Additional Comments: None. Confidence 1n the RfD: Study: Medium Data Base: High RfD: Medium Confidence 1n the chosen study Is rated medium because only one sex was tested and the duration was rather short. Confidence 1n the supporting data base Is rated high because several animal studies support the chosen effect level. Confidence 1n the RfD Is rated medium to high. Documentation of RfD and Review: The ADI 1n this 1984 Health and Environmental Effects Profile has received a limited Agency review with the help of two external scientists. U.S. EPA. 1984. Health and Environmental Effects Profile for Malathlon. Environmental Criteria and Assessment Office, Cincinnati, OH. ECAO-CIN-P101. 0421P -2- 01/11/86 ------- Agency RfD Review: First Review: 07/22/85 Second Review: Verification Date: 07/22/85 U.S. EPA Contact: Primary: M.L. Dourson FTS/684-7544 or 513/569-7544 Secondary: C.T. DeRosa FTS/684-7534 or 513/569-7534 0421P -3- 01/11/86 ------- REFERENCE DOSES (RfDs) FOR ORAL EXPOSURE Chemical: MCPA Carclnogenlclty: None. Systemic Toxlcity: See below. CAS #: 94-74-6 Endpolnt Experimental Doses UF MF RfD (ADI) Reuzel et al. (1980) 1.0 mg/kg/day (NOEL) 1000 0.001 mg/kg/day Dog subchc.onlc oral bloassay Kidney and liver toxldty 3.0 mg/kg/day (LOAEL) Endpolnt and Experimental Doses: Reuzel et al. 1980. CBI (Confidential Business Information) Two 13-week studies were conducted In dogs by Reuzel et al. (1980). Col- lectively five doses were given to groups of four dogs/sex. A clinical syn- drome which Included Icterus, diarrhea, cornea! ulcers, severe dermatitis, dehydration and severe weight loss led to the death or humane kill of 7/8 high-dose dogs. Elevated blood creatlnlne and urea nitrogen were observed In a dose-related fashion at the three highest doses, suggesting Impaired kidney function. (The lowest of these doses . was 3.0 mg/kg/day.) The two lowest doses showed, no effects outside normal limits. (The highest of these doses was 1.0 mg/kg/day.) Preparation Date: 01/06/86 0421P -1- 01/11/86 ------- Uncertainty Factors (UFs The uncertainty factor of 1000 reflects 10 for both Intraspecies and Interspecles variability to the toxlcity of this chemical In Heu of specific data, and 10 for extrapolation of a subchronlc effect level to Us chronic equivalent. Modifying Factors (MFs): None. Additional Comments: None. Confidence 1n the RfD: Study: Medium Data Base: Medium RfD: Medium Confidence in the chosen study Is medium because the study appears to be well conducted with four beagle dogs/sex in each of five dose groups. Con- fidence In the data base is medium because the CBI study for the derivation of the ADI is moderately well supported by studies 1n the open literature. Medium confidence In the RfD follows. Documentation of RfD and Review: The ADI In the 1984 Health and Environmental Effects Profile has received a limited Agency review with the help of two external scientists. U.S. EPA. 1984. Health and Environmental Effects Profile for MCPA and MCPB. Environmental Criteria and Assessment Office, Cincinnati, OH. ECAO-CIN-P082AP. Agency RfD Review: First Review: 07/22/85 Second Review: Verification Date: 07/22/85 U.S. EPA Contact: Primary: M.L. Dourson FTS/684-7544 or 513/569-7544 Secondary: C.T. DeRosa FTS/684-7534 or 513/569-7534 0421P -2- 01/11/86 ------- REFERENCE DOSES (RfDs) FOR ORAL EXPOSURE Chemical: Mercury Fulminate Cardnogenlclty: None. Systemic Toxlclty: See below. CAS #: 628-86-4 Endpolnt Experimental Doses UF MF RfD (ADI) FHzhugh et al. (1950) Rat oral chronic study Renal and kidney damage NOEL: A well defined 1000 level was not avail- able 0.003 mg/kg/day or 0.2 mg/day for a 70 kg man 40 ppm Hg or 2 mg Hg/kg/day (LOAEL) converted to 2.83 mg/kg/day mercury fulminate Conversion Factors: 5% food consumptlon/g body weight; molecular weight of mercury fulminate (C2HgN202) to mercury (Hg) 1s 285/201; thus, 40 mg/kg of diet (I.e., 40 ppm) x 0.05 kg of diet/kg bw/day x 285/201 = 2.83 mg/kg bw/day Endpolnt and Experimental Doses: FHzhugh, O.G., A.A. Nelson, ties of mercuric phenyl and 433-441. E.P. Lang and F.M. Kunze. 1950. mercuric salts. Arch. Ind. Hyg. Chronic toxld- Occup. Med. 2: Tht-s-ls the only chronic Ingestlon study designed to evaluate the. toxldty of Inorganic mercury salts. In this study, rats of both sexes (20-24/group) were given 0.5, 2.5, 10, 40 or 160 ppm mercury as mercury acetate for up to 2 years. Assuming food consumption was equal to 554 bw/day, the dally Intake of Hg was 0.025, 0.125, 0.5, 2.0 or 8.0 mg/kg/day, respectively. Detailed micro- scopic evaluation of various tissues Indicated that only the kidney was affected to any degree with lesions 1n the proximal convoluted tubules and cortex. Treatment related changes did not appear to be present at doses Preparation Date: 01/10/86 0421P -1- 01/11/86 ------- Endpolnt and Experimental Doses (cont.): greater than 40 ppm. However, the description of effects occurring at the lower doses was not well characterized. Therefore, 40 ppm (2.0 mg/kg) was Identified as a LOAEL In the study. There 1s no Information concerning the toxldty of mercury fulminate. Assuming that the toxldty of this compound 1s due primarily to Us mercury component, It Is appropriate to derive an ADI for mercury fulminate based on analogy to mercury. This assumption 1s supported by the fact that cyanates do not exhibit 'the high toxldty of cyanides and that mercury compounds are con- siderably more toxic. Therefore, using the LOAEL 2 mg/kg/day provided by the FHzhugh et al. (1950) study, an ADI of 0.003 mg/kg/day or 0.2 mg/day Is derived. Uncertainty Factors (UFs): An uncertainty factor of 1000 was used to account for )nterspedes extrap- olation, differences in sensitivity among humans and for the conversion of a LOAEL to a NOAEL. Modifying Factors (HFs): None. Additional Comments: No data are available on the toxlclty of mercury fulminate. Confidence 1n the RfD: Study: Medium Data Base: Low RfD: Low Confidence In the study Is rated medium as a medium amount of animals/sex was used- In each of five dose groups and several parameters were measured. The NOAEL, however, was not well defined. Confidence In the supporting data base and RfD are both low; since the toxlclty of mercury fulminate has not been tested, this RfD 1s based on analogy to Inorganic mercury. -2- 01/11/86 ------- Documentation of RfD and Review: ECAO-C1nc1nnat1 Internal Review, August 1985. U.S. EPA. 1985. Mercury Fulminate: Review and Evaluation of ADI. Contract No. 68-03-3228. Environmental Criteria and Assessment Office, Cincinnati, OH, Agency RfD Review: First Review:' 08/19/85 Second Review: Verification Date: 08/19/85 U.S. EPA Contact: Primary: C.T. DeRosa FTS/684-7534 .or 513/569-7534 Secondary: M.L. Dourson FTS/684-7544 or 513/569-7544 0421P -3- 01/11/86 ------- REFERENCE DOSES (RfDs) FOR ORAL EXPOSURE Chemical: Mercury (Inorganic) Cardnogenldty: None. Systemic Toxlclty: See below. CAS #: 7439-97-6 Endpolnt Experimental Doses UF MF RfD (ADI1 FHzhugh et al. (1950) Rat oral chronic study Renal and kidney damage NOAEL: None 1000 0.002 mg/kg/day or 0.1 mg/day for a 70 kg man 40 ppm verted bw/day Of diet con to 2 mg/kg (LOAEL) Conversion Factor: Food consumption 5/4 body weight; thus, 40 mg/kg of diet (I.e., 40 ppm) x 0.05 kg of diet/kg bw/day = 2 mg/kg/day Endpolnt and Experimental Doses: FHzhugh, O.G., A.A. Nelson, E.P. Laug and P.M. 1c1t1es of mercuric phenyl and mercuric salts. 2: 433-441. Kunze. 1950. Chronic'tox- Arch. Ind. Hyg. Occup. Med. This Is the only chronic Ingestlon study designed to evaluate the toxldty of Inorganic mercury salts. In this study, rats of both sexes (20-24/ group) were given 0.5, 2.5, 10, 40 or 160 ppm mercury as mercury acetate for up to 2 years. Assuming food consumption was equal to 5% bw/day, the dally Intake was equal to- 0.025, 0.125, 0.5, 2.0 and 8.0 mg/kg bw, respectively. Detailed microscopic evaluation of various tissues Indicated that only the kidney was affected to any degree with lesions In the promlxal convoluted tubules and cortex. Treatment-related changes did not appear to be present at doses less than 40 ppm. Also, 1t was noted present to some degree ' that the damage occurring at these lower doses was n older control animals. The 40 ppm feeding level was Preparation Date: 01/09/86 0421P -1 01/11/86 ------- Endpolnt and Experimental Doses (cont.): Identified as a LOAEL In this study. Although It appears that the 10 ppm feeding level, as well as the two lower doses, may have been a NOAEL the descriptive manner 1n which the data are presented makes 1t difficult to ade- quately evaluate the hlstopathologlcal data for these doses. As a result of this uncertainty and since the use of the 40 ppm LOAEL will result in a some- what more protective estimate than a 10 ppm NOAEL, the 40 ppm LOAEL Is chosen as the basis for an ADI calculation. Short-term and subchronlc studies were conducted by Barlety et al. (1971), Druet et al. (1978), Weening et al. (1978) and Makker and Alkawa (1979). A NOAEL of 50 ug/kg for antibody formation could be derived from the study of Druet et al. (1978). However, this study Is not chosen because the route of exposure was subcutaneous Injection, the Immune response occurred only 1n a genetically susceptible strain of rats and the duration of the study was only 8-12 weeks. Uncertainty Factors (UFs): Based upon these factors the Fltzhugh et al. (1950) study was considered most appropriate for the development of an ADI. This study established a LOAEL of 2 mg/kg bw/day. Applying scaling factors of 100 to account for extrapolation from animals to humans and differences In sensitivity among human population and an additional 10 for conversion of a LOAEL to a NOAEL an ADI or 0.002 mg/kg/day or 0.1 mg/day for a 70 kg human was derived. Modifying Factors (MFs): None. Additional Comments: The data base for this chemical Is characterized by only one chronic 1ngest1on study with a small number of animals surviving past 18 months (20-24 animals/group). Short-term and subchronlc studies by 1.p. or s.c. exposures and supporting ep1dem1olog1cal data are not well characterized. Confidence In the RfD: Study: Medium Data Base: Medium RfD: Medium Confidence 1n the study 1s rated medium as a medium amount of animals/sex was used in each of five dose groups and several parameters were measured. 0421P -2- 01/11/86 ------- Confidence In the RfD (cont.): The NOAEL, however, was not well defined. Confidence In the data base U medium because a small number of studies lends some support. Medium confi- dence 1n the RfD follows. Documentation of RfD and Review: Limited peer review and Agency-wide Internal review, 1984. U.S. EPA. 1984. Health Effects Assessment Document for Mercury. Environ- mental Criteria and Assessment Office, Cincinnati, OH. Agency RfD Review: First Review: 08/05/85 Second Review: Verification Date: 08/05/85 U.S. EPA Contact: Primary: C.T. DeRosa' FTS/684-7534 or 513/569-7534 Secondary: M.L. Dourson FTS/684-7544 or 513/569-7544 0421P -3- 01/11/86 ------- REFERENCE DOSES (RfDs) FOR ORAL EXPOSURE Chemical: Hethylene Chloride Carc1nogen1c1ty: CAG, U.S. EPA - Category B2. Systemic ToxIcHy: See below. CAS #: 75-09-2 Endpolnt Experimental Doses UF MF RfD (ADI) National Coffee Association (1982) 2-year rat drinking water bloassay Liver toxldty NOEL: 5.85 and 6.47 mg/kg/day for males and females, respec- tively LOAEL: 52.58 and 58.32 mg/kg/day for males and females, respectively 100 0.06 mg/kg/day Endpolnt and Experimental Doses: National Coffee Association. 1982. 24-Month chronic toxldty and oncogenl- dty study of methylene chloride 1n rats. Final Report. Prepared by Hazelton Laboratories America, Inc., Vienna, VA, August 11. The chosen study appears to have been very well conducted with 85 rats/ sex at each of four dose groups. A high-dose recovery group of 25 rats/sex, as well as two control groups of 85 and 50 rats/sex, was also tested. Many effects were monitored. The supporting data base, In addition to this study, 1s limited with an Inhalation NOEL of 87 mg/cu. m (Haun et al., 1972). [The equivalent oral dose Is about 28 mg/kg bw/day (I.e., 87 mg/cu. m x 0.5 x 0.223 cu. m/day / 0.35 kg; these exposure values are for rats).] Preparation Date: 01/06/86 0421P -1- 01/11/86 ------- Uncertainty Factors (UFs): The 100-fold factor accounts for both the expected 1ntra- and Inter- species variability to the toxldty of this chemical In lieu of specific data. Modifying Factors (HFs): None. Additional Comments: None. Confidence In the RfD: Study: High Data Base: Medium RfD: Medium The study 1s given a high confidence rating because a large number of ani- mals was tested of both sexes In four dose groups, with a large number of con- trols. Many effects were monitored and a good dose-severity was obtained. The data base Is rated medium to low because only a few studies support the chosen NOAEL. Medium confidence In the RfD follows. Documentation of RfD and Review. The ADI has only been reviewed by the U.S. EPA's ADI Work Group during the summer of 1985. U.S. EPA. 1985. Drinking Water Criteria Document for Methylene Chloride. Office of Drinking Hater, Washington, DC. (Draft) Agency RfD Review: First Review: 06/24/85 Second Review: 07/08/85 Verification Date: 07/08/85 U.S. EPA Contact: Primary: K. Khanna FTS/382-7588 or 202/382-7588 Secondary: M.L. Dourson FTS/684-7544 or 513/569-7544 0421P -2- 01/11/86 ------- REFERENCE DOSES (RfDs) FOR ORAL EXPOSURE Chemical: Methyl Ethyl Ketone Cardnogenldty: None. Systemic Toxlclty: See below. CAS #: 78-93-3 Endpolnt Experimental Doses UF MF RfD (ADI) LaBelle and Brleger (1955) Rat 1nhalat1on/sub- chronlc study Schwetz et al. (1974) Teratology bloassay Fetotoxldty tera- togenlclty 235 ppm (693 mg/ cu. m) converted to 46 mg/kg/day (NOAEL) 130.5 mg/kg/day (estimated LOAEL) 1000 0.05 mg/kg/day or 3 mg/day for a 70 kg man Conversion Factors: 7 hour/24 hour, 5 days/7 days, 0.223 cu. m/day/0.35 kg (rat breathing rate/rat body weight) 0.5 absorption rate; thus, 693 mg/cu. m x 7 hour/24 hour x 5 days/7 days x 0.223 cu. m/day / 0.35 kg x 0.5 = 46 mg/kg/day Endpolnt and Experimental Doses: LaBelle, W. and H. Brleger. 1955. The vapor toxlclty of a composite solvent and Its principal components. Am. Med. Assoc. Arch. Ind. Health. 12: 623-627. Adequate chronic toxldty testing has not been performed with methyl ethyl ketone. Although several more recent subchronlc studies have been conducted (Freddl et al., 1982; Cavender et al., 1983; Takeuchl et al., 1983). only the NOAEL of the LaBelle and Brleger (1955) provides the lowest and most protec- tive dose for deriving an ADI. In this study, 25 rats were exposed to 235 ppm of methyl ethyl ketone for 7 hour/day, 5 days/week for 12 weeks. No effects were observed, but only a few parameters were measured. Methyl ethyl ketone has also been tested for teratogenldty (Schwetz et al., 1974; Deacon et al.. Preparation Date: 01/09/86 0421P -1- 01/11/86 ------- Endpoint and Experimental Doses (cont.): 1981) and the observed LOAELs for fetotoxIcHy are higher than the NOAELs of LaBelle and Brieger (1955). The animal NOAEL of 693 mg/cu. m was converted to a human NOAEL of 46 mg/kg/day to derive an ADI of 0.05 mg/kg/day. The route extrapolation raises a level of uncertainty due to- differences In pharmacoklnetlc parameters, notably, absorption and elimination. Uncertainty Factors (UFs): The uncertainty factor of 1000 reflects 10 for both Intraspecles and Interspedes variability to the toxlclty of this chemical In lieu of specific data, and 10 for extrapolation of a subchronlc effect level to Us chronic equivalent. Modifying Factors (MFs): None. Additional Comments: No oral chronic studies are available at this time. Several subchronlc Inhalation studies provided adequate data 1n support of a RfD with a medium level of confidence. Confidence 1n the RfD: Study: Medium Data Base: Medium RfD: Medium The study 1s given medium to low confidence because only 25 rats were exposed to only one dose, and the sex, strain and amount of control animals were unspecified. The data base Is given a medium rating because four differ- ent studies lend some support to the chosen NOAEL. Medium to low confidence In the -RfO follows. Documentation of RfD and Review: ECAO-C1ndnnat1 Internal Review, May 1985. U.S. EPA. 1985. Methyl Ethyl Ketone: Review and Evaluation of ADI. Contract NO. 68-03-3228. Environmental Criteria and Assessment Office, Cincinnati, OH. 0421P- -2- 01/11/86 ------- Agency RfD Review: First Review: 07/08/85 Second Review: Verification Date: 07/08/85 U.S. EPA Contact: Primary: C.T. DeRosa FTS/684-7534 or 513/569-7534 Secondary: M.L. Dourson FTS/684-7544 or 513/569-7544 0421P -3- 01/11/86 ------- REFERENCE DOSES (RfDs) FOR ORAL EXPOSURE Chemical: Methyl Ethyl Ketone Peroxides CAS #: 1338-23-4 Carclnogenlclty: None. Systemic Toxlclty: See below. Endpolnt Experimental Doses UF MF RfD (ADI) ACGIH (1984) 1.5 mg/cu. m (TLV) 10 - 0.008 mg/kg/day converted to 0.077 or mg/kg/day 0.5 nig/day for a 70 kg man Conversion Factors: x 5 days/7 days x 10 cu. m/day (human breathing rate In 8 work hours) 0.5% absorption / 70 kg; thus, 1.5 mg/cu. m x 5 days/7 days x 10 cu. m/day x 0.5 / 70 kg = 0.077 mg/kg/day Endpolnt and Experimental Doses: ACGIH (American Conference of Governmental Industrial Hyglenlsts). 