OFFICE OF RESEARCH AND DEVELOPMENT ENVIRONMENTAL …

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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY OFFICE OF RESEARCH AND DEVELOPMENT

ENVIRONMENTAL CRITERIA AND ASSESSMENT OFFICE CINCINNATI. OHIO 45268

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SDMS Document

113465

SUBJECT:

FROM:

Toxicity Information for Multiple Chemicals (Fried Industries/East Brunswick, NJ)

Joan S. Dollarhid4-yO^^-i^v^^/cr/x><^, Associate Director ' Superfund Health Risk Technical Support Center Chemical Mixtures Assessment Branch

TO: Thomas Porucznik U.S. EPA Region II

This memorandum is in response to a request from you and Mark Moese of EBASCO Environmental for any available toxicity information for multiple chemicals for the Fried Industries site. East Brunswick, NJ.

We have no information available for most of the chemicals in the tables you sent. For those compounds, we cannot conclude that there is no risk, only that we have no way of identifying what the risk might be.

An oral RfD for 2-butanone (methyl ethyl ketone) is available on IRIS as of 5/01/93.

Attached please find the following Risk Assessment Issue Papers:

Attachment I.

Attachment II.

Attachment III.

Attachment IV.

Attachment V.

Evaluation of the Inhalation concentration of I,2-DICHLOROBENZENE (CASRN 95-50-1)

Derivation of a Provisional RfD and Evaluation of Carcinogenicity of l/l-DICHLOROETHANE (CASRN 75-34-3)

Provisional Inhalation Slope Factor for 1,1-DICHLOROETHYLEME (CASRN 73-35-4)

Evaluation of Carcinogenicity for 4-METHYL-2-PENTANONE (METHYL ISOBUTYL KETONE) (CASRN 108-10-1)

Evaluation of Systemic Toxicity after Oral Exposure toN-BUTYLBENZENE (CASRN 104-51-8), SEC-BUTYLBENZENE (CASRN 135-98-8), TERT-BUTYLBENZENE (CASRN 98-06-6) and N-PROPYLBENZENE (CASRN 103-65-1)

Printed on Recycled Paper

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Attachment VI.

Attachment vil.

Attachment VIII.

(Please note t ha t we are cu r ren t ly reeva lua t ing the chemicals in Attachment V, and therefore t h i s assessment might change,)

Feasibility of Developing an Oral RfD for 1,1,2,2-TETRACHLOROETHANE (CASRN 79-34-5) by Analogy to cis-1,2-DICHLOROETHYLENE (CASRN 156-59-2)

Oral RfD and Inhalation RfC Derivation Issues for TETRAHYDROFURAN (CASRN 109-99-9)

Evaluation of the Inhalation Concentration for 1,1,1-TRICHLOROETHANE (CASRN 71-55-6)

The last attachment (Attachment IZ) includes old assessments for various chemicals. Please realize that there may be new data that we are not aware of that could change the information. However, per your request, we have not undertaken any additional research beyond updating the IRIS, HEAST and Work Group Status Tables references that are cited. The Risk Assessment Issue Papers for Evaluation of Systemic Toxicity and Carcinogenicity are for the following chemicals:

HEZADECANOIC ACID (CASRN 75-10-3) TETRAMETHYLCYCLOHEZANB TRIBROMOPHENOL 1,3,5-TRIMETHYLBENZENE (CASRN 108-67-8) 2(3H)-BENZOTHIAZOLONE

Please do not hesitate to contact the Superfund Technical Support Center at (513) 569-7300 if you need additional assistance.

Attachments

cc: P. Grevatt (Region II) M. Moese (EBASCO Environmental) C. Sonich-Mullin (ECAO-Cin) M. Stefanidis (Region II)

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Attachment I.

Risk Assessment Issue Paper for: Evaluation of the Inhalation Concentration of

1,2-DICHLOROBENZENE (CASRN 95-50-1)

The HEAST (U.S. EPA, 1992) lists an RfC for 1,2-dichlorobenzene of 2E-1 mg/m^. This RfC is derived from U.S. EPA (1987) and is based on an inhalation study in rats by Hollingsworth et al. (1958). The NOAEL in that study was defined at 49 ppm (290 mg/m') 1,2-dichlorobenzene and the LOAEL at 93 ppm (560 mg/m', 7 hours/day, 5 days/week) for decreased body weight. The NOAEL was duration adjusted, multiplied by the ratio of the rat reference inhalation rate (0.223 mVday) to actual final body weight (0.305 kg) and divided by the ratio of human reference inhalation rate (20 mVday) to body weight (70 kg) . An uncertainty factor of 1000 was applied (for inter- and intraspecies variation and extrapolation from a subchronic study). This derivation is not consistent with current methodology for the development of inhalation RfCs (U.S. EPA, 1989).

No inhalation toxicity values for 1,2-dichlorobenzene are under discussion by the RfD/RfC Work Group (U.S. EPA, 1993a) and no additional, more recent OHEA documentation was encountered (U.S. EPA, 1991a). 1,2-Dichlorobenzene has not been the subject of an ATSDR toxicological profile.

ACGIH (1991) has adopted a TLV-ceiling of 50 ppm (301 mg/m') with a notice of intended changes to a TLV-ceiling of 25 ppm (150 mg/m') and adoption of a 50 ppm (301 mg/m') STEL. These values are aimed to protect workers from the irritative properties of 1,2-dichlorobenzene (ACGIH, 1986). The OSHA standard and NIOSH REL are also 50 ppm as a ceiling limit (OSHA, 1989; NIOSH, 1990).