1984. Methyl Ethyl Ketone Peroxides. Documentation of Threshold Limit Values, 4th ed. Threshold Limit Values for Chemical Substances and Physical Agents In the Workroom Environment with Intended Changes for 1984-1985. p. 279-280. The ACGIH (1984) has set a celling limit TLV of 0.2 ppm for methyl ethyl ketone peroxides, by analogy to hydrogen peroxide. Floyd and Stoklnger (1958) conducted Inhalation and oral acute testing of this compound establishing Us LD50 and LC50 In rats and mice. The results of this study Indicated that methyl ethyl ketone peroxide was more toxic than benzozyl peroxide (TLV=5 mg/cu. .m) and similar In toxlclty to hydrogen peroxide (TLV=1.4 mg/cu. m). Based on these findings the ACGIH (1984) recommended a TLV for methyl ethyl ketone peroxide as 1.5 mg/cu. m (0.2 ppm). As of April 1985, the NTP (1985) has been conducting skin painting tests and hlstopathology assays on this chemical. The results are not yet available. Preparation Date: 01/07/86 0421P -1- 01/11/86 ------- Endpolnt and Experimental Doses (cont.): Limited carcinogenic and mutagenlc data studies have been conducted, but results are Inconclusive (Koten and Falk, 1963). Using the TLV of 0.2 ppm (1.5 mg/cu. m) an ADI of 0.076 mg/kg/day can be derived. This ADI should be used only until the results of the NTP (1985) testing becomes available, at which time H should be revised. Uncertainty Factors (UFs): The 10-fold factor accounts for the expected Interhuman variability to the toxldty of this chemical 1n Heu of specific data. Modifying Factors (MFs): None. Additional Comments: No adequate chronic or subchronlc data are available upon which to base an ADI. No supporting ep1dem1olog1cal data are available. Confidence 1n the RfD: Study: Low Data Base: Low RfD: Low The confidence in the chosen effect level, supporting data base, and resulting RfD are all low. TLV-based RfDs are only estimated when sufficient oral or inhalation toxicity data are not available. Documentation of RfD and Review: ECAO-Ctndnnat1 Internal Review, August 1985. U.S. EPA. 1985. Methyl Ethyl Ketone Peroxide: Review and Evaluation of ADI. Contract No. 68-03-3228, Environmental Criteria and Assessment Office, Cin- cinnati. OH. 0421P -2- 01/11/86 ------- Agency RfD Review: First Review: 08/19/85 Second Review: Verification Date: 08/19/85 U.S. EPA Contact: Primary: C.T. DeRosa FTS/684-7534 or 513/569-7534 Secondary: M.L. Dourson FTS/684-7544 or 513/569-7544 0421P -3- 01/11/86 ------- REFERENCE DOSES (RfDs) FOR ORAL EXPOSURE Chemical: Nickel Cyanide Carclnogenlclty: None. Systemic Toxlclty: See below. CAS #: 557-19-7 Endpolnt Experimental Doses UF MF RfD (ADI Ambrose et al. (1976) Rat oral chronic study Decreased body weight 100 ppm of diet 100 (NOAEL) converted to 1.89 mg/kg/day nickel cyanide 0.02 mg/kg/day or 1 mg/day for a 70 kg man 1000 ppm of diet (50 mg/kg bw/day) nickel (LOAEL) Conversion Factors: 554 food consumptlon/g body weight; 0.2% assumed difference In nickel absorption 1n water vs. diet; molecular weight N1(CN)2/N1: x 110.74/58.69; thus, 100 mg/kg of diet (ppm) x 0.05 mg/kg of diet/kg bw/day x 0.2 x 110.74/58.69 = 1.89 mg/kg bw/day Endpolnt and Experimental Doses: Ambrose, A.M., P.S. Larson, J.R. Borselleca and G.R. Hennlgar, Jr. 1976. Long-term toxlcologlc assessment of nickel In rats and dogs. J. Food Scl. Techno!. 13: 181-187. Nickel cyanide 1s 47% cyanide and 53X nickel. Therefore, 1f nickel cyanide were to completely dissociate 1n water or dilute adds, approximately equal amounts would be released on a weight basis. Based on recommended ADI for nickel (0.7 mg/day, U.S. EPA, 1985), the toxlclty of nickel Is approximately 2 times greater than the currently reported toxlclty of Cyanide (ADI of 1.5 mg/day, U.S. EPA, 1985). It 1s apparent, therefore that an ADI for nickel cyanide based on the toxlclty of cyanide might not be protective for adverse effects caused by nickel. Preparation Date: 01/09/86 0421P -1- 01/11/86 ------- Endpolnt and Experimental Doses (cont.): Ambrose et al., (1976) reported the results of a 2-year study 1n groups of 25 rats/sex given 0, 100, 1000 or 2500 ppm nickel (estimated as 0, 5, 50 and 125 mg N1/kg bw) 1n the diet. Consistently, body weights In both high dose male and female rats were significantly decreased compared with controls. Groups of females on the 1000 or 2500 ppm-nickel diets had significantly higher heart-to-body weight ratios and lower 11ver-to-bbdy weight ratios than controls. No significant effects were reported at 100 ppm nickel (5 mg/kg bw). The dose of 1000 ppm (50 mg N1/kg bw) represents a LOAEL from this study, while the 100 ppm (5 mg N1/kg bw) dose is a NOAEL. The fact that nickel was administered In the diet rather than 1n water caused some problem. Nickel 1n the diet 1s absorbed at a different rate than N1 1n water; there- fore, Foulkes (1984) recommeded an absorption factor of 0.2 to be applied to the dietary data to derive an ADI for nickel 1n water. Uncertainty Factors (UFs): The 100-fold factor accounts for both Intra- and Inter'specles variability to the toxlclty of the chemical 1n Heu of specific data. Modifying Factors (MFs): None. Additional Comments: By applying an uncertainty factor of 100 (10 for Intraspedes extrapola- tion and 10 for sensitive population) and an absorption factor of 0.2 to the NOAEL of 5 mg/NI/kg bw an ADI of 0.7 mg/day for nickel was derived. Because nickel cyanide Is not soluble In water and 1s slightly soluble 1n dilute adds, 1ngest1on of nickel cyanide would expose an Individual to nickel cyanide as well as small amounts of cyanide and nickel. Based on toxldty data an ADI of 6 mg/day for nickel cyanide (ADI CN 1.5/0.47CN x 2 moles CN) may not provide adequate protection when compared to an ADI of 1 mg/day for nickel cyanide (ADI N1 0.7/0.53 N1). Therefore, an ADI of 1 mg/day for nickel cyanide 1s recommended. 0421P -2- 01/11/86 ------- Confidence In the RfD: Study: Medium Data Base: Low RfD: Low Medium confidence In the study 1s chosen because three doses were admin- istered to a moderate number of animals and several parameters were measured. Dogs were also tested. Low confidence 1s chosen for both the supporting data base and RfD since nickel cyanide has not been tested for toxlclty and thus, the RfD 1s by analogy. Until additional chronic/reproductive toxlclty data are Is available a low confidence In the RfD Is recommended. Documentation of RfD and Review: Extensive Agency-wide and Peer review, 1985. U.S. EPA. 1985. Drinking Water Criteria Document for Nickel. Office of Drinking Hater, Washington, DC. Agency RfD Review: First Review: 08/05/85 Second Review: Verification Date: 08/05/85 U.S. EPA Contact: Primary: C.T. DeRosa FTS/684-7534 or 513/569-7534 Secondary: M.L. Dourson FTS/684-7544 or 513/569-7544 0421P -3- 01/11/86 ------- REFERENCE DOSES (RfDs) FOR ORAL EXPOSURE Chemical: Nitric Oxide Cardnogenldty: None. Systemic Toxlclty: See below. CAS #: 10102-43-9 Endpolnt Walton (1951) Infant chronic expo- sure to drinking water Methemoglob1nem1a Experimental Doses UF MF RfD (ADI) 10 ppm of drinking water or 10 mg/L (NOEL) converted to 1.0 mg/kg/day 11-20 ppm (LOAEL) 10 0.1 mg/kg/day or 1 mg/day for a 10 kg child Conversion Factor thus, 10 mg/L x 1 : 1 L drinking water/day 10 kg child; L/day / 10 kg = 1.0 mg/kg/day Endpolnt and Experimental Doses: Walton, G. 1951. Survey of literature relating to Infant methemoglob1nem1a due to nitrate-contaminated water. Am. J. Public Health. 41: 986-996. This 1s an ep1dem1olog1cal study on the formation of methemogloblnemla In Infants routinely fed milk prepared from nitrate contaminated water. This study analyzed all known cases of Infant methemoglob1nem1a occurring In 37 U.S. states Irrespective of date or type of water supply. Nitrate (nitrogen) content ranged from 10 ppm to over 100 ppm. No Incidences of methemoglobl- nemla were found to occur in drinking water containing greater than 10 ppm (10 mg/L) nitrate (nitrogen). A NOEL of 10 mg/L was derived from these studies. NHrlc oxide 1n water generates N02 (nitrite). Methemogloblnemla 1s formed by the oxidation of hemoglobin to methemoglob1nem1a by nitrite. Infants are particularly susceptible to the formation of methemoglobln. Preparation Date: 01/09/86 0421P -1- 01/11/86 ------- Endpolnt and Experimental Doses (cont.): Several more recent studies support Walton's (1951) 10 mg/L NOAEL for Infant methemogloblnemla formation (NAS, 1977; Wlnton, 1971; Calabrese, 1978). Using the. NOAEL from the Walton study, the ADI for lated (U.S. EPA, 1985) for a 10 kg child drinking 1 L 1fy1ng factor of 10. An ADI of 0.1 mg/kg/day or 1 derived for nitric oxide. nitric oxide was calcu- of water/day and a mod- mg/day was, therefore, Uncertainty Factors (UFs): No uncertainty factor was used In the derivation of the RfD because the NOEL was of the critical toxic effect (I.e., methemogloblnemla) In the sensitive human population (I.e., Infants). The length of exposure encompassed both the critical effect and the sensitive population. Modifying Factors (MFs): A modifying factor of 10 was applied because of the direct toxlclty of nitrite. Additional Comments: An RfD of 0.2 mg/kg/day could be calculated using the body weight of 4 kg and fluid consumption of 0.64 L/day from the Walton (1951) study. The lower value of 0.1 mg/kg/day Is maintained, however, due to the uncertainties 1n the changing fluid consumption and body weight as a neonate (4 kg) ages to a 2-year-old child (10 kg), and the varying lengths of weaning time among families. Confidence In the RfD: Study: High Data Base: High RfD: High Confidence In the study, data base and RfD are all considered high because the NOEL 1s determined 1n the known sensitive human population. The data base contains several recent supporting ep1dem!olog1cal studies. 0421P -2- 01/11/86 ------- Documentation of RfD and Review: ECAO-C1nc1nnat1 Internal Review, August 1985. U.S. EPA. 1985. Nitric Oxide: Review and Evaluation of ADI. Contract No 68-03-3228. Environmental Criteria and Assessment Office, Cincinnati, OH. Agency RfD Review: First Review: 08/19/85 Second Review: Verification Date: 08/19/85 U.S. EPA Contact: Primary: C.T. DeRosa FTS/684-7534 or 513/569-7534 Secondary: M.L. Dourson FTS/684-7544 or 513/569-7544 0421P -3- 01/11/86 ------- REFERENCE DOSES (RfDs) FOR ORAL EXPOSURE Chemical: Nitrobenzene Carclnogenlclty: None. Systemic ToxIcHy: See below. CAS #: 98-95-3 Endpolnt Experimental Doses UF MF RfD (ADI) CUT (1984) Rat/m1ce subchronlc Inhalation study Hematologlc, adrenal, renal and hepatic lesions NOAEL: None 10,000 - 0.0005 mg/kg/day or 0.03 mg/day for a 70 kg man 25 mg/cu. m (mice) converted to 4.6 mg/kg/day LOAEL) Conversion Factors: 6 hour/24 hour, 5 days/7 days, 0.039 cu. m/day/0.03 kg (mice breathing rate/body weight) and 0.8 absorption factor; thus, 25 mg/cu. m x 6 hour/24 hour x 5 days/7 days x 0.039 cu. m/day / 0.03 kg x 0.8 = 4.6 mg/kg/day Endpolnt and Experimental Doses: CUT (Chemical Industry Institute of Toxicology). 1984. tlon toxldty study of nitrobenzene in F344 rats and Research Triangle Park, NC. FYI-OTS-0874-0333. Ninety day inhala- B6C3F1 mice. CUT, The CUT study provides the most appropriate data currently available to derive an ADI. Ten animals/sex/specles/dose group were administered nitroben- zene at J of 3 doses In a 90-day Inhalation study. Other than Increased Inci- dence of hemolytlc anemia In rats at 25 mg/cu. m and vacuollzatlon of adrenal cortical cells In female mice at 25 mg/cu. m and higher, adverse effects of nitrobenzene exposure In mice and rats were comparable to unexposed controls at this dose. Mice and rats exposed to nitrobenzene at 81 mg/cu. m showed Increased Incidence and severity of liver and kidney lesions. Environ, Inc. (1984) recommended an ADI of 0.057 mg/kg/day or 4 mg/day which 1s based on the TLV of 1 ppm, a predicted level to protect workers Preparation Date: 01/09/86 0421P -1- 01/11/86 ------- Endpolnt and Experimental Doses (cont.): against cyanogenlc and hematologlc effects. Absorption coefficients of 0.8 and dermal to Inhalation absorption ratio of 7:18, based on pharmacoklnetlc data of P1otrowsk1 (1967, 1977) and Salmowa et al. (1963) were employed to derive the dally exposure level of nitrobenzene. Data regarding the effects of nitrobenzene 1n humans are limited to symptoms and observations 1n workers Including headaches, vertigo, methemo- globlnemla (ACGIH, 1980). The ADI derived from the TLV appears adequate to protect workers from above adverse effects; however, the effects of occupa- tional exposure to nitrobenzene on the liver and/or kidneys have not been ade- quately evaluated. The CUT (1984) study Indicates that the liver and kidney may be target organs of chronlc/subchronlc nitrobenzene exposure, and the ADI based on the TLV may not be protective for the toxic effects of nitrobenzene on the liver and/or kidney. Therefore, until more definitive chronic data are available, the ADI of 0.0005 mg/kg/day 1s recommended to protect against adverse health effects of nitrobenzene. Uncertainty Factors (UFs): The uncertainty factor of 1000 represents two 10-fold factors for both Intra- and Interspedes variability to the toxlclty of this chemical In Heu of specific data, a 10-fold factor for estimating a chronic effect level from Us subchronlc equivalent and a 10-fold factor for estimating a RfD from a LOAEL rather than a NOAEL. Modifying Factors (MFs): None. Additional Comments: Subchronlc animal Inhalation study provided adequate data over the recom- mended TLV (ACGIH, 1985) to derive an ADI. Further chronic studies are needed to recommend an ADI at a higher level of confidence. Confidence In the RfD: Study: Medium Data Base: Medium RfD: Medium Medium confidence In the study Is recommended because a limited number of an1mals/sex/dose was tested and a NOEL for the critical toxic effect (I.e., adrenal toxldty) was not determined; however, two species were used and many 0421P -2- 01/11/86 ------- Confidence 1n the RfD (cont.): parameters were measured. Medium confidence 1n the data base 1s recommended because many unpublished studies support the chosen LOAEL. Medium confidence In the RfD follows. Documentation of RfD and Review: ECAO-C1ndnnat1 Internal Review, May 1985. U.S. EPA. 1985. Health and Environmental Effects Profile for Nitrobenzene. Environmental Criteria and Assessment Office, Cincinnati, OH. ECAO-CIN-P145. U.S. EPA. 1985. Nitrobenzene: Review and Evaluation of ADI. Contract No. 68-03-3228. Environmental Criteria and Assessment Office, Cincinnati, OH. Agency RfD Review: First Review: 07/08/85 Second Review: Verification Date: 07/08/85 U.S. EPA Contact: Primary: C.T. DeRosa FTS/684-7534 or 513/569-7534 Secondary: M.L. Dourson FTS/684-7544 or 513/569-7544 0421P -3- 01/11/86 ------- REFERENCE DOSES (RfDs) FOR ORAL EXPOSURE Chemical: Nitrogen Dioxide Cardnogenlclty: None. Systemic Toxlclty: See below. CAS #: 10102-44-0 Endpolnt Walton (1951) Infant chronic expo- sure drinking water Methemoglob1nem1a Experimental Doses UF MF RfD (ADI 10 ppm of drinking water or 10 mg/L (NOEL) converted to 1.0 mg/kg/day 11-20 ppm (LOAEL) 1 mg/kg/day or 10 mg/day for 10 kg child Conversion Factor: 1 L water consumed/day 10 kg child; thus, 10 mg/L x 1 L/day / 10 kg = 1.0 mg/kg/day Endpolnt and Experimental Doses: Walton, G. 1951. Survery of literature relating to Infant methemogloblnemla due to nitrate - contaminated water. Am. J. Public Health. 41: 986-996. This Is an epldemlologlc study on the formation of methemogloblnemla In Infants who routinely consumed milk prepared from water containing various levels of nitrate. The study analyzed all cases of Infant methemogloblnemla occurlng In 37 U.S. states Irrespective of date of occurrence or type of water supply. Nitrate (nitrogen) content ranged for 10 ppm to greater than 100 ppm. No Incidences of methemogloblnemla were found to occur In drinking waters con- taining -less than 10 ppm (10 mg/L) nitrate (nitrogen). Therefore, a NOEL of 10 ppm (10 mg/L) was derived. Several more recent epldemlologlcal studies support threshold for Infant methemogloblnemla (NAS, 1977; Wlnton, 1978). Walton's (1951) 1971: Calabrese, Nitrogen dioxide In water dissociates to form nitrates and nitrite. Nitrate toxldty appears to be due to Its conversion to nitrites which results Preparation Date: 01/07/86 0421P 01/11/86 ------- Endpolnt and Experimental Doses (cont.): In the oxidation of hemoglobin to methemoglobln 1n humans. Animals are not a good model for methemoglobln formation because many species lack nitrate reducing bacteria. Infants are, however, particularly susceptible due to the high nitrate reducing bacteria content, their lower enzymatic capacity to reduce methemoglobln to hemoglobin and finally to the presence of hemoglobin F which Is more susceptible to oxidation. An ADI of 1.0 mg/kg/day (U.S. EPA, 1985) for nitrate/nitrogen was derived based on the NOEL of 10 mg/L (Walton, 1951). Uncertainty Factors (UFs): No uncertainty factor was used In the derivation of the RfD because the NOEL was of the critical toxic effect (I.e., methemogloblnemla) 1n the sensi- tive human population (I.e., Infants). The length of exposure encompassed both the critical effect and the sensitive population. Modifying Factors (MFs): None. Additional Comments: A RfD of 2 mg/kg/day could be calculated using the body weight of 4 kg and fluid consumption of 0.64 L/day from the Walton (1951) study. The lower value of 1 mg/kg/day Is maintained, however, due to the uncertainties In the chang- ing fluid consumption and body weight as a neonate (4 kg) ages to a 2-year-old child (10 kg), and the varying lengths of weaning time among families. Confidence 1n the RfD: Study: High Data Base: High RfD: High Confidence 1n the study, data base and RfD are all considered high because the NOEL Is determined In the known sensitive human population. The data base contains several recent supporting ep1dem1olog1cal studies. 0421P -2- 01/11/86 ------- Documentation of RfD and Review: ECAO-Clnc1nnat1 Internal Review, August 1985. U.S. EPA. 1985. Nitrogen Dioxide: Review and Evaluation of ADI. Contract No. 68-03-3228. Environmental Criteria and Assessment, Cincinnati, OH. Agency RfD Review: First Review: 08/19/85 Second Review: Verification Date: 08/19/85 U.S. EPA Contact: Primary: C.T. DeRosa FTS/684-7534 or 513/569-7534 Secondary: M.L. Dourson FTS/684-7544 or 513/569-7544 0421P -3- 01/11/86 ------- REFERENCE DOSES (RfDs) FOR ORAL EXPOSURE Chemical: Pentachloronltrobenzene (PCNB) Carclnogenlclty: None. Systemic ToxIcHy: See below. CAS #: 82-68-8 Endpolnt Experimental Doses UF MF RfD (ADI) Borzelleca and Larson (1968) 2-year feeding study In dogs Liver toxlclty 0.008 mg/kg/day NOEL: 30 mg/kg of 100 diet converted to 0.75 mg/kg bw/day LOAEL: 180 mg/kg of diet Conversion Factor: x 0.025 kg of diet/kg of bw/day (an assumed factor); thus, 30 mg/kg of diet x 0.025 kg of diet/kg bw/day = 0.75 mg/kg/day Endpolnt and Experimental Doses: Borzelleca, J.F. and P.S. Larson. 1968. Toxldty study of the effect of add- ing Terraclor to the diet of Beagle dogs for a period of two years. Unpub- lished report prepared by the Dept. of Pharmacology, Medical College of Virginia. Submitted by OUn Corp. as Report No. 2490. EPA Ace. No. 248283, June 10. Groups of four male and four female beagle dogs (4.5 months of age) were given diets containing 0, 5, 30, 180 or 1080 ppm of the test substance for 2 years. "Minimal" cholesteral hepatosls with secondary bile nephrosls was observed-1n all dogs In the 180 ppm groups (LOAEL). The dose of 30 ppm was the highest NOEL 1n this study. Chronic feeding studies need to be done In another species (rats). The small sample size of Borzelleca and Larson (1968) reduces the statistical validity of the study. PCNB may act synerglstlcally with oncogenlc HCB. Preparation Date: 01/09/86 0421P -1- 01/11/86 ------- Uncertainty Factors (UFs): The uncertainty factor of 100 accounts for both 1ntra- and Interspedes variability to the toxlclty of this chemical 1n lieu of specific data. Modifying Factors (MFs): None. eeťeťoceťŤťŤoťťŤŤťťťŤťťť°ťťťoot*9eo°°*ool'**eooeo"ct'<>00e*0ee**0******"***''**'**t Additional Comments: None. Confidence 1n the RfD: Study: Medium Data Base: Low RfD: Medium The confidence In the chosen study 1s medium because only eight animals/ dose were used; however, four doses were tested, several effects were mon- itored and a dose-severity was observed. The data base Is rated low because of the general lack of supporting data. The RfD 1s rated medium to low. Documentation of RfD and Review: This ADI has been Internally reviewed by the Office of Pesticide Programs, U.S. EPA. Agency RfD Review: First Review: 05/20/85 Second Review: Verification Date: 05/20/85 U.S. EPA Contact: Primary: T. Farber FTS/557-3710 or 513/557-3710 Secondary: M.L. Dourson FTS/684-7544 or 513/569-7544 0421P -2- 01/11/86 ------- REFERENCE DOSES (RfDs) FOR ORAL EXPOSURE Chemical: Pentachlorophenol CAS #: 87-86-5 Carclnogenldty: None. Systemic Toxlclty: See below. Endpolnt Experimental Doses UF MF RfD (ADI) Schwetz et al. 3 mg/kg/day (NOEL) 100 - 0.03 mg/kg/day (1978) or 2 mg/day for a Rat oral chronic 70 kg man study Liver and kidney 10 mg/kg/day (LOEL) pathology Endpolnt and Experimental Doses: Schwetz, B.A., J.F. Quast, P.A. Keelev, C.G. Humlston and R.J. Kodba. 1978. Results of 2-year toxlclty and reproduction studies on pentachlorophenol In rats. In: Pentachlorophenol: Chemistry, Pharmacology and Environmental Toxicology, K.R. Rao, Ed. Plenum Press, NY. p. 301. Only one chronic study regarding oral exposure (Schwetz et al., 1978) was located 1n the available literature. Twenty-five rats/sex were administered 1 of 3 doses 1n the diet. At the 30 mg/kg/day level of treatment, a reduced rate of body weight gain and Increased specific gravity of the urine were observed In females. Pigmentation of the liver and kidneys was observed In females exposed at 10 mg/kg/day or higher levels and 1n males exposed to 30 mg/kg/ day. The 3 mg/kg/day level of exposure was reported as a chronic NOEL. A number of studies that have Investigated the teratogenldty of orally administered pentachlorophenol In rodents are available In the literature. Although these studies (Larsen et al., 1975; Schwetz and Gehrlng, 1973; Schwetz et al., 1978; Hlnkle, 1973), did not reveal teratogenlc effects feto-maternal toxlclty were seen at 30 mg/kg/day. Since pentachlorophenol apparently does not cross the placenta! barrier, the observed fetotoxldty may be a reflection of maternal toxlclty (Larsen et al., 1975). The NOEL 1n these studies was 3.0 mg/kg, which 1s the same as for the chronic study reported earlier. Preparation Date: 01/07/85 0421P -1- 01/11/86 ------- Uncertainty Factors (UFs): The 100-fold factor accounts for the expected Intra- and interspedes variability to the toxlcity of this chemical In lieu of specific data. Modifying Factors (MFs): None. Additional Comments: None. Confidence In the RfD: Study: High Data Base: Medium RfD: Medium The confidence 1n the chosen study is rated high because a moderate number of animals/sex were used In each of three doses, a comprehensive analysis of parameters was conducted, and a reproductive study was also run. Confidence In the supporting data base Is rated medium because only one chronic study Is available. Other subchronlc studies provide adequate but weaker supporting data. The confidence In the RfD 1s medium. More chronic/reproductive studies are needed to provide a higher confidence in the RfD. Documentation of RfD and Review: Limited Peer Review and Agency-wide Internal Review, 1984. U.S. EPA. 1984. Health Effects Assessment for Pentachlorophenol. Environ- mental Criteria and Assessment Office, Cincinnati, OH. ECAO-CIN-H043. U.S. EPA. 1985. Drinking Hater Criteria Document for Pentachlorophenol. Office of Drinking Hater, Hashington, DC. Agency RfD Review: First Review: 05/20/85 Second Review: Verification Date: 05/20/85 U.S. EPA Contact: Primary: C.T. DeRosa FTS/684-7534 or 513/569-7534 Secondary: M.L. Dourson FTS/684-7544 or 513/569-7544 0421P -2- 01/11/86 ------- REFERENCE DOSES (RfDs) FOR ORAL EXPOSURE Chemical: Phenol CAS #: 108-95-2 Carclnogenldty: None. Systemic Toxldty: See below. Endpolnt Experimental Doses UF MF RfD (ADI) Dow Chemical (1976) NOAEL: None 500 - 0.1 mg/kg/day or Rat oral s.ubchronlc 7 mg/day for a study 70 kg man Kidney and liver 50 mg/kg/day (135 pathology doses) (LOAEL) Endpolnt and Experimental Doses: Dow Chemical Co. 1976. References and literature review pertaining to toxlcologlcal properties of phenol. Toxlcol. Res. Lab. Unpublished Report. This study reported slight kidney damage 1n rats treated by gavage at 50 mg/kg/day of phenol for 6 months. Higher doses produced moderate kidney and slight liver damage. However, no effects on liver, kidneys or any other organs were observed 1n 90-day studies 1n rats (780 mg/kg/day of phenol)" and mice (1700 mg/kg/day of phenol) which received various doses of phenol 1n the drinking water (NCI, 1980). In this study, when extended for 2 more weeks, rats and mice treated with 153 and 313 mg/kg/day phenol, respectively, showed decreased weight gain and reduced water Intake. In addition, male and female rats at 344 mg/kg/day dose had a significantly Increased Incidence of chronic kidney Inflammation. The difference 1n LOAELs of the NCI (1980) study (344 mg/kg) and the Dow Chemical (1976) study (50 mg/kg) are plausibly attributed to differences 1n mode of administration with the gavage study of Dow Chemical producing the lowest LOAEL. Dlechmann and Oespar (1940) noted no effects on water consumption and weight gain at phenol concentrations as high as 1600 mg/L. Further, 1n studies using rats and spanning 3-5 generations, Heller and Purcell (1938) Preparation Date: 01/07/86 0421P -1- 01/11/86 ------- Endpolnt and Experimental Doses (cont.): observed normal growth and reproduction at phenol concentrations up to 5000 mg/l. Taking the drinking water consumption data provided by Delchmann and Oesper (1940) for the 1600 mg/L group, this NOEL represents an average dose of 49 mg/kg/day which Is equivalent to that used In the derivation of the ADI. Consideration of all these factors suggest that the previously estimated ADI of 7 mg/day (U.S. EPA, 1980) based on the LOAEL of 50 mg/kg/day from the Dow Chemical (1976) study should provide adequate protection. Uncertainty Factors (UFs): A 500-fold uncertainty factor was applied to the LOAEL of 50 mg/kg/day (10 for subchronlc data, 10 for species extrapolation and 5 for use of LOAEL). A factor of 500 was used because H was judged that the existing data did not Justify the use of a factor of 100, but were better than the requirements for a factor of 1000. Modifying Factors (MFs): None. Additional Comments: None. Confidence In the RfD: Study: Low Data Base: Medium RfD: Medium The chosen study Is given a confidence rating of low because few animals were used, a NOEL was not established and the study was never published. The data base Is given a medium confidence rating because several studies support the chosen effect level. Until other chronic studies are available, a medium confidence In the RfD 1s recommended. Documentation of RfD and Review: The Health and Environmental Effects Profile has had a limited peer review and Agency-wide Internal review during 1985. The Ambient Hater Quality Criteria document was extensively reviewed by the Agency and underwent public comments during 1980. 0421P _2- 01/11/86 ------- Documentation of RfD and Review (cont.): U.S. EPA. 1985. Health and Environmental Effects Profile for Phenol. Env1 ronmental Criteria and Assessment Office, Cincinnati, OH. ECAO-CIN-P125. U.S. EPA. 1980. Ambient Water Quality Criteria Document for Phenol. Envi- ronmental Criteria and Assessment Office, Cincinnati, OH. EPA 440/5-80-066. Agency RfD Review: First Review: 08/05/85 Second Review: Verification Date: 08/05/85 U.S. EPA Contact: Primary: C.T. DeRosa FTS/684-7534 or 513/569-7534 Secondary: M.L. Dourson FTS/684-7544 or 513/569-7544 0421P -3- 01/11/86 ------- REFERENCE DOSES (RfDs) FOR ORAL EXPOSURE Chemical: Phenyl Mercuric Acetate Carclnogenldty: None. Systemic Toxlclty: See below. CAS #: 62-38-4 Endpolnt Experimental Doses UF MF RfD (ADI! FHzhugh et al. (1950) Rat oral chronic study Renal damage 0.1 ppm Hg diet or 100 0.0084 mg/kg/day phenyl mercuric acetate (NOAEL) 0.08 ug/kg/day or 6 ug/day for a 70 kg man 0.5 ppm Hg or 0.042 mg/kg/day phenyl mercuric acetate (LOAEL) Conversion Factor: Food consumption molecular weight PHA/Hg Is 337/201; thus, diet (ppm) x 0.05 kg of diet/kg bw/day 0.0084 mg/kg bw/day 5X bw/day, 0.1 mg/kg of x 337/201 - Endpolnt and Experimental Doses: FHzhugh, O.G, A.A. Nelson, E. tox1cH1es of mercuric phenyl Hed. 2: 433-442. P. Laug and and mercuric I.H. Kunze. 1950. salts. Arch. Ind. Chronic oral Hyg. Occup. Phenyl mercuric acetate was administered to rats (10-24/group/sex) at levels of 0, 0.1, 0.5, 2.5. 10, 40 and 160 mercury In their diet for 2 years. Detailed, microscopic examinations of the liver and kidney were performed at Microscopic examination of the As little as 0.5 ppm mercury resulted In detectable kidney damage In females after 2 years. No differences were seen between controls and females receiving 0.1 ppm mercury. At higher doses (greater than 2.5 ppm) renal lesions were observed In both males females. A NOEL of 0.1 ppm was determined from these results. and 2 years of age. at the 2-year mark. were performed at 1 viscera was also performed as phenyl mercuric acetate and FHzhugh et IcHy of phenyl al. (1950) 1s the mercuric acetate. only chronic study regarding the oral tox- Therefore, assuming that the rat consumed Preparation Date: 01/09/86 0421P -1- 01/11/86 ------- Endpolnt and Experimental Doses (cont,): the equivalent of 5X of Us body weight In food/day, the 0.1 ppm Hg NOEL Is equivalent to 0,005 mg/kg/day Hg or 0,0084 mg/kg bw phenyl mercuric acetate. Uncertainty Factors (UFs): An ADI o,f 0.08 ug/kg/day or 6 ug/kg/day for a 70 kg human was derived by dividing the NOEL by an uncertainty factor of 100 to account for species extrapolation and differences In human sensitivity. Modifying Factors (MFs): None. Additional Comments: The data base contains very Tittle Information on the oral toxlclty of phenyl mercuric acetate. Some subchronlc testing has been conducted. Limited data are available on the mutagenlc and teratogenlc effects of this compound. No relevant carcinogenic data Is available. Confidence In the RfD: Study: Medium Data Base: Low RfD: Medium The chosen study Is given a medium confidence rating because a moderate number of animals/sex were tested at each of six doses; several parameters were measured. The data base Is given a low confidence rating because IHtle or no supporting data exist. Medium confidence 1n the RfD follows. Documentation of RfD and Review: ECAO-C1nc1nnat1 Internal Review, August 1985. U.S. EPA. 1985. Phenyl Mercuric Acetate: Review and tract No. 68-03-3228. Environmental Criteria and clnnatl, OH. Evaluation Assessment of ADI. Office, Con- Cln- 0421P -2- 01/11/86 ------- Agency RfD Review: First Review: 08/19/85 Second Review: Verification Date: 08/19/85 U.S. EPA Contact: Primary: C.T. DeRosa FTS/684-7534 or 513/569-7534 Secondary: M.L. Dourson FTS/684-7544 or 513/569-7544 0421P -3- 01/11/86 ------- REFERENCE DOSES (RfDs) FOR ORAL EXPOSURE Chemical: Phosphlne Carclnogenlclty: None. Systemic ToxIcHy: See below. CAS #: 7803-51-2 Endpolnt Experimental Doses UF MF RfD (ADI) Hackenburg (1972) Rat chronic oral study Body weight and clinical parameters 0.51 mg/kg food con- 100 verted to 0.026 mg/ kg/day (NOEL) LOAEL: None Conversion Factor: Food thus, 0.51 mg/kg of diet > 0.026 mg/kg bw/day 0.0003 mg/kg/day or 0.02 mg/day for a 70 kg man consumption of 5X bw/day; 0.05 kg of diet/kg bw/day = Endpolnt and Experimental Doses: Hackenburg, U. 1972, Chronic Ingestlon by rats of standard diet treated with aluminum phosphate. Toxlcol. Appl. Pharmacol. 23(1): 147-153. This study reported a no effects dose level for rats fed diet fumigated with phastoxln over a 2-year period. The mean phosphlne concentration during that time period was 0.51 mg/kg of feed.' Based on an average 5X food consump- tion and average rat body weight of 610.4 g (reported In the study), the phos- phlne dose can be calculated as 0.026 mg/kg bw/day. Hackenburg (1972) found a slight, yet statistically Insignificant, tendency for test females to gain weight faster than their control counterparts. There were no other differ- ences be.tween controls and treated rats In hemoglobin content, hematocrlt, differential white blood cell count, glucose levels, SGPT, serum urea, pro- thrombln time, organ weights or tissue hlstopathology. Survival rates and tumor Incidences were similar between controls and experimental animals. Preparation Date: 01/09/86 0421P -1- 01/11/86 ------- Uncertainty Factors (UFs): Application of an uncertainty factor latlon and 10 for sensitive population) an ADI of 0.02 mg/day. of 100 (10 for to the rat NOEL Intraspecles extrapo- of 0.026 mg/kg yields Modifying Factors (MFs): None. Additional Comments: The ACGIH (1984) has recommended a TLV of 0.3 ppm (0.42 mg/cu. m) for phosphlne, based principally upon an ep1dem1olog1cal study by Jones (1964). In this s.tudy, workers exposed Intermittently to about 10 ppm phosphlne gas experienced GI, cardloresplratory and CNS symptomatology. > Based on the TLV, an ADI of 0.021 mg/kg/day can be recommended. However, the Hackenburg (1972) study was a 2-year study 1n rats which explored a number of functional and morphological endpolnts. This study forms a better basis for an RfD. Confidence 1n the RfD: Study: High Data Base: High RfD: High The confidence In the study was rated high because of the moderate number of animals/dose, the extensive methodology employed to assure proper admin- istration of the test compound, and the extensive number of parameters mea- sured. The data base was rated high because of the effectiveness and safety of this chemical has been long reported. The overall rating for the RfD Is, thus, high. Documentation of RfD and Review: ECAO-C1nc1nnat1 Internal Review, August 1985. U.S. EPA. 1985. Phosphlne: Review and Evaluation of ADI. Contract No. 68-03-3228, Environmental Criteria and Assessment Office, Cincinnati, OH. Agency RfD Review: First Review: 08/19/85 Second Review: Verification Date: 08/19/85 U.S. EPA Contact: Primary: C.T. DeRosa FTS/684-7534 or 513/569-7534 Secondary: M.L. Dourson FTS/684-7544 or 513/569-7544 0421P -2- 01/11/86 ------- REFERENCE DOSES (RfOs) FOR ORAL EXPOSURE Chemical: Potassium Cyanide Cardnogenlclty: None. Systemic Toxlclty: See below. CAS #: 151-50-8 Endpolnt Experimental Oases UF MF RfD (ADI) Howard and Hanzal (1955) Rat oral chronic study PhUbrlck et al. (1979) Rat chronic oral bloassay Decreased body and thyroid weights, myelln degeneration 10.8 mg/kg/day CN '(NOAEL) converted to 27.0 mg/kg/day of potassium cyanide 30 mg/kg/day CN (LOAEL) 100 0.05 mg/kg/day or 4 mg/day for a 70 kg man Conversion Factors: Molecular weight of KCN/CN 1s 65/26; thus, 10.8 mg/kg/day x 65/26 = 27.0 mg/kg/day Endpolnt and Experimental Doses: Howard, J.W. and R.F. Hanzal. 1955. Chronic toxlclty to rats of food treated with hydrogen cyanide. AgMc. Food Chem. 3: 325-329. Potassium cyanide 1s soluble In water and dilute add (which Includes the gastric environment) and Is readily hydrolyzed to 1 molar equivalent of cyanide and 1 molar equivalent of potassium (Hartung, 1982). Since potassium 1s present 1n very high levels In food and the environ- ment, an ADI of 3.8 mg/day for potassium cyanide, based on cyanide content Is recommended. Preparation Date: 01/09/86 0421P -1- 01/11/86 ------- Endpolnt and Experimental Doses (cont.): In this 2-year dietary study, rats (10/sex/group) were administered food fumigated with HCN. The average dally concentrations were 73 and 183 mg CN/kg diet. From the data reported on food consumption and body weight, dally esti- mated doses were 4.3 mg and 10.8 mg CN/kg bw. The average food CN concentra- tions were estimated based on the authors' data for concentration at the beginning and end of each food preparation period and by assuming a first order rate of loss for the Intervening period., There were no treatment related effects on growth rate, no gross signs of toxlclty, and no hlstopatho- loglcal lesions. Studies by Phllbrlck et al. (1979) showed decreased weight gain and thyroxln levels and myelln degeneration In rats at 30 mg/kg/day CN. Other chronic studies either gave higher effect levels or used subcutaneous route (Crampton et al., 1979; Lessen, 1971; Herthlng et al., 1960). Human data do not provide adequate Information from which to derive an ADI because effective dose levels of chronically Ingested CN are not documented. Therefore, the study of Howard and Hanzel (1955) provides the highest NOAEL 10.8 mg/kg/day for CN and -1s chosen for the derivation of an ADI for CN of '1.5 mg/day or 0.02 mg/kg/day. Cyanide 1s metabolized extensively In the liver, Indicating that the only relevant route of administration for quantitative risk assessment In the deri- vation of an oral ADI 1s the oral route of administration. Uncertainty Factors (UFs): According to the U.S. EPA (1985) an uncertainty factor of 100 1s used to derive the ADI (10 for species extrapolation, 10 for sensitive population). Modifying Factors (MFs): A modifying factor of 5 1s used for apparent tolerance of cyanide when It 1s Ingested with food than when administered by gavage or drinking water. Additional Comments: Decreased protein efficiency ratio was produced by dietary cyanide treat- ment of rats during gestation, lactation and postweanlng growth phase 1n the Tewe and Haner (1981a) experiment; the dose level of cyanide (10.6 mg/kg/day) producing that effect is slightly lower than the currently accepted NOAEL of 10.8 mg/kg/day (U.S. EPA, 1985). Furthermore, Tewe and Maner (1981b) tested sows. Possible effects observed at about 9.45 mg/kg/day were proliferation of glomerular cells of the kidneys and reduced activity of the thyroid glands In the gilts. However, the number of animals 1n this experiment was very small. 0421P -2- 01/11/86 ------- Additional Comments (cont.): A Japanese study (Amo, 1973) Indicated that 0.05 mg/kg/day of cyanide obtained from drinking water decreased the fertility rate and survival rate 1n the Fl generation and produced 100% mortality 1n the F2 generation In mice. However, these data are not consistent with the body of available literature. Thus, until additional chronic studies are available, an ADI of 3.8 mg/day for a 70 kg human 1s recommended. Confidence 1n the RfD: Study: Medium Data Base: Medium RfD:Med1um The confidence 1n the study 1s medium because adequate records of food consumption and body weight were maintained, and animals of both sexes were tested at two doses for 2 years. The data base 1s rated medium because a small but., sufficient number of studies support the chosen study. The confi- dence In the RfD follows. Additional chronic/reproductive* studies are needed to support a higher level of confidence 1n the RfD. Documentation of RfD and Review: ECAO-Clndnnatl Internal Review, 1985. Limited peer review and Agency-wide review, 1985. U.S. EPA. 1985. Cyanides: Review and Evaluation of ADI. Contract No. 68-03-3228. Environmental Criteria and Assessment Office, Cincinnati, OH. U.S. EPA. 1984. Health Effects Assessment for Cyanides. Environmental Cri- teria and Assessment Office, Cincinnati, OH. ECAO-CIN-H011. Agency RfD Review: First Review: 08/05/85 Second Review: Verification Date: 08/05/85 U.S. EPA Contact: Primary: C.T. DeRosa FTS/684-7534 or 513/569-7534 Secondary: M.L. Dourson FTS/684-7544 or 513/569-7544 0421P -3- 01/11/86 ------- REFERENCE DOSES (RfDs) FOR ORAL EXPOSURE Chemical: Potassium Silver Cyanide Carc1nogen1c1ty: None. Systemic ToxIcHy: See below. CAS #: 506-61-6 Endpolnt Experimental Doses UF MF RfD (ADI) Howard and Hanzal (1955) Rat oral chronic study Phllbrlck et al. (1979) Rat chronic oral bloassay Decreased body and thyroid weights, myelln degeneration 10.8 mg/kg/day CN (NOAEL) converted to 82.7 mg/kg/day potassium silver cyanide 30.0 mg/kg/day CN (LOAEL) 100 0.2 mg/kg/day or 10 mg/day for a 70 kg man Conversion Factor: Molecular weight KAg{CN)2/CN: x 199/26; thus, 10.8 mg/kg/day x 199/26 = 82.7 mg/kg/day Endpolnt and Experimental Doses: Howard, J.W. and R.F. Hanzal. with hydrogen cyanide. Agrlc. 1955. Chronic toxlclty Food Chem. 3: 325-329. to rats of food treated Because of potassium, silver cyanide dissociates to form potassium, cyanide and silver cyanide, only 1 molar equivalent of cyanide Is generated (Wlndholz, 1983). Based on free cyanide liberated by the dissociation of potassium silver cyanide an ADI of 12 mg/day for 70 kg man 1s recommended. In this 2-year dietary study, rats (10/sex/group) were administered food fumigated with HCN. The average dally concentrations were 73 and 183 mg CN/kg diet. From the data reported on food consumption and body weight, dally esti- mated doses were 4.3 mg and 10.8 mg CN/kg bw. The average food CN concentra- Preparatlon Date: 01/09/86 0421P -1- 01/11/86 ------- Endpolnt and Experimental Doses (cont.): tlons were estimated based on the author's data for concentration at the beginning and end of each food preparation period and by assuming a first order rate of loss for the Intervening period. There were no treatment related effects on growth rate, no gross signs of toxldty, and no hlstopatho- loglcal lesions. Studies by PhUbrlck et al. (1979) showed decreased weight gain and thyroxln levels and myelln degeneration 1n rats at 30 mg/kg/day CN. Other chronic studl'es either gave higher effect levels or used subcutaneous route (Crampton et al., 1979; Lessen, 1971; Herthlng et al., 1960). Human data do not provide adequate Information from which to derive an ADI because effective dose levels of chronically Ingested CN are not documented. Therefore, the study of Howard and Hanzel (1955) provides the highest NOAEL 10.8 mg/kg/day for CN and Is chosen for the derivation of an ADI for CN of 1.5 mg/day or- 0.02 mg/kg/day. Cyanide Is metabolized extensively In the liver. Indicating that the only relevant route of administration for quantitative risk assessment 1n the deri- vation of an oral ADI Is the oral route of administration. Uncertainty Factors (UFs): According to the U.S. EPA (1985) an uncertainty factor of 100 Is used to derive the ADI (10 for species extrapolation, 10 for sensitive population). Modifying Factors (HFs): A modifying factor of 5 was used for apparent tolerance of cyanide when It Is Ingested with food than when administered by gavage or drinking water. Additional Comments: Decreased protein efficiency ratio was produced by dietary cyanide treat- ment of rats during gestation, lactation and postweanlng growth phase In the Tewe and-Maner (1981a) experiment: the dose level of cyanide (10.6 mg/kg/day) producing that effect Is slightly lower than the currently accepted NOAEL of 10.8 mg/kg/day (U.S. EPA, 1985). Furthermore, Tewe and Maner (1981b) tested sows. Possible effects observed at about 9.45 mg/kg/day were proliferation of glomerular cells of the kidneys and reduced activity of the thyroid glands 1n the gilts. However, the number of animals In this experiment was very small. A Japanese study (Amo, 1973) Indicated that 0.05 mg/kg/day of cyanide obtained from drinking water decreased the fertility rate and survival rate 1n the Fl generation and produced 100% mortality In the F2 generation In mice. However, 0421P -2- 01/11/86 ------- Additional Comments (cont.): these data are not consistent with the body of available literature. Thus, until additional chronic studies are available, an ADI of 12 mg/day for a 70 kg man 1s recommended. Confidence In the RfD: Study: Medium Data Base: Medium RfD: Medium The confidence 1n the study 1s medium because adequate records of food consumption and body weight were maintained and animals of both sexes were tested at two doses for 2 years. The data base 1s rated medium because a small but sufficient number of studies support the chosen study. The confi- dence In the RfD follows. Additional chronic/reproductive studies are needed to support a higher level of confidence 1n the RfD. Documentation of RfD and Review: ECAO-C1nc1nnat1 Internal Review, July 1985. U.S. EPA. 1985. Cyanides: Review and Evaluation of ADI. Contract No. 68-03-3228. Environmental Criteria and Assessment Office, Cincinnati, OH. Agency RfD Review: First Review: 08/05/85 Second Review: Verification Date: 08/05/85 U.S. EPA Contact: Primary: C.T. DeRosa FTS/684-7534 or 513/569-7534 Secondary: M.L. Dourson FTS/684-7544 or 513/569-7544 0421P -3- 01/11/86 ------- REFERENCE DOSES (RfDs) FOR ORAL EXPOSURE Chemical: PyMdlne Cardnogenlclty: None. Systemic Toxlclty: See below. CAS #: 110-86-1 Endpolnt Experimental Doses UF 1000 MF RfD (ADI) Encyclopedia of Occupational Safety and Health. (1983) Rats subchronlc to chronic Inhalation bloassay Reduced liver weight NOEL: None 0.002 mg/kg/day or 0.2 mg/day for a 70 kg man 10 ppm (32.35 mg/ cu. m) converted to 2.15 mg/kg/day (LOEL) Conversion Factors: 7 hour/24 hour, 5 days/7 days, 0.223 cu. m/day/0.35 kg (rat breathing rate/rat body weight) 0.5 absorption rate; thus, 32.35 mg/cu. m x 7 hour/24 hour x 5 days/7 days x 0.223 cu. m/day / 0.35 kg x 0.5 = 2.15 mg/kg/day Endpolnt and Experimental Doses: Encyclopedia of Occupational Safety and Health. national Labour Office, Geneva, p. 1810-1811. 1983. Vol. II: L-Z. Inter- The -study reported In the above encyclopedia contains data taken from a rat Inhalation study 1n which the exposure chamber contained 10-50 ppm pyrl- dlne vapor over 7 hours/day. 5 days/week for a 6-month period. The lower dose, 10 ppm pyrldlne (2.15 mg/kg/day) had no effect upon growth rate and mortality, but an Increase 1n the relative Hver weights was observed. Fur- ther details of the study were unavailable from the data base. The 2.15 mg dose was considered a LOEL. Preparation Date: 01/07/86 0421P -1- 01/11/86 ------- Uncertainty Factors (UFs): The 1000-fold represents 10 for both Intra- and Interspedes variability to the toxldty of this chemical In lieu of specific data and an additional lo because the RfD 1s based on a LOAEL and not a NOAEL. Modifying Factors (MFs): None. Additional Comments: Chronic oral studies for a RfD of high level of confidence are unavail- able. Need data base on chronic/reproductive studies. Confidence 1n the RfD: Study: Low Data Base: Low RfD: Low The confidence In the chosen study Is low because many details were unavailable and a NOEL was not determined. Confidence In the data base 1s low because of the general lack of Information. Low confidence In the RfD follows. Documentation of RfD and Review: ECAO-C1nc1nnat1 Internal Review, May and July 1985. U.S. EPA. 1985. Pyr1d1ne: Review and Evaluation of ADI. Contract No. 68-03-3228. Environmental Criteria and Assessment Office, Cincinnati, OH. Agency RfD Review: First Review: 07/08/85 Second Review: Verification Date: 07/08/85 U.S. EPA Contact: Primary: C.T. DeRosa FTS/684-7534 or 513/569-7534 Secondary: M.L. Dourson FTS/684-7544 or 513/569-7544 0421P -2- 01/11/86 ------- REFERENCE DOSES (RfDs) FOR ORAL EXPOSURE Chemical: Selenlous Add CAS #: 7783-00-8 CarclnogenlcHy: None. Systemic Toxlclty: See below. Endpolnt Experimental Doses UF MF RfD (ADI) Yang et al. (1983) 0.750 mg/day (NOAEL) 10 1.5 0.003 mg/kg/day or Human epidemiology 0.2 mg/day for a study 70 kg man Selenosls 3.2 mg/day or 0.046 mg/kg/day (LOAEL) Endpolnt and Experimental Doses: Yang, G., S. Wang, R. Zhou and S. Sun. 1983. Endemic selenium Intoxication of humans 1n China. Am. J. CUn. Nutr. 37: 872-881. In solution selenium from selenlous acid and selenlte salts 1s present predominantly as the blselenlte Ion (NAS, 1976). The toxldty of selenlte salts and selenlous add would therefore be expected to be similar at sub- lethal doses. It would thus be appropriate to derive a selenlous add ADI by analogy to selenium. The effects of oral selenium exposure have been relatively thoroughly studied In experimental animals and man. The NAS (1980) has determined an adequate and safe range for selenium Intake of 0.05-0.2 mg/day for an adult man. The. affects of selenium deficiency are potentially as serious as those of selenium toxlclty. Selenosls has been reported In high selenium areas where the average Intake was 5 mg/day (range 3.2-6.7), but no selenosls occurred when the average Intake was 0.750 mg/day (range 0.240-1.51) (Yang et al., 1983). Therefore, care must be exercised 1n deriving an ADI to Insure that minimum dietary requirements are met. Preparation Date: 01/09/86 0421P -1- 01/11/86 ------- Uncertainty Factors (UFs An uncertainty factor of 10 applied to derive an ADI of 0.2 against adverse population of variability 1s for the LOAEL for selenosls (3.2 mg/day) was mg selenlous add/day for adequate protection Since the LOAEL 1s from a large humans the usual uncertainty factor of 10 for Interhuman not thought to be necessary. health effects In humans. Modifying Factors (MFs): A modifying factor of 1.5 Is used based on Information suggesting that selenium 1n water Is absorbed more efficiently than selenium In food (U.S. EPA, 1985). Additional Comments: None. Confidence 1n the RfD: Study: Medium Data Base: High RfD: High Confidence 1n the chosen study Is medium because doses are given as ranges. Confidence In the data base and RfD are both high because many supportive animal studies (reviewed by NAS, 1977) and ep1dem1olog1cal studies exist. Documentation of RfD and Review: Office of Drinking Water and ECAO-C1nc1nriat1 Internal Reveiw, 1985. U.S. EPA. 1985. Health Effects Assessment for Selenium (and Compounds), Environmental Criteria and Assessment Office, Cincinnati, OH. ECAO-CIN-H058. Agency RfD Review: First Review: 08/19/85 Second Review: Verification Date: 08/19/85 U.S. EPA Contact: Primary: C.T. DeRoa FTS/684-7534 or 513/569-7534 Secondary: M.L. Dourson FTS/684-7544 or 513/569-7544 0421P -2- 01/11/86 ------- REFERENCE DOSES (RfDs) FOR ORAL EXPOSURE Chemical: Selenourea Cardnogen1c1ty: None. Systemic Tox1c1ty: See below. CAS #: 630-10-4 Endpolnt Experimental Doses UF MF RfD (ADI) Yang et al. (1983) Human epidemiology study Selenosls 0.005 mg/kg/day or 0.3 mg/day for a 70 kg man 0.750 mg/day (NOAEL) 10 1.5 3.2 mg/day Se or 0.046 mg/kg/day con- verted to 0.072 mg/ kg/day equivalent exposure of seleno- urea by analogy to selenium (LOAEL) Conversion Factor: Molecular weight of Se(NH2)2/Se(-2] Is 123.03/78.96; thus, 0.046 mg/kg/day x 123.03/78.96 = 0.072 mg/kg/day Endpolnt and Experimental Doses: Yang, G., S. Wang, R. Zhou and S. Sun. 1983. Endemic selenium Intoxication of humans 1n China. Am. J. CUn. Nutr. 37: 872-881. There 1s little Information regarding the toxldty of selenourea. Cummins and Klmura (1971) reported a rat oral LD50 of 50 mg/kg, compared with 7 mg/kg for sodium selenlte. It was postulated that the lower toxldty of selenourea was probably due to Its lower water solubility and consequent poorer GI absorption compared with sodium selenlte. Because of the lack of data regard- Ing the-toxiclty of selenourea, the best approach In deriving an ADI for selenourea Is by analogy to selenium. The NAS (1980) has determined an adequate and safe range for selenium Intake of 50-200 ug/day for an adult man. The effects of selenium deficiency are potentially as serious as those of selenium toxldty. Selenosls has been reported In high selenium areas where the average Intake was 5 mg/day (range 3.2-6.7), but no selenosis occurred when the average Intake was 0.75 mg/day (range 0.24-1.51; Yang et al., 1983). U.S. EPA (1985) recommended an ADI of Preparation Date: 01/09/86 042 IP -1- 01/11/86 ------- Endpolnt and Experimental Doses (cont.): 0.21 mg/day for selenium by applying an uncertainty factor of 15 to the LOAEL of 3.2 mg/day (Yang et a!., 1983). This ADI was derived on the Intake of selenium 1n drinking water, and an uncertainty factor of 15 rather than 10 was applied because of Information that selenium in water Is absorbed more effi- ciently than selenium In' food. This ADI should be adjusted for differences In molecular weight between selenourea (123.03) and selenium (78.96) and, thus, an ADI of 0.005 mg/kg/day (0.003 mg Se ,x 1.6) or 0.33 mg/day for selenourea 1s recommended to provide adequate protection against adverse health effects. Uncertainty Factors (UFs): An uncertainty factor of 10 for the LOAEL for selenosls (3.2 mg/day) was applied to derive an ADI of 0.2 mg selenlous add/day for adequate protection against a'dverse health effects In humans. Since the LOAEL Is from a large population of humans the usual uncertainty factor of '10 for Interhuman variability Is not thought to be necessary. Modifying Factors (MFs): A modifying factor of 1.5 1s used based on Information suggesting that selenium 1n water 1s absorbed more efficiently than selenium 1n food (U.S. EPA, 1985). Additional Comments: None. o6ctteoeoŤťBoať*ťBBBťtoBeťeťŤoŤťŤŤictŤec*Ťťeeťe*eťBŤeŤ.ťŤŤťť,,...,..ť,ť,,Ť,ť.ť*t Confidence 1n the RfD: Study: Medium Data Base: High RfD: High Confidence In the chosen study Is medium because doses are given as ranges. Confidence In the data base and RfD are both high because many supportive animal studies (reviewed by NAS, 1977) and ep1dem1olog1cal studies exist. 0421P -2- 01/11/86 ------- Documentation of RfD and Review: ECAO-C1ndnnat1 Internal Review, August 1985. U.S. EPA. 1985. Selenourea: Review and Evaluation of ADI. Contract No. 68-03-3228. Environmental Criteria and Assessment Office, Cincinnati, OH. U.S. EPA. 1985. Health Effects Assessment for Selenium (and Compounds). Environmental Criteria and Assessment Office, Cincinnati, OH. ECAO-CIN-H058. Agency RfD Review: First Review: 08/19/85 Second Review: Verification Date: 08/19/85 U.S. EPA Contact: Primary: C.T. DeRosa FTS/684-7534 or 513/569-7534 Secondary: M.L. Doursorr FTS/684-7544 or 513/569-7544 0421P -3- 01/11/86 ------- REFERENCE DOSES (RfDs) FOR ORAL EXPOSURE Chemical: Silver Cyanide Carclnogenldty: None. Systemic Toxldty: See below. CAS #: 506-64-9 Endpolnt Experimental Doses UF MF 5 RfD (ADI) Howard and Hanzal (1955) Rat oral chronic bloassay PhUbrlck et al. (1979) Rat chronic oral bloassay Decreased body and thyroid weights, myelln degeneration 10.8 mg/kg/day CN (NOAEL) converted to 55.66 mg/kg/day silver cyanide 30.0 mg/kg/day (LOAEL) 100 0.1 mg/kg/day or 8 mg/day for a 70 kg man Conversion Factor: Molecular weight of AgCN/CN Is 134/26; thus, 10.8 mg/kg/day x 134/26 = 55.66 mg/kg/day Endpolnt and Experimental Doses: Howard, J.W. and R.F. Hanzal. 1955. Chronic treated with hydrogen cyanide. Agrlc. Food Chem. toxlclty for 3: 325-329. rats by food Silver cyanide Is not soluble In water or dilute add (Wlndholz, 1983). Currently the data base does not provide any toxlclty Information on silver cyanide. It Is, therefore, recommended that an ADI of 8 mg/day for a 70 kg human based on cyanide will provide adequate protection against an adverse health effects. Note that this Is a conservative protective assumption In light of silver cyanide's lack of solubility. In this 2-year fumigated with HCN. dietary study, rats (10/sex/group) were administered food The average dally concentrations were 73 and 183 mg CN/kg Preparation Date: 01/09/86 0421P -1- 01/11/86 ------- Endpolnt and Experimental Doses (cont.): diet. From the data reported on food consumption and body weight, dally esti- mated doses were 4.3 mg and 10.8 mg CN/kg bw. The average food CN concentra- tions were estimated based on the authors' data for concentration at the beginning and end of each food preparation period and by assuming a first order rate of loss for the Intervening period. There were no treatment related effects on growth rate, no gross signs of toxlclty, and no hlstopatho- loglcal lesions. Studies by Phllbrlck et al. (1979) showed decreased weight gain and thyroxln levels and myelln degeneration In rats at 30 mg/kg/day CN. Other chronic studies either gave higher effect levels or used s-ubcutaneous route (Crampton et al., 1979; Lessell, 1971; Herthlng et al., 1960). Human data do not provide adequate Information from which to derive an ADI because effective dose levels of chronically Ingested CN are not documented. Therefore, the study of Howard and Hanzel (1955) provides the highest NOAEL 10.8 mg/kg/day for CN and Is chosen for the derivation of an ADI for CN of 1.5 mg/day or 0.02 mg/kg/day.. Cyanide Is metabolized extensively In the liver. Indicating that the only relevant route of administration for quantitative risk assessment In the deri- vation of an oral ADI Is the oral route of administration. Uncertainty Factors (UFs): According to the U.S. EPA (1985) an uncertainty factor of 100 Is used to derive the ADI (10 for species extrapolation, 10 for sensitive population). Modifying Factors (MFs): A modifying factor of 5 Is used for apparent tolerance of cyanide when It Is Ingested with food than when administered by gavage or drinking water. Additional Comments: Decreased protein efficiency ratio was produced by dietary cyanide treat- ment of rats during gestation, lactation and postweanlng growth phase In the Tewe and Maner (1981a) experiment; the dose level of cyanide (10.6 mg/kg/day) producing that effect Is slightly lower than the currently accepted NOAEL of 10.8 mg/kg/day (U.S. EPA, 1985). Furthermore, Tewe and Maner (1981b) tested sows. Possible effects observed at about 9.45 mg/kg/day were proliferation of glomerular cells of the kidneys and reduced activity of the thyroid glands In the gilts. However, the number of animals In this experiment was very small. A Japanese study (Amo, 1973) Indicated that 0.05 mg/kg/day of cyanide obtained from drinking water decreased the fertility rate and survival rate In the Fl generation and produced 100% mortality In the F2 generation In mice. However, 0421P -2- 01/11/86 ------- Additional Comments (cont.): these data are not consistent with the body of available literature. Thus, until additional chronic studies are available, an ADI of 7.8 mg/day for a 70 kg man Is recommended. Confidence In the RfD: Study: Medium Data Base: Low RfD: Low The confidence 1n the study 1s medium because adequate records of food consumption and body weight were maintained and animals of both sexes were tested at two doses for 2 years. The data base Is rated low because this chemical has not been tested. The confidence In the RfD 1s low because It Is based on analogy. Chronic/reproductive studies are needed to support a higher level of confidence 1n the RfD. Documentation of RfD and Review: ECAO-C1nc1nnat1 Internal Review, July 1985. U.S. EPA. 1985. Cyanides: Review and Evaluation of ADI. Contract No. 68-03-3228. Environmental Criteria and Assessment Office, Cincinnati, OH. Agency RfD Review: First Review: 08/05/85 Second Review: Verification Date: 08/05/85 U.S. EPA Contact: Primary: C.T. DeRosa FTS/684-7534 or 513/569-7534 Secondary: H.L. Dourson FTS/684-7544 or 513/569-7544 0421P -3- 01/11/86 ------- REFERENCE DOSES (RfDs) FOR ORAL EXPOSURE Chemical: Sodium Cyanide Carclnogenlclty: None. Systemic Toxlclty: See below. CAS #: 143-33-9 Endpolnt Experimental Doses UF MF RfD (ADI) Howard and Hanzal (1955) Chronic rat feeding study as HCN PhUbrlck et al. (1979) Rat chronic oral bloassay Body weight loss, myelln degeneration, thyroid effects 10.8 mg/kg/day CN (NOAEL) converted to 20.4 mg/kg/day of sodium cyanide 30.0 mg/kg/day CN (LOAEL) 100 0.04 mg/kg/day or 3 mg/day for a 70 kg man Conversion Factor: Molecular weight of NaCN/CN 1s 49/26; thus, 10.8 mg/kg/day x 49/26 = 20.4 mg/kg/day Endpolnt and Experimental Doses: Howard, J.W. and R.F. Hanzal. treated with hydrogen cyanide. 1955. Chronic Agrlc. Food Chem. toxldty for 3: 325-329. rats of food Since sodium Is present In very high levels physiologically, an ADI for sodium cyanide of 0.04 mg/kg/day or 3 rag/day can be calculated based on the maximum molar equivalents (1) of cyanide generated In aqueous solution or dilute acids. In this 2-year dietary study, rats (10/sex/group) were administered food fumigated with HCN. The average dally concentrations were 73 and 183 mg CN/kg diet. From the data reported on food consumption and body weight, dally esti- mated doses were 4.3 rag and 10.8 rag CN/kg bw. The average food CN concentra- Preparatlon Date: 01/08/86 0421P -1- 01/11/86 ------- Endpolnt and Experimental Doses (cont.): tlons were estimated based on the authors' data for concentration at the beginning and end of each food preparation period and by assuming a first order rate of loss for the Intervening period. There were no treatment related effects on growth rate, no gross signs of toxldty. and no hlstopatho- loglcal lesions. Studies by Phllbrlck et al. (1979) showed decreased weight gain and thyroxln levels and myelln degeneration 1n rats at 30 mg/kg/day CN. Other chronic studies either gave higher effect levels or used subcutaneous route (Crampton et al.. 1979; Lessen, 1971; Herthlng et al., 1960). Human data do not provide adequate Information from which to derive an ADI.because effective dose levels of chronically Ingested CN are not documented. Therefore, the study of Howard and Hanzel (1955) provides the highest NOAEL 10.8 mg/kg/day for CN and 1s chosen for the derivation of an ADI for CN of 1.5 mg/day or 0.02 mg/kg/day. Cyanide 1s metabolized extensively 1n the liver. Indicating that the only relevant route of administration for quantitative risk assessment 1n the deri- vation of an oral ADI 1s the oral route of administration. ' Uncertainty Factors (UFs): According to the U.S. EPA (1985) an uncertainty factor of 100 Is used to derive the ADI (10 for species extrapolation, 10 for sensitive population). Modifying Factors (MFs): A modifying factor of 5 1s used for apparent tolerance of cyanide when It 1s Ingested with food than when administered by gavage or drinking water. Additional Comments: Decreased protein efficiency ratio was produced by dietary cyanide treat- ment of rats during gestation, lactation and postweanlng growth phase 1n the Tewe and. Maner (1981a) experiment; the dose level of cyanide (10.6 mg/kg/day) producing that effect 1s slightly lower than the currently accepted NOAEL of 10.8 mg/kg/day (U.S. EPA, 1985). Furthermore, Tewe and Maner (1981b) tested sows. Possible effects observed at about 9.45 mg/kg/day were proliferation of glomerular cells of the kidneys and reduced activity of the thyroid glands In the gilts. However, the number of animals In this experiment was very small. A Japanese study (Amo. 1973) Indicated that 0.05 mg/kg/day of cyanide obtained from drinking water decreased the fertility rate and survival rate 1n the Fl generation and produced 100% mortality 1n the F2 generation In mice. However, 0421P -2- 01/11/86 ------- Additional Comments (cont.): these data are not consistent with the body of available literature. Thus, until additional chronic studies are available, an ADI of 2.8 mg/day for a 70 kg man Is recommended. Confidence 1n the RfD: Study: Medium Data Base: Medium RfD: Medium The confidence In the study Is medium because adequate records of food consumption and body weight were maintained and animals of both sexes were tested at two doses for 2 years. The data base 1s rated medium because a small but sufficient number of studies support the chosen study. The confi- dence In the RfD follows. Additional chronic/reproductive studies are needed to support a higher level of confidence 1n the RfD. Documentation of RfD and Review: ECAO-C1nc1nnat1 Internal Review, July 1985. U.S. EPA. 1985. Cyanides: Review and Evaluation of ADI. Contract No. 68-03-3228. Environmental Criteria and Assessment Office, Cincinnati, OH. Agency RfD Review: First Review: 08/05/85 Second Review: Verification Date: 08/05/85 U.S. EPA Contact: Primary: C.T. DeRosa FTS/684-7534 or 513/569-7534 Secondary: M.L. Dourson FTS/684-7544 or 513/569-7544 0421P -3- 01/11/86 ------- REFERENCE DOSES (RfDs) FOR ORAL EXPOSURE Chemical: Strychnine Cardnogenldty: None. Systemic Toxldty: See below. CAS #: 57-24-9 Endpolnt Experimental Doses UF MF RfD (ADI) Seldl and Zblnden (1982) Rat oral short-term to subchronlc study Tox1dty/h1sto- pathology NOAEL: None 10,000 2.5 mg/kg/day LOAEL/FEL 0.0003 mg/kg/day vOr 0.02 mg/day for a 70 kg man Endpolnt and- Experimental Doses: Seldl, I. and G. Zblnden. 1982. Subchronlc oral toxldty of strychnine In rats. Arch. Toxlcol. 51(3): 267-271. This Is the only oral subchronlc study reported, 1n which rats received dally doses of 0 through 10 mg/kg of strychnine by gavage for 28 days. Data recorded for the surviving animals Included blood cell count, electrocardio- grams, eye examinations, urine chemistry, weight gain, tissue histology, organ weights, behavioral tests, and food and water consumption. Mortality was observed 1n 5/12 male rats receiving 10 mg/kg, 1/12 1n each of the 5 mg and 2.5 mg/kg groups. All deaths occurred 0.5-6 hours after oral doses. While one rat that died 1n the 2.5 mg/kg/day group showed signs of poisoning, no symptoms were exhibited by survivors, nor did any of the survivors differ from controls hlstologlcally or 1n any of the parameters monitored. The systemic level of. this rapidly degradable toxicant [based on pharmacoklnetlcs data, Sgaragll and Mannalon (1973)] was probably much higher than In normal oral Intake with food and water because H was administered all at once by gavage. Thus, 2.5 mg/kg/day could be considered a subchronlc LOAEL for rats. Additional studies (GrHzelmann et al., 1978) reported that a 6-month-old human patient received strychnine doses of 0.3-1.1 mg/kg/day over an 18-month period without any adverse effects. However, the patient may have had a Preparation Date: 01/12/86 0421P -1- 01/12/86 ------- Endpolnt and Experimental Doses (cont.): higher strychnine tolerance as a result of nonketotlc hyperglydnemla. The 011 and Hazardous Materials-Technical Assistance Data Systems (1984) reported that "adults may safely drink dally 0.078-0.25 gallons of water containing 10 mg/L of strychnine" (equivalent to 2.9-9.5 mg/day). This corresponds to 0.041-0.136 mg/kg. Uncertainty Factors (UFs): An ADI of 0.0003 mg/kg/day or 0.02 mg/day for a 70 kg man 1s derived from the Seldl and Zblnden (1982) short-term to subchronlc study by applying an uncertainty factor of 1000 to account for extrapolation from a subchronlc to a chronic exposure study, extrapolation from animals to humans and differences 1n sensitivity among the human population. An additional 10 Is used because a LOAEL/FEL (2.5 mg/kg/day) was utilized In the estimation of the RfD Instead of a NOAEL. ..In view of this concern and the limitations In the data base, the derived ADI should be viewed as an Interim estimate. Despite the limitations of the data base the additional factor of 10 should result In a sufficiently protective level. Modifying Factors (MFs): None. Additional Comments: The data base contained only one rat subchronlc study for ADI with suppor- tive clinical data. Until further chronic/reproductive studies are available, a low confidence 1n the RfD Is recommended. Confidence 1n the RfD: Study: Low Data Base: Low RfD: Low Confidence 1n the chosen study Is low because a small number of animals was tested, a NOEL was not established, and the study Is extremely short. Confidence 1n the data base Is low because of the limited supporting studies. Low confidence In the RfD follows. 0421P -2- 01/12/86 ------- Documentation of RfD and Review: ECAO-C1ndnnat1 Internal Review, July 1985. U.S. EPA. 1985. Strychnine: Review and Evaluation of ADI. Contract No 68-03-3228. Environmental Criteria and Assessment Office, Cincinnati, OH. Agency RfD Review: First Review: 08/05/85 Second Review: Verification Date: 08/05/85 U.S. EPA Contact: Primary: C.T. OeRosa FTS/684-7534 or 513/569-7534 Secondary: M.L. Dourson FTS/684-7544 or 513/569-7544 0421P -3- 01/12/86 ------- REFERENCE DOSES (RfDs) FOR ORAL EXPOSURE Chemical: Tetrachloroethylene Carc1nogen1c1ty: CAG, U.S. EPA - Category B2. Systemic Toxlclty: See below. CAS #: 127-18-4 Endpolnt Carpenter (1937) Rat Inhalation, 7 months at 8 hour/ day, 5 days/week Kidney and liver changes Experimental Doses UF MF RfD (ADI) NOAEL: 70 ppm Inha- lation converted to an oral dose of 19.4 mg/kg/day LOAEL: 230 ppm 1000 0.02 mg/kg/day Conversion Factors: 70 ppm = 475 mg/cu. m x 1 cu. m/hour (assumed ventilation rate) x 8 hours/day x 5 days/7 days x 0.5 (assumed Inhalation retention factor) / 70 kg (assumed human body weight) = 19.4 mg/kg/day Endpolnt and Experimental Doses: Carpenter, C.P- 1937. The chronic toxlclty of tetrachloroethylene. J. Ind. Hyg. Toxlcol. 19: 323-336. Carpenter (1937) exposed groups of 24 rats (12/sex) to 1 of 3 doses by Inhalation for 8 hours/day. 5 days/week for 7 months. No significant changes were observed at the low dose of 70 ppm. At 230 ppm, renal congestion and swelling were noted. At 470 ppm, the liver aslo was congested and exhibited cloudy swelling, which remained for 46 days after termination of exposure. The kidney showed Increased secretion, cloudy swelling and desquamatlon; the spleen was congested and showed an Increase In pigment content. The study showed good dose-response, but the U.S. EPA was obligated to use the Inhalation route of exposure since no good oral data are available. Preparation Date: 01/09/86 0421P -1- 01/11/86 ------- Uncertainty Factors (UFs The uncertainty factor of 1000 reflects 10 for both Intraspedes and to the toxldty of this chemical 1n Heu of specific of a subchronlc effect level to Us chronic Interspecles variability data, and 10 for extrapolation equivalent. Modifying Factors (MFs): None. Additional Comments: None. Confidence In the RfD: Study: Medium Data Base: High RfD: Medium Confidence In the chosen study Is medium because while only a small number of animals/sex were tested at each dose, the number of parameters measured was large. Confidence 1n the supporting data base 1s high to medium because several Inhalation studies support the chosen effect level. Medium to high confidence In the RfD normally would follow, but medium 1s chosen because the data are from Inhalation exposures. Documentation of RfD and Review: Extensive Internal (I.e., Red Border) and Steering Committee review. Public comment period was June 12 to September 15, 1984. U.S. EPA. 1985. Drinking Water Criteria Document for Tetrachloroethylene. Office of Drinking Water, Washington, DC. Agency RfD Review: First Review: 05/20/85 Second Review: Verification Date: 05/20/85 U.S. EPA Contact: Primary: P. Fenner-Crlsp FTS/382-7589 or 513/382-7589 Secondary: M.L. Dourson FTS/684-7544 or 513/569-7544 0421P -2- 01/11/86 ------- REFERENCE DOSES (RfDs) FOR ORAL EXPOSURE Chemical: 2,3,4,6-Tetrachlorophenol Cardnogenldty: None. Systemic Toxlclty: See below. CAS #: 58-90-2 Endpolnt Experimental Doses UF HF RfD (ADI) Hattula et al. (1981) Rat oral short-term to subchronlc study Liver necrosis 10 mg/kg/day (NOEL; 1000 50 mg/kg/day (LOAEL) 0.01 mg/kg/day or 0.7 mg/day for a 70 kg man Endpolnt and Experimental Doses: Hattula, M.L., V.M. Wasenius, R. Krees, A.N. ArstHa and H. Klhlstrom. 1981. Acute and short-term toxldty of 2,3,4,6-tetrachlorophenol In rats. Bull. Environ. Contam. Toxlcol. 26: 795-800. The reported study Is a short-term toxldty study 1n which body weight changes and organ hlstopathology were observed. There Is concern about the duration of exposure (55 days) which could be mitigated by rapid rate of urinary elimination of the compound. Based on the data the 10 mg/kg/day 1s considered as a NOEL and application of an uncertainty factor of 1000 (10 for subchronlc study, 10 for Interspecles conversion and 10 for sensitive popula- tion) was used to derive the ADI of 0.01 mg/kg/day. Additional data are pre- sented to substantiate the above ADI. Schwetz et al. (1974) Incorporated an acute range finding toxldty study which resulted In the selection of an MTD of 30 mg/kg/day for the reproduction study. The lower dose (10 mg/kg) was a NOAEL, although subcutaneous edema In exposed fetuses was considered a chance alone Incidence. The subcutaneous edema was not observed In the high-dose group. High dose exposure (30 mg/kg) caused significant delayed ossification of the skull bones; however, this anomaly normally occurs in all control populations. No other maternal or fetal toxldty was reported 1n any of the doses tested 1n this study. Since subcutaneous edema was a chance alone Incidence, It Is recommended that the 10 mg/kg dose may be used as a NOEL. Preparation Date: 01/09/86 0421P -1- 01/11/86 ------- Uncertainty Factors (UFs): The uncertainty factor of 1000 reflects 10 for both Interspecles variability to the toxlclty of this chemical 1n data, and 10 for extrapolation of a subchronlc effect equivalent. Intraspedes and Heu of specific level to Us chronic Modifying Factors (HFs): None. Additional Comments: Chronic studies are not available. Subchronlc and reproductive studies provided adequate data for a RfD of medium level confidence. Confidence In the RfD: Study: Medium Data Base: Medium RfD: Medium Medium confidence In the critical study 1s selected because although only a few animals were tested/dose and sex was unspecified, dosing was conducted 7 days/week, and several parameters were measured. Medium confidence 1n the data base Is selected as two bloassays are available that support the chosen NOEL. Medium confidence In the RfD follows. Documentation of RfD and Review: ECAO-C1nc1nnat1 Internal Review, May 1985. U.S. EPA. 1985. 2.3,4.6-Tetrachlorophenol: Review and Evaluation of ADI. Contract No. 68-03-3228. Environmental Criteria and Assessment Office, Cincinnati, OH. Agency RfD Review: First Review: 07/08/85 Second Review: Verification Date: 07/08/85 U.S. EPA Contact: Primary: C.T. DeRosa FTS/684-7534 or 513/569-7534 Secondary: M.L. Dourson FTS/684-7544 or 513/569-7544 0421P -2- 01/11/86 ------- REFERENCE DOSES (RfDs) FOR ORAL EXPOSURE Chemical: Tetraethyl Lead Cardnogenldty: None. Systemic Toxlclty: See below. CAS #: 78-00-2 Endpolnt Experimental Doses UF MF RfD (ADI) Schepers (1964) Rat subchronlc study/ gavage 5 days/7 days Hlstopathology of liver and thymus NOAEL: None 10,000 0.0001 ug/kg/day or 0.008 ug/day for a 70 kg man 1.7 ug/kg/day (LOAEL) converted to 1.2 ug/ kg/day Conversion Factor: 5 days/7 days; thus. 1.7 ug/kg/ day x 5 days/7 days =1.2 ug/kg/day Endpolnt and Experimental Doses: Schepers, G.W. 1964. Tetraethyl Health. 8: 277-295. and tetramethyl lead. Arch. Environ. In a 20-week study, Schepers (1964) administered tetraethyl lead In peanut oil by gavage to groups of 12 CD rats (6/sex) at 1.7 and 170 ug/kg/bw 5 days/ week. Gross observations revealed swollen Hvers and fatty plaques In the thymus at both dose groups. H1stolog1cal preparations revealed hepatocyte vacuoHzatlon, cytoplasmlc degeneration and neuronal damage among low-dose rats. Rats exposed to the higher dose developed similar, but more severe, hlstopathologles. Based on these findings a LOAEL of 1.2 ug/kg/day (1.7 ug/kg/da.y x 5 days/7 days) was determined. A subchronlc Inhalation study by Davis et al. (1963) In rats and dogs sup- ports these findings. However, the equivalent oral doses derived from this study are substantially higher than the LOAEL derived from the Schepers (1964) study. Therefore, a human ADI of 0.0001 ug/kg/day was derived based on the LOAEL of 1.2 ug/kg/day from Schepers (1964) and on a standard scaling factor of 10,000. Preparation Date: 01/09/86 0421P -1- 01/11/86 ------- Uncertainty Factors (UFs): The uncertainty factor of 10,000 represents 10 to extrapolate from animal to human, 10 to convert subchronlc to chronic exposure and 10 to protect for sensitive humans, and an additional factor of 10 to convert a LOAEL to a NOAEl. Modifying Factors (MFs): None. Additional Comments: The data base contained limited long-term oral studies, as well as limited subchronlc Inhalation and oral data. Reproductive, carcinogenic and terato- genlc data are available but Inconclusive. Limited ep1dem,1olog1cal data are also available. Confidence In the RfD: Study: Medium Data Base: Medium RfD: Medium The chosen study Is given medium confidence because although only a few animals/sex/dose were tested, a good hlstopathology was conducted, and a dose-severity was observed. The data base was considered to have medium to low confidence because some supporting Information was available. Medium (that tends to low) confidence 1n the RfD follows. Documentation of RfD and Review: ECAO-C1nc1nnat1 Internal Review, July 1985. U.S. EPA. 1985. Tetraethyl Lead: Review and Evaluation of ADI. Contract No. 68-03-3228. Environmental Criteria and Assessment Office, Cincinnati, OH. Agency RfD Review: First Review: 08/05/85 Second Review: Verification Date: 08/05/85 U.S. EPA Contact: Primary: C.T. DeRosa FTS/684-7534 or 513/569-7534 Secondary: M.L. Dourson FTS/684-7544 or 513/569-7544 0421P -2- 01/11/86 ------- REFERENCE DOSES (RfDs) FOR ORAL EXPOSURE Chemical: ThaTMc Oxide Cardnogenlclty: None. Systemic Tox1c1ty: See below. CAS #: 563-68-8 Endpolnt Experimental Doses UF MF RfD (ADI) Downs et al. (I960) Rat subchronlc feed- Ing Increased kidney weight, alopecia 5 ppm In diet thai- 1000 llum^acetate (NOEL) converted to 0.39 mg/kg/day as thal- lium or 0.43 mg/kg/ day thalUc oxide 0.0004 mg/kg/day thallium or 0.0004 mg/kg/day thalllc oxide or 0.03 mg/day thalUc oxide for a 70 kg man 15 ppm In diet as thallium acetate (LOAEL) converted to 1.16 mg/kg/day thallium or 1.30 mg/kg/day thalUc oxide Conversion Factor: Young rat food consumption 10% bw/day; molecular weight of T1/T1C2H30 Is 204/263; molecular weight of T1203/2 Tl Is 456/408; thus, 5 mg/kg of diet (ppm) x 0.1 kg of diet/kg bw/day x 204/263 x 456/408 = 0.433 mg/kg/day Endpolnt and Experimental Doses: Downs, W.L., J.K Scott, L.T. Steadman and E.A. subacute toxldty studies of thallium compounds. 399-406. Maynard. Am. Ind. 1960. Acute and Hyg. Assoc. 21: Groups of rats (5/sex/dose) were fed diets containing nominal concentra- tions of thallium acetate of 0, 5, 15 or 50 ppm. An additional group (30 ppm) was added partway through (time not specified). Animals were allowed ad lib Preparation Date: 01/08/86 0421P -1- 01/11/86 ------- Endpoint and Experimental Doses (cont.): access to these diets for 15 weeks. The 50 ppm level resulted in 100% mortal- ity by week 5. The 30 ppm level resulted in 100% mortality by week 9. Four of 10 control animals died (2/sex) by week 15 making interpretation of sur- vival 1n the remaining dose groups difficult (15 ppm 3/5 males died, 1/5 females; 5 ppm 2/6 males died, 0/4 females). At termination, the only gross finding was alopecia in the 15 and 30 ppm groups. The authors state there was a slight Increase in kidney weight (doses not specified, data not shown). The authors reported that histopathologlcal evaluations did not Indicate treat- ment-related pathology. In addition, other groups of rats (10/sex/dose) were fed thai He oxide at dietary levels of 20, 35, 50, 100 and 500 ppm for 15 weeks. All animals fed greater than or equal to 50 ppm died. Increased mor- tality was seen at 35 ppm. At 20 ppm males showed weight depression, both sexes showed alopecia and both sexes showed increased kidney weight. These data Indicate that the toxldty of thalHc oxide is substantially similar to thallium acetate. Unfortunately, lower feeding levels corresponding to a NOAEL were not utilized for this salt. It is proposed that the, NOEL for thal- lium acetate, 5 ppm (0.39 mg/kg/day as thallium), be used Ło calculate an ADI for thalllc oxide. A feeding level of 0.43 mg/kg/day thai lie oxide would pro- vide an equivalent thallium intake. Uncertainty Factors (UFs): The uncertainty factor of 1000 reflects 10 for both intraspecies and Interspedes variability to the toxldty of this chemical In lieu of specific data, and 10 for extrapolation of a subchronic effect level to its chronic equivalent. Modifying Factors (HFs): None. Additional Comments: Downs et al. (1960) is the only subchronic study available for the oral route. .There appear to be no chronic data. An abstract of a Russian study was located which reported administration of thallium sulfate or carbonate by l.p. or s.c. Injection. However, 1n the absence of data for oral absorption efficiency, H 1s difficult to compare these doses. Further chronic/reproduc- tive toxldty data are needed for a higher level of confidence In the RfD. 0421P -2- 01/11/86 ------- Confidence in the RfD: Study: Low Data Base: Low RfD: Low Confidence In the group sizes, mortality chosen study 1s low. This study Is flawed by small In the control group, failure to monitor food consump- tion and lack of detail in the reported results. However, four doses were tested and were preceded by a short-term bloassay that tested six doses. Confidence In both the data base and the RfD is low because no supporting data are available. Documentation of RfD and Review: ECAO-C1nc1nnat1 Internal Review, July 1985. U.S. EPA. 1985. Thallium Compounds: Review and Evaluation of.ADI. Contract No. 68-03^3228. Environmental Criteria and Assessment Office, Cincinnati, OH. Agency RfD Review: First Review: Second Review: Verification Date: 08/05/85 08/05/85 U.S. EPA Contact: Primary: C.T. DeRosa FTS/684-7534 or 513/569-7534 Secondary: M.L. Dourson FTS/684-7544 or 513/569-7544 0421P -3- 01/11/86 ------- REFERENCE DOSES (RfDs) FOR ORAL EXPOSURE Chemical: Thai 1lum Acetate CarclnogenlcHy: None. Systemic Toxldty: See below. CAS #: 563-68-8 Endpolnt Experimental Doses UF MF RfD (ADI) Downs et al. (1960) Rat subchr.onlc feed- Ing study Increased kidney weight, alopecia 5 ppm 1n diet (NOEL) 1000 converted to 0.5 mg/kg/day 0.0005 mg/kg/day or 0.04 mg/day for a 70 kg human 15 ppm In diet (LOAEL) converted to 1.5 mg/kg/day Conversion Factor: Young rat food consumption 10% bw/day; thus, 5 mg/kg of diet (ppm) x 0.1 kg of diet/kg bw/day = 0.5 mg/kg bw/day Endpolnt and Experimental Doses: Downs, W.L., J.K Scott, L.T. Steadman and E.A. subacute toxldty studies of thallium compounds. 399-406. Maynard. Am. Ind. 1960. Acute and Hyg. Assoc. 21: Groups of rats (5/sex/dose) were fed diets containing nominal concentra- tions of thallium acetate of 0, 5, 15 or 50 ppm. An additional group (30 ppm) was added partway through (time not specified). Animals were allowed ad lib access to these diets for 15 weeks. The 50 ppm level resulted In 100% mortal- ity by week 5. The 30 ppm level resulted In 100% mortality by week 9. Four of 10 control animals died (2/sex) by week 15 making Interpretation of survival In the remaining dose groups difficult (15 ppm 3/5 males died, 1/5 females; 5 ppm 2/6 males died, 0/4 females). At termination, the only gross finding was alopecia In the 15 and 30 ppm groups. The authors state there was a slight Increase In kidney weight (doses not specified, data not shown). The authors reported that hi stopathologlcal evaluations did not Indicate treat- ment-related pathology Preparation Date: 01/09/86 0421P -1- 01/11/86 ------- Uncertainty Factors (UFs): The uncertainty factor of 1000 reflects 10 for both Intraspecles and Interspecles variability to the toxlclty of this chemical In Heu of specific data, and 10 for extrapolation of a subchronlc effect level to Its chronic equivalent. Modifying Factors (HFs): None. Additional Comments: Downs et al. (1960) Is the only subchronlc study available for the oral route. There appear to be no chronic data. An abstract of a Russian study was located which reported administration of thallium sulfate or carbonate by l.p. or s.c. Injection. However, In the absence of data for oral absorption efficiency, It 1s difficult to compare these doses. Further chronic/reproduc- tive toxlclty data are needed for a higher level of confidence In the RfD. Confidence In the RfD: Study: Low Data Base: Low RfD: Low Confidence In the chosen study 1s low. This study 1s flawed by small group sizes, mortality In the control group, failure to monitor food consump- tion and lack of detail 1n the reported results. However, four doses were tested and were preceded by a short-term bloassay that tested six doses. Confidence In both the data base and the RfD 1s low because no supporting data are available. Documentation of RfD and Review: ECAO-Clnclnnatl Internal Review, July 1985. U.S. EPA. 1985. Thallium Compounds: Review and Evaluation of ADI. Contract No. 68-03-3228. Environmental Criteria and Assessment Office, Cincinnati, OH. Agency RfD Review: First Review: 08/05/85 Second Review: Verification Date: 08/05/85 U.S. EPA Contact: Primary: C.T. DeRosa FTS/684-7534 or 513/569-7534 Secondary: M.L. Dourson FTS/684-7544 or 513/569-7544 0421P -2- 01/11/86 ------- REFERENCE DOSES (RfDs) FOR ORAL EXPOSURE Chemical: Thallium Carbonate Cardnogenlclty: None. Systemic Toxlclty: See below. CAS #: 6533-73-9 Endpolnt Experimental Doses UF MF RfD (ADI) Downs et al. (1960) Rat subchronlc feed- Ing study Increased kidney weight, alopecia 5 ppm In diet as 1000 thallium acetate (NOEL) converted to 0.39 mg/kg/day thallium or 0.44 mg/kg/day thallium carbonate 0.0004 mg/kg/day thallium or 0.0004 mg/kg/day thallium carbonate or 0.03 mg/day thal- lium carbonate for a 70 kg man 15 ppm In diet (LOAEL) converted to 1 .2 mg/kg/day as thalllum or 1.3 mg/ kg/day thallium carbonate Conversion Factors: Young rat food consumption 10% bw/day; molecular weight of T1/T1C2H302 1s 204/263; molecular weight of T12C03/2 Tl is 467/408; thus, 5 mg/kg of diet (ppm) x 0.1 kg of diet/kg bw/day x 204/263 x 467/408 = 0.44 mg/kg/day Endpolnt and Experimental Doses: Downs, W.L., J.K Scott, L.T. Steadman and E.A. Maynard. 1960. Acute and subacute toxldty studies of thallium compounds. Am. Ind. Hyg. Assoc. 21: 399-406. Groups of rats (5/sex/dose) were fed diets containing nominal concentra- tions of thallium acetate of 0, 5, 15 or 50 ppm. An additional group (30 ppm) Preparation Date: 01/08/86 0421P -1- 01/11/86 ------- Endpolnt and Experimental Doses (cant.): was added partway through (time not specified). Animals were allowed ad lib access to these diets for 15 weeks. The 50 ppra level resulted In 100% mortal- ity by week 5. The 30 ppra level resulted In 10054 mortality by week 9, Four of 10 control animals died (2/sex) by week 15 making Interpretation of sur- vival In the remaining dose groups difficult (15 ppra 3/5 males died, 1/5 females; 5 ppra 2/6 males died, 0/4 females). At termination, the only gross finding was alopecia In the 15 and 30 ppra groups. The authors state there was a slight Increase In kidney weight {doses not specified, data not shown). The authors reported that hlstopathologlcal evaluations did not Indicate treat- ment-related pathology. Data concerning the toxicity of thallium carbonate per se were not located. The toxicity of thallium acetate and thallium carbonate should be substantially similar. This assumes that gastrointestinal absorption of the two compounds Is also substantially similar. An Interim ADI 1s proposed by analogy to thallium acetate based upon the feeding level of 5 ppnt thallium acetate which corresponds to a NOEL. This feeding level provided a thallium equivalent of 0.39 rag/kg/day corresponding to a feeding level of 0.44 rog/kg/ day thallium carbonate. Uncertainty Factors (UFs): The uncertainty factor of 1000 reflects 10 for both intraspecles and Interspecles- variability to the toxicity of this chemical in lieu of specific data, and 10 for extrapolation of a subchronic effect level to Its chronic equivalent. Hodlfylng Factors (HFs): None. Additional Comments: Downs et al. (I960) is the only subchronic study available for the oral route, - There appear to be no chronic data. An abstract of a Russian study was located wfoleh reported administration of thallium sulfate or carbonate by- l.p. or s,c. Injection, However, in the absence of data for oral absorption efficiency, it Is difficult to compare these doses. Further chronic/reproduc- tive toxicity data are needed for a higher level of confidence In the RfD. 0421P .2- 01/11/86 ------- Confidence In the RfD: Study: Low Data Base: Low RfD: Low Confidence In the chosen study Is low. This study Is flawed by small group sizes, mortality 1n the control group, failure to monitor food consumption and lack of detail 1n the reported results. However, four doses were tested and were preceded by a short-term bloassay that tested six doses. Confidence In both the data base and the RfD are low because no supporting data are available. Documentation of RfD and Review: ECAO-C1nc1nnat1 Internal Review, July 1985. U.S. EPA. 1985. Thallium Compounds: Review and Evaluation of ADI. Contract No. 68-03^3228. Environmental Criteria and Assessment Office, Cincinnati, OH. Agency RfD Review: First Review: 08/05/85 Second Review: Verification Date: 08/05/85 U.S. EPA Contact: Primary: C.T. DeRosa FTS/684-7534 or 513/569-7534 Secondary: M.L. Dourson FTS/684-7544 or 513/569-7544 0421P -3- 01/11/86 ------- REFERENCE DOSES (RfDs) FOR ORAL EXPOSURE Chemical: Thallium Chloride Carclnogenldty: None. Systemic Toxldty: See below. CAS #: 7791-12-0 Endpolnt Experimental Doses UF MF RfD (ADI) Downs et al. (1960) Rat subchronlc feed- Ing study Increased kidney weight, alopecia 5 ppm 1n diet thai- 1000 Hum acetate (NOEL) converted to 0.39 mg/kg/day thallium or 0.45 mg/kg/day thallium chloride 0.0004 mg/kg/day thallium or ' 0.0005 mg/kg/day thallium chloride or 0.03 mg/day thal- lium chloride for a 70 kg man 15 ppm In diet as thallium acetate (LOAEL) converted to 1.16 mg/kg/day thal- lium or 1.36 mg/kg/ day thallium chloride Conversion Factor: Young rat food consumption 10% bw/day; molecular weight of T1/T1C2H303 Is 204/263; molecular weight of T1C1/T1 1s 239/204; thus, 5 mg/kg of diet (ppm) x 0.1 kg of diet/kg bw/day x 204/263 x 239/204 = 0.454 mg/kg/day Endpolnt and Experimental Doses: Downs, H.L., J.K Scott, L.T. Steadman and E.A. Haynard. 1960. Acute and subacute toxlclty studies of thallium compounds. Am. Ind. Hyg. Assoc. 21: 399-406. Groups of rats (5/sex/dose) were fed diets tlons of thallium acetate of 0, 5, 15 or 50 ppm. was added partway through (time not specified). containing nominal concentra- An additional group (30 ppm) Animals were allowed ad Hb Preparation Date: 01/09/86 0421P -1- 01/11/86 ------- Endpolnt and Experimental Doses (cont.): access to these diets for 15 weeks. The 50 ppm level resulted In 100% mortal- ity by week 5. The 30 ppm level resulted In 100% mortality by week 9. Four of 10 control animals died (2/sex) by week 15 making Interpretation of sur- vival 1n the remaining dose groups difficult (15 ppm 3/5 males died, 1/5 females; 5 ppm 2/6 males died, 0/4 females). At termination, the only gross finding was alopecia In the 15 and 30 ppm groups. The authors state there was a slight Increase 1n kidney weight (doses not specified, data not shown). The authors reported that hlstopathologlcal evaluations did not Indicate treat- ment-related pathology. No data were located concerning the toxicology of thallium chloride per The toxlclty of thallium chloride should be substantially similar to that thallium acetate. This presumes that absorption by the gastrointestinal Is also substantially similar for the two compounds. Utilizing the feeding level from the thallium acetate study an Interim se of tract no-observable effect ADI may be calculated for thallium chloride by correcting for differences In thallium .content. Thallium acetate (5 ppm) contributes 0.39 mg/kg/day thal- lium which would be equivalent (In terms of thallium content) to 0.45 mg/kg/ day thallium chloride. Uncertainty Factors (UFs): The uncertainty factor of 1000 reflects 10 for both Intraspedes and Interspedes variability to the toxlclty of this chemical In Heu of specific data, and 10 for extrapolation of a subchronlc effect level to Us chronic equivalent. Modifying Factors (MFs): None. Additional Comments: Downs et al. (1960) 1s the only subchronlc study available for the oral route. -There appear to be no chronic data. An abstract of a Russian study was located which reported administration of thallium sulfate or carbonate by l.p. or s.c. Injection. However, In the absence of data for oral absorption efficiency. It Is difficult to compare these doses. Further chronic/reproduc- tive toxlclty data are needed for a higher level of confidence 1n the RfD. 0421P -2- 01/11/86 ------- Confidence In the RfD: Study: Low Data Base: Low RfD: Low Confidence 1n the chosen study Is low. This study Is flawed by small group sizes, mortality 1n the control group, failure to monitor food consump- tion and lack of detail In the reported results. However, four doses were tested and were preceded by a short-term bloassay that tested six doses. Confidence In both the data base and the RfD Is low because no supporting data are available*. Documentation of RfD and Review: ECAO-C1nc1nnat1 Internal Review, July 1985. U.S. EPA. 1985. Thallium Compounds: Review and Evaluation of ADI. Contract No. 68-03-.3228. Environmental Criteria and Assessment Office, Cincinnati, OH. Agency RfD Review: First Review: Second Review: Verification Date: 08/05/85 08/05/85 U.S. EPA Contact: Primary: C.T. DeRosa FTS/684-7534 or 513/569-7534 Secondary: M.L. Dourson FTS/684-7544 or 513/569-7544 0421P -3- 01/11/86 ------- REFERENCE DOSES (RfDs) FOR ORAL EXPOSURE Chemical: Thallium Nitrate Cardnogenlclty: None. Systemic ToxUity: See below. CAS #: 10102-45-1 Endpolnt Experimental Doses UF MF RfD (ADI) Down et al. (1960) Rat subchr.onlc feed- Ing study Increased kidney weight, alopecia 5 ppm 1n diet as thallium acetate (NOEL) converted 0.39 mg/kg/day thallium or 0.51 kg/day thallium nitrate 1000 to mg/ 0.0004 mg/kg/day thallium or 0.0005 mg/kg/day thallium nitrate or 0.04 mg/day thal- lium nitrate for a 70 kg man 15 ppm 1n diet (LOAEL) converted to 1.16 mg/kg/day as thallium or 1.52 mg/kg/day thallium nitrate Conversion Factor: Young rat food consumption 10% bw/day; molecular weight of T1/T1C2H302 1s 204/263; molecular weight of T1N03/T1 Is 266/204; thus, 5 mg/kg of diet (ppm) x 0.1 kg of diet/kg bw/day x 204/263 x 266/204 = 0.506 mg/kg/day Endpolnt and Experimental Doses: Downs, W.L., J.K Scott, L.T. subacute toxlclty studies of 399-406. Steadman and E.A. thallium compounds. Maynard. Am. Ind. 1960. Hyg. Acute and Assoc. 21: Groups of rats (5/sex/dose) were fed diets containing tlons of thallium acetate of 0, 5, 15 or 50 ppm. An was added partway through (time not specified). nominal concentra- addHlonal group (30 ppm) Animals were allowed ad lib Preparation Date: 01/08/86 0421P -1- 01/11/86 ------- Endpolnt and Experimental Doses (cont.): access to these diets for 15 weeks. The 50 ppm level resulted In 100% mortal- ity by week 5. The 30 ppm level resulted In 10054 mortality by week 9. Four of 10 control animals died (2/sex) by week 15 making Interpretation of sur- vival In the remaining dose groups difficult (15 ppm 3/5 males died, 1/5 females; 5 ppm 2/6 males died, 0/4 females). At termination, the only gross finding was alopecia In the 15 and 30 ppm groups. The authors state there was a slight Increase In kidney weight (doses not specified, data not shown). The authors reported that hlstopathologlcal evaluations did not Indicate treat- ment-related pathology. No data were located concerning the toxlclty of thallium nitrate per se. The toxlclty of thallium nitrate and thallium acetate should be substantially similar. This presumes that absorption of these compounds from the gastro- intestinal tract 1s similar. By analogy an ADI for thallium nitrate may be calculated from the NOEL for thallium acetate. The thallium nitrate feeding level equivalent to the NOEL dose was 5 ppm. This corresponds to 0.39 mg/kg/day..thallium, which would be equivalent (In terms of- thallium content) to 0.51 mg/kg/day thallium nitrate. Uncertainty Factors (UFs): The uncertainty factor of 1000 reflects 10 for both Intraspecles and Interspedes variability to the toxlclty of this chemical In Heu of specific data, and 10 for extrapolation of a subchronlc effect level to Us chronic equivalent. Modifying Factors (MFs): None. Additional Comments: Downs et al. (1960) Is the only subchronlc study available for the oral route. There appear to be no chronic data. An abstract of a Russian study was located which reported administration of thallium sulfate or carbonate by 1.p. or s.c. Injection. However, In the absence of data for oral absorption efficiency. It Is difficult to compare these doses. Further chronic/reproduc- tive toxlclty data are needed for a higher level of confidence In the RfD. 0421P -2- 01/11/86 ------- Confidence In the RfD: Study: Low Data Base: Low RfD: Low Confidence 1n the chosen group sizes, mortality Tn the study Is low. This study Is flawed by small control group, failure to monitor food consump- tion and lack of detail In the reported results. However, four doses were tested and were preceded by a short-term bloassay that tested six doses. Confidence In both the data base and the RfD 1s low because no supporting data are available. Documentation of RfD and Review: Limited In-house review by ECAO-C1nc1nnat1, July 1985. U.S. EPA. 1985. Thallium Compounds: Review and Evaluation of,ADI. Contract No. 68-03-3228. Environmental Criteria and Assessment Office, Cincinnati, OH. Agency RfD Review: First Review: 08/05/85 Second Review: Verification Date: 08/05/85 U.S. EPA Contact: Primary: C.T. DeRosa FTS/684-7534 or 513/569-7534 Secondary: H.L. Dourson FTS/684-7544 or 513/569-7544 0421P -3- 01/11/86 ------- REFERENCE DOSES (RfDs) FOR ORAL EXPOSURE Chemical: Thallium Selenlte Carc1nogen1c1ty: None. Systemic Toxldty: See below. CAS #: 12039-52-0 Endpolnt Experimental Doses UF MF RfD (ADI) Downs et al. (1960) Rat subchr.onlc feed- Ing study Increased kidney weight, alopecia 5 ppm 1n diet as 1000 thallium acetate (NOEL) converted to 0.39 mg/kg/day thal- lium or 0.54 mg/kg/ day thallium selenlte 0.0004 mg/kg/day thallium or 0.0005 mg/kg/day thallium selenHe or 0.04 mg/day thal- lium selenlte for a 70 kg man 15 ppm 1n diet (LOAEL) converted to 1.16 mg/kg/day thal- lium or 1.62 mg/kg/ day thallium selenlte Conversion Factor: Young rat food consumption 10% bw/day; molecular weight of T1/T1C2H302 1s 204/263; molecular weight of TISe/Tl 1s 284/204; thus, 5 mg/kg of diet (5 ppm) x 0.1 kg of diet/kg bw/day x 204/263 x 284/204 = 0.540 mg/kg/day Endpolnt and Experimental Doses: Downs, W.L., J.K Scott, L.T. Steadman and E.A. subacute- tox1c1ty studies of thallium compounds. 399-406. Maynard. Am. Ind. 1960. Acute and Hyg. Assoc. 21: Groups of rats (5/sex/dose) were fed diets containing nominal concentra- tions of thallium acetate of 0, 5, 15 or 50 ppm. An additional group (30 ppm) was added partway through (time not specified). Animals were allowed ad lib access to these diets for 15 weeks. The 50 ppm level resulted In 100% mortal- ity by week 5. The 30 ppm level resulted In 100% mortality by week 9. Four Preparation Date: 01/08/86 0421P -1- 01/11/86 ------- Endpolnt and Experimental Doses (cont.): of 10 control animals died (2/sex) by week 15 making Interpretation of sur- vival In the remaining dose groups difficult (15 ppm 3/5 males died, 1/5 females; 5 ppm 2/6 males died, 0/4 females). At termination, the only gross finding was alopecia 1n the 15 and 30 ppm groups. The authors state there was a slight Increase In kidney weight (doses not specified, data not shown). The authors reported that hlstopathologlcal evaluations did not Indicate treat- ment-related pathology. No toxlcologlcal data were located concerning thallium selenlte per se. It 1s possible to develop an ADI based on equivalent thallium exposure from data concerning thallium acetate. However, this extrapolation 1s considered more uncertain than extrapolations among the simple thallium salts. The no-effect feeding level for thallium acetate was 5 ppm which con- tributed 0.39 mg/kg/day thallium. The dietary thallium selenlte Intake which would provide an equivalent thallium Intake 1s 0.54 mg/kg/day thallium selenlte... The exposure to selenium from this compound, based upon the pro- posed Interim ADI of 38 yg/day, should be well below the toxic range for selenium alone. Uncertainty Factors (UFs): The uncertainty factor of 1000 reflects 10 for both Intraspedes and Interspecles variability to the toxldty of this chemical 1n Heu of specific data, and 10 for extrapolation of a subchronlc effect level to Its chronic equivalent. Modifying Factors (MFs): None. Additional Comments: Downs et al. (1960) Is the only subchronlc study available for the oral route. -There appear to be no chronic data. An abstract of a Russian study was located which reported administration of thallium sulfate or carbonate by 1.p. or s.c. Injection. However, 1n the absence of data for oral absorption efficiency, It 1s difficult to compare these doses. Further chronic/reproduc- tive toxldty data are needed for a higher level of confidence 1n the RfD. 0421P -2- 01/11/86 ------- Confidence 1n the RfD: Study: Low Data Base: Low RfD: Low Confidence In the chosen study 1s low. This study Is flawed by small group sizes, mortality 1n the control group, failure to monitor food consump- tion and lack of detail 1n the reported results. However, four doses were tested and were preceded by a short-term bloassay that tested six doses. Confidence 1n both the data base and the RfD Is low because no supporting data are available. Documentation of RfD and Review: ECAO-Clndnnatl limited Internal Review, July 1985. U.S. EPA. 1985. Thallium Compounds: Review and Evaluation of.ADI. Contract No. 68-03r3228. Environmental Criteria and Assessment Office, Cincinnati, OH. Agency RfD Review: First Review: 08/05/85 Second Review: Verification Date: 08/05/85 U.S. EPA Contact: Primary: C.T. DeRosa FTS/684-7534 or 513/569-7534 Secondary: M.L. Dourson FTS/684-7544 or 513/569-7544 0421P -3- 01/11/86 ------- REFERENCE DOSES (RfDs) FOR ORAL EXPOSURE Chemical: Thallium Sulfate Cardnogenlclty: None. Systemic Toxlclty: See below. CAS #: 7446-18-6 Endpolnt Experimental Doses UF MF RfD (ADI) Downs et al. (1960) Rat subchronlc feed- Ing study Increased kidney weight, alopecia 5 ppm In diet as 1000 thallium' acetate (NOEL) converted to 0.39 mg/kg/day thal- lium or 0.48 mg/kg/ day thallium sulfate 0.0004 mg/kg/day thallium or 0.0005 mg/kg/day thallium sulfate or 0.03 mg/day thal- lium sulfate for a 70 kg man 15 ppm 1n diet (LOEL) converted to 1.16 mg/kg/day thallium or 1.44 mg/kg/day thallium sulfate Conversion Factor: Young rat food consumption 10% bw/day; molecular weight of T1/T1C2H302 1s 204/263; molecular weight of T12S04/2 Tl 1s 504/408; thus, 5 mg/kg of diet (ppm) x 0.1 of diet/kg bw/day x 204/263 x 504/408 = 0.479 mg/kg/day Endpolnt and Experimental Doses: Downs, W.L., J.K Scott, L.T. Steadman and E.A. subacute.. toxldty studies of thallium compounds. 399-406. Maynard. 1960. Acute and Am. Ind. Hyg. Assoc. 21: Groups of rats (5/sex/dose) were fed diets containing nominal concentra- tions of thallium acetate of 0, 5, 15 or 50 ppm. An additional group (30 ppm) was added partway through (time not specified). Animals were allowed ad lib access to these diets for 15 weeks. The 50 ppm level resulted In 100% mortal- ity by week 5. The 30 ppm level resulted in 100% mortality by week 9. Four Preparation Date: 01/08/86 0421P -1- 01/11/86 ------- Endpolnt and Experimental Doses (cont.): of 10 control animals died (2/sex) by week 15 making Interpretation of sur- vival 1n the remaining dose groups difficult (15 ppm 3/5 males died, 1/5 females; 5 ppm 2/6 males died, 0/4 females). At termination, the only gross finding was alopecia In-the 15 arxd 30 ppm groups. The authors state there was a slight Increase 1n kidney weight (doses rrot specified, data not shown). The authors reported that hlstopathologlcal evaluations did not Indicate treat- ment-related pathology. No data concerning the toxldty of thallium sulfate per se were located. The toxldty of thallium sulfate and thallium acetate should be substantially similar. This presumes that gastrointestinal absorption 1s substantially sim- ilar. An ADI for thallium sulfate may be estimated by analogy to thallium acetate. The no-effect feeding level for thallium acetate was 5 ppm which provided 0.39 mg/kg/day thallium. A thallium sulfate Intake providing a cor- responding thallium Intake would be 0.48 mg/kg/day. Uncertainty Factors (UFs): The uncertainty factor of 1000 reflects 10 for both Intraspecles and Interspedes variability to the toxldty of this chemical 1n Heu of specific data, and 10 for extrapolation of a subchronlc effect level to Us chronic equivalent. Modifying Factors (MFs): None. Additional Comments: Downs et al. (1960) 1s the only subchronlc study available for the oral route. There appear to be no chronic data. An abstract of a Russian study was located which reported administration of thallium sulfate or carbonate by l.p. or s.c. Injection. However, In the absence of data for oral absorption efficiency, 1t 1s difficult to compare these doses. Further chronic/reproduc- tive toxJclty data are needed for a higher level of confidence 1n the RfD. 0421P -2- 01/11/86 ------- Confidence In the RfD: Study: Low Data Base: Low RfD: Low Confidence 1n the chosen study 1s low. This study Is flawed by small group sizes, mortality In the control group, failure to monitor food consump- tion and lack of detail In the reported results. However, four doses were tested and were preceded by a short-term bloassay that tested six doses. Confidence in both the data base and the RfD is low because no supporting data are available. Documentation of RfD and Review: Limited In-house review by ECAO-C1nc1nnat1, July 1985. U.S. EPA. 1985. Thallium Compounds: Review and Evaluation of ADI. Contract No. 68-03-3228. Environmental Criteria and Assessment Office. Cincinnati, OH. Agency RfD Review: First Review: 08/05/85 Second Review: Verification Date: 08/05/85 U.S. EPA Contact: Primary: C.T. DeRosa FTS/684-7534 or 513/569-7534 Secondary: M.L. Dourson FTS/684-7544 or 513/569-7544 0421P -3- 01/11/86 ------- REFERENCE DOSES (RfDs) FOR ORAL EXPOSURE Chemical: Toluene Carclnogenldty: None. Systemic Toxlcity: See below. CAS #: 108-88-3 Endpolnt Experimental Doses UF MF RfD (ADI) CITT (1980) Rat chronic Inha- lation study Clinical chemistry and hematologlcal parameters 300 ppm (1130 mg/ cu. m) converted to 29 mg/kg/day (NOAEL) LOAEL: None 100 0.3 mg/kg/day or 20 mg/day for a 70 kg man Conversion Factors: 5 days/7 days, 6 hour/24 hour; 0.5 absorption factor, 20 cu. m human breathing rate; 70 kg; thus, 1130 mg/cu. m x 5 day/7 days x 6 hours/24 hours x 0.5 x 20 cu. m/day / 70 kg = 28.8 mg/kg/day Endpolnt and Experimental Doses: CUT (Chemical Industry Institute of Toxicology). 1980. A twenty-four month Inhalation toxicology study In F1scher-344 rats exposed to atmospheric toluene. CUT, Research Triangle Park, NC. Toluene Is most likely a potential source of respiratory hazard. The only chronic toxlclty study on toluene was conducted for 24 months In male and female F344 rats (CUT, 1980). Toluene was administered by Inhalation at 30, 100 or 300 ppm (113, 377 or 1130 mg/cu. m) to 120 male and female F344 rats for 6 .hours/day. 5 days/week. The same number of animals (120 male and female) was used as a control. Clinical chemistry, hematology and urlnalysls testing was conducted at 18 and 24 months. All parameters measured at the termination of the study were normal except for a dose-related reduction 1n hematocrlt values In females exposed to 100 and 300 ppm toluene. Based on these An oral ADI of 20 findings, a NOAEL of 300 ppm or 1130 mg/cu. m was derived. mg/day can be derived using route-to-route extrapolation. Preparation Date: 01/08/86 0421P -1- 01/11/86 ------- Endpolnt and Experimental Doses (cont.): This was done by expanding the exposure from 6 hours/day, 5 days/week to con- tinuous exposure and multiplying by 20 cu. m/day and 0.5 to reflect a 50% absorption factor. Uncertainty Factors (UFs): An uncertainty factor of 100 (10 for sensitive Individuals and 10 for Intraspecles extrapolation was also applied. Modifying Factors (MFs): None. Additional Comments: The only oral study found in the data base (Wolf et al., 1956) contains subchronlc data 1n which no adverse effects of toluene were reported at the highest dose tested (590 mg/kg/day). Confidence 1n the RfD: Study: High Data Base: Medium RfD: Medium A high confidence 1s chosen for the critical study because a large number of animals/sex were tested In each of three dose groups and many parameters were studied. Interim kills were performed. The data base 1s rated medium because several studies support the chosen effect level. The confidence of the RfD Is not any higher than medium because the critical study was by the Inhalation route. Documentation of RfD and Review: Limited Peer Review and Agency-wide Internal Review, 1984. U.S. EPA. 1985. Drinking Water Criteria Document for Toluene. Office of Drinking Hater, Washington, DC. 0421P -2- 01/11/86 ------- Agency RfD Review: First Review: 05/20/85 Second Review: 08/05/85 Verification Date: 08/05/85 U.S. EPA Contact: Primary: C.T. DeRosa FTS/684-7534 or 513/569-7534 Secondary: M.L. Dourson FTS/6B4-7544 or 513/569-7544 0421P -3- 01/11/86 ------- REFERENCE DOSES (RfDs) FOR ORAL EXPOSURE Chemical: Trlchloromonof luoromethane Carclnogenldty: None. Systemic Toxlclty: See below. CAS #: 75-69-4 Endpolnt Experimental Doses UF MF RfD (ADI; NCI (1978) Cancer blpassay studies 1n rats and mice Survival and hlsto- pathology NOAEL: None 1000 - 0.3 mg/kg/day or 20 mg/day for a 70 kg man 488 mg/kg/day (LOAEL) converted to 349 mg/ kg/day Conversion Factor: 5 days/7 days; thus, 488 mg/kg/ day x 5 days/7 days = 349 mg/kg/day Endpolnt and Experimental Doses NCI (National for possible 78-1356. Cancer Institute) carclnogenlclty. 1978. Bloassay of trlchlorofluoromethane Report. No. 106, PHS/NIH, DHEW Pub!.' No. The NCI bloassay was performed on rats and mice exposed to various doses of tr Ichloromonof luoromethane by gavage over a period of 78 weeks (50 animals/ specles/sex/dose for each of two doses with 20 an1mals/spedes/sex for each of two control groups. A statistically significant positive association between Increased dosage and accelerated mortality by the Tarone test In male and female .rats and female mice was observed. In treated rats of both sexes there were also elevated Incidences of pleurltls and pericarditis not seen 1n con- trols. Inhalation studies which employed multlspedes exposures to higher levels of the compound than used by NCI (Leuschner et al., 1983; Colman et al., 1981; Hansen et al., 1984), reported no adverse clinical/pathological signs of toxldty due to subchronlc or short-term exposures. The LOAEL of 488 mg/kg/day (mortality mg/kg/day on a 7-day exposure basis. In rats) was converted to 349 Preparation Date: 01/09/86 0421P -1- 01/11/86 ------- Uncertainty Factors (UFs): An uncertainty factory of 1000 (10 for LOAEL, 10 for species conversion, and 10 for sensitive human population), results In an ADI of 0.3 mg/kg/day. Modifying Factors (MFs): None. Additional Comments: None. Confidence In the RfD: Study: High Data Base: High RfD: High The chosen study Is given a high to medium confidence because large numbers of animals/sex were tested 1n two doses for chronic exposures. One difficult was the study did not establish a NOEL. The data base 1s given a high confidence because multi-species Inhalation studies provide supporting data. High to medium confidence In the RfD follows. Documentation of RfD and Review: ECAO-Clnclnnatl Internal Review, May 1985. U.S. EPA. 1985. Trlchloromonofluoromethane: Review and Evaluation of ADI. Contract No. 68-03-3228. Environmental Criteria and Assessment Office, Cin- cinnati, OH. Agency RfD Review: First Review: 07/08/85 Second Review: Verification Date: 07/08/85 U.S. EPA Contact: Primary: C.T. DeRosa FTS/684-7534 or 513/569-7534 Secondary: M.L. Dourson FTS/684-7544 or 513/569-7544 0421P -2- 01/11/86 ------- REFERENCE DOSES (RfDs) FOR ORAL EXPOSURE Chemical: 2,4,5-Trlchlorophenol Carc1nogen1c1ty: None. Systemic Toxlcity: See below. CAS #: 95-95-4 Endpolnt Experimental Doses UF MF RfD (ADI) McColHster et al. (1961) Rat oral subchronlc study Liver and kidney pathology 100 mg/kg/day (1000 ppm) (NOEL) 1000 0.1 mg/kg/day or 7 mg/day for a 70 kg man 300 mg/kg/day ppm) (LOAEL) '3000 Conversion Factor: Food consumption 10X of body weight young adult animals; thus, 1000 mg/kg of diet x 0.1 kg of diet/kg bw/day = 100 mg/kg/day Endpolnt and Experimental Doses: McColllster, D.D., D.T. Lockwood and V.K. Rowe. 1961. tion on 2,4,5-trlchlorophenol . Toxlcol. Appl. Pharmacol Toxlcologlc 3: 63-70. Informa- This Is the only subchronlc (98 days) oral study In rodents available In the literature. Ten rats of each sex were exposed to different levels (from 100 through 10,000 ppm) of 2,4,5-trlchlorophenol for 98 days. Mild diuresis and slight degenerative changes In the liver and kidneys were observed In rats of both sexes In the 3000 ppm and higher doses. In this study 1000 ppm (100 mg/kg/day based on food consumption as 10% of body weight In young adults) was considered to be a NOEL, as Judged by behavior, mortality, food consumption, growth, body and organ weights and hlstopathology . Until further chronic/ reproductive studies are available,. this ADI, 0.1 mg/kg/day. Is recommended. Preparation Date: 01/09/86 0421P -1- 01/11/86 ------- Uncertainty Factors (UFs): The uncertainty factor of 1000 reflects 10 for both intraspecles Interspedes variability to the toxldty of this chemical In lieu of specific data, and 10 for extrapolation of a subchronlc effect level to Us chronic equivalent. Modifying Factors (MFs): None. Additional Comments: None. Confidence 1n the RfD: Study: Medium Data Base: Low RfD: Medium The confidence 1n the chosen study Is medium because five dose groups were tested and several parameters were monitored. It Is not higher than medium because only a few animals were tested/dose. Confidence In the data base Is low because little, If any, supporting data exist. Confidence 1n the RfD 1s medium to low. Additional chronic/reproductive toxlclty studies are needed to support a higher confidence In the RfD. Documentation of RfD and Review: limited Peer Review and Agency-wide Internal Review, 1984. U.S. EPA. 1984. Health Effects Assessment for 2,4,5-Trlchlorophenol. Envi- ronmental Criteria and Assessment Office, Cincinnati, OH. ECAO-CIN-H034. Agency RfD Review: First Review: 05/20/85 Second Review: Verification Date: 05/20/85 U.S. EPA Contact: Primary: C.T. DeRos.a FTS/684-7534 or 513/569-7534 Secondary: M.L. Dourson FTS/684-7544 or 513/569-7544 0421P -2- 01/11/86 ------- REFERENCE DOSES (RfDs) FOR ORAL EXPOSURE Chemical: 1,1,2-TMchloro-l ,2,2-trlfluoroethane CAS #: 76-13-1 Cardnogenlclty: None. Systemic Toxlclty: See below. Endpolnt Experimental Doses UF MF RfD (ADI) Imbus and Adklns (1972) Ep1dem1olog1c study: Human occupational exposure Psychomotor Impair- ment 5358 mg/cu. m con- verted to 273 mg/kg/ day {'NOAEL) 10 30 mg/kg/day or 2000 mg/day for a 70 kg man Conversion Factors: 10 cu. m (8-hour human breathing volume), 5 days/7 days, 0.5 absorption factor, 70 kg bw; thus, 5358 mg/cu. m x 10 cu. m x 5 days/7 days x 0.5/70 kg = 273 mg/kg/day Endpolnt and Experimental Doses Imbus, H.R. and C. Adklns trlchlorotrlfluoroethane. 1972. Physical examination of workers exposed to Arch. Environ. Health. 24(4): 257-261. Several animal Inhalation studies reported negative results In dogs, rab- bits, and rats chronically exposed to very high concentrations of trlchloro- trlfluoroethane (U.S. EPA, 1983, Health Assessment Docuement). No apparent adverse effects have been reported In humans occupatlonally exposed to tr1- chlorotrifluoroethane at either 500 mg/cu. m levels for 11 years or 5358 mg/cu. m levels for 2.77 years (Imbus and Adklns, 1972). Slight Impairment of psychomotor performance was reported 1n male volun- teers exposed to tMchlorotrlfluoroethane concentrations of 19,161 mg/cu. m for 2.75 hours (Stopps and Mclaughlin, 1967). This exposure period was too brief to consider a NOAEL for chronic exposure. Therefore, the ADI of 30 mg/kg/day Is considered protective. Preparation Date: 01/09/86 0421P -1- 01/11/86 ------- Uncertainty Factors (UFs): The uncertainty factor of 10 accounts for the expected Interhuman vaM ability to the toxldty of this chemical In lieu of specific data. Modifying Factors (MFs): None. Additional Comments: None. Confidence 1n the RfD: Study: Low Data Base: Low RfD: Low Confidence In the chosen study, data base and RfD are all considered low. Although based on human data, and the fact that several chronic studies In animals support the human NOEL, uncertainties In both the exposure levels and route extrapolation preclude a higher confidence rating. Documentation of RfD and Review: ECAO-C1nc1nnat1 Internal Review, Hay 1985. U.S. EPA. 1985. l,l,2-Tr1chloro-l,2,2-tr1fluoroethane: Review and Evaluation of ADI. Contract No. 68-03-3228. Environmental Criteria and Assessment Office, Cincinnati, OH. Agency RfD Review: First Review: Second Review: Verification Date: 07/08/85 07/08/85 U.S. EPA Contact: Primary: C.T. DeRosa FTS/684-7534 or 513/569-7534 Secondary: M.L. Dourson FTS/684-7544 or 513/569-7544 0421P -2- 01/11/86 ------- REFERENCE DOSES (RfDs) FOR ORAL EXPOSURE Chemical: Z1nc Cyanide CarclnogenlcHy: None. Systemic Toxlclty: See below. CAS #: 557-21-1 Endpolnt Experimental Doses UF MF RfD (ADI) Howard and Hanzal (1955) Chronic rat feeding study as HCN PhlbMck et al. (1979) Rat subchronlc to chronic oral bloassay Body weight loss, thyroid effects, myelln degeneration 10.8 mg/kg/day CN (NOAEL) converted to 24.3 mg/kg/day zinc cyanide 100 30.0 mg/kg/day (LOAEL) CN 0.05 mg/kg/day or 3 mg/day for a 70 kg man Conversion 1s 117/52; kg/day Factor: Molecular weight of Zn(CN)2/(CN)2 thus, 10.8 mg/kg/day x 117/52 = 24.3 mg/ Endpolnt and Experimental Doses: Howard, J.W. and R.F. Hanzal. 1955. Chronic toxlclty for rats by food treated with hydrogen cyanide. Agrlc. Food Chem. 3: 325-329. Since zinc 1s present at high levels 1n foods and Is considerably less toxic than cyanide, an ADI for zinc cyanide of 0.05 mg/kg/day or 3.4 mg/day can be calculated based on the maximum molar equivalents (2) of cyanide gen- erated 1n aqueous solution or dilute adds. In this 2-year dietary study, rats (10/sex/group) were administered food fumigated with HCN. The average dally concentrations were 73 and 183 mg CN/kg Preparation Date: 01/09/86 0421P -1- 01/11/86 ------- Endpolnt and Experimental Doses: diet. From the data reported on food consumption and body weight, dally esti- mated doses were 4.3 mg and "10.8 mg CN/kg bw. The average food CN concentra- tions were estimated based on the authors' data for concentration at the beginning and end of each food preparation period and by assuming a first order rate of loss for the Intervening period. There were no treatment related effects on growth rate, no gross signs of toxldty. and no hlstopatho- loglcal lesions. Studies by PhllbMck et al. (1979) showed decreased weight gain and thyroxln levels and myelln degeneration In rats at 30 mg/kg/day CN. Other chronic studies either gave higher effect levels or used subcutaneous route (Crampton et al., 1979; Lessen, 1971; Herthlng et al., 1960). Human data do not provide adequate Information from which to derive an ADI because effective dose levels of chronically Ingested CN are not documented. Therefore, the study of Howard and Hanzel (1955) provides the highest NOAEL 10.8 mg/kg/day for CN and Is chosen for the derivation of an ADI for CN of 1.5 mg/day or 0.02 mg/kg/day. Cyanide Is metabolized extensively In the liver, Indicating that the only relevant route of administration for quantitative risk assessment In the deri- vation of an oral ADI Is the oral route of administration. Uncertainty Factors (UFs): According to the U.S. EPA (1985) an uncertainty factor of 100 1s used to derive the ADI (10 for species extrapolation, 10 for sensitive population). Modifying Factors (HFs): A modifying factor of 5 1s used for apparent tolerance of cyanide when It 1s Ingested with food than when administered by gavage or drinking water. Additional Comments: Decreased protein efficiency ratio was produced by dietary cyanide treat- ment of rats during gestation, lactation and postweanlng growth phase 1n the Tewe and Maner (1981a) experiment; the dose level of cyanide (10.6 mg/kg/day) producing that effect 1s slightly lower than the currently accepted NOAEL of 10.8 mg/kg/day (U.S. EPA, 1985). Furthermore, Tewe and Maner (1981b) tested sows. Possible effects observed at about 9.45 mg/kg/day were proliferation of g.lomerular cells of the kidneys and reduced activity of the thyroid glands In the gilts. However, the number of animals 1n this experiment was very small. A Japanese study (Amo, 1973) Indicated that 0.05 mg/kg/day of cyanide obtained from drinking water decreased the fertility rate and survival rate In the Fl 0421P -2- 01/11/86 ------- Additional Comments (cont.): generation and produced 100% mortality in the F2 generation in mice. However, these data are not consistent with the body of available literature. Thus, until additional chronic studies are available, an ADI of 3.4 mg/day for a 70 kg man 1s recommended. Confidence In the RfD: Study: Medium Data Base: Medium RfD: Medium The confidence 1n the study 1s medium because adequate records of food consumption and body weight were maintained and animals of both sexes were tested at two doses for 2 years. The data base 1s rated medium because a small but sufficient number of studies support the chosen study. The confi- dence In the RfD follows. Additional chronic/reproductive studies are needed to support a higher level of confidence 1n the RfD. Documentation of RfD and Review: ECAO-Cincinnatl Internal Review, July 1985. U.S. EPA. 1985. Cyanides: Review and Evaluation of ADI. Contract No. 68-03-3228. Environmental Criteria and Assessment Office, Cincinnati, OH. Agency RfD Review: First Review: 08/05/85 Second Review: Verification Date: 08/05/85 U.S. EPA Contact: Primary: Secondary: C.T. DeRosa FTS/684-7534 or 513/569-7534 M.L. Dourson FTS/684-7544 or 513/569-7544 0421P -3- 01/11/86 ------- |