1,2-Dichlorobenzene has a verified oral RfD of 0.09 mg/kg/day based on lack of adverse effects in rats administered the chemical at 120 mg/kg on 5 days/week (86 mg/kg/day; highest dose tested) by gavage for 2 years (NTP, 1985; U.S. EPA, 1993b). 1,2-Dichlorobenzene has a verified carcinogenicity classification of Group D (U.S. EPA, 1993b).

Although little information is available regarding the long-term inhalation toxicity of 1,2-dichlorobenzene, the studies considered during derivation of the original RfC (Hayes et al., 1985; Hollingsworth et al. 1958), along with a more recent study (Bio/dynamics, 1989), provide limited but sufficient information for the derivation of a provisional RfC for 1,2-dichlorobenzene using current methodology.

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1) Review of pertinent data

Hollingsworth et al. (1958) exposed groups of 16-20 Wistar albino rats of each sex, 7-8 albino guinea pigs of each sex, 2 albino rabbits of each sex plus 2 female monkeys to 0, 49, or 93 ppm (0, 290, or 560 mg/m^, respectively) 1,2-dichlorobenzene (99% pure) vapor 7 hours/day, 5 days/week for up to 7 months. In addition, groups of 10 female mice (strain not reported) were exposed to 0 or 49 ppm 1,2-dichlorobenzene for 7 hours/day, 5 days/week for six and a half months. No compound-related adverse effects were observed in any of the animal species exposed to 49 ppm 1,2-dichlorobenzene as judged by gross appearance, behavior, growth, mortality, organ weights, and gross and microscopical examination of tissues (including lungs, but not upper respiratory tract). Effects seen at the 93 ppm 1,2-dichlorobenzene level were limited to a statistically significant decrease in absolute spleen weight in male guinea pigs, but without histopathologic changes, and a 9% reduction in final body weight in male rats (initial weights not reported). This reduction in final body weight had a statistical significance of p<0.05. Water and food consumption data were not provided. In addition to the endpoints examined at the 49 ppm level, parameters monitored at 93 ppm included qualitative urine tests on female animals of all species for blood, sugar, albumin, and sediment, terminal blood urea nitrogen for female rats, female guinea pigs and rabbits. Based on these results, the exposure level of 93 ppm (560 mg/m') 1,2-dichlorobenzene could be regarded as a NOAEL for rats and guinea pigs in this study. No effects were seen in rabbits or monkeys at this exposure level, but the group sizes were inadequate; mice were tested only at the lower exposure level, with no adverse effects.

Hayes et al. (1985) exposed groups of 30-32 pregnant Fischer 344 rats and 28-30 pregnant New Zealand white rabbits to 0, 100, 200, or 400 ppm 1,2-dichlorobenzene (98.81% pure) vapors (0, 600, 1200, and 2400 mg/m', respectively) 6 hours/day on days 6-15 (rats) or 6-18 (rabbits) of gestation. Endpoints evaluated included maternal and fetal body weights, maternal organ weights, number of litters/group, number of fetuses/litter, number of resorptions/litter, number of litters with resorptions, sex ratio, and the incidence of visceral and skeletal malformations. Rats were sacrificed on day 21 of gestation and rabbits on day 29. Maternal effects in rats were limited to a slight to moderate degree of urine soaking of the perineal area in 8 of 32 rats in the 400 ppm group, slight reduction in food consumption (quantitative data not provided) during the first 3 exposure days, a significant reduction in body weight gain for the interval gestation day 6 through 20 in all 1,2-dichlorobenzene treated groups, and a significant increase in both absolute and relative liver weight at the 400 ppm level and in relative liver weight at the 100 ppm level. Exposure-related developmental

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effects in rats were limited to a statistically significant increased incidence of litters with delayed ossification of cervical vertebral centra. The only maternal effect observed in rabbits was a significant body weight loss during the first three days of exposure at all exposure levels. Food consumption data for rabbits were not provided. No exposure-related developmental effects were observed in rabbits. In this study, developmental NOAELs of 200 and 400 ppm (1200 and 2400 mg/m^, respectively) can be defined for rats and rabbits, respectively. The exposure concentration of 2400 mg/m' is considered a minimal developmental LOAEL in rats. Based on the changes in body weight gain, the exposure level of 100 ppm (600 mg/m^) can be defined as a maternal LOAEL in both rats and rabbits. Similar results were reported in rats and rabbits in an unpublished probe study conducted by Dow Chemical (1981) in which smaller numbers of animals/group were used.

Charles River CD rats (30/sex/exposure group/generation) were exposed by inhalation to vapor concentrations of 0, 50, 150, or 394 ppm (0, 301, 902, and 2370 mg/m', respectively) 1,2-dichlorobenzene (99.2% purity) (Bio/dynamics, 1989). FO adults were exposed for 6 hours/day, 7 days/week for a 10 week pre-mating period and during mating. Following mating, FO males were exposed 6 hours/day, 7 days/week until sacrifice three to four weeks post-mating. Bred FO females were exposed for 6 hours/day on gestation days 0-19 and lactation days 5-28, then sacrificed post-weaning. Fl pups (29 days old) received similar exposures throughout an 11 week pre-mating period, mating, gestation, and lactation. The following parameters were used to assess toxicity in the FO and Fl adults: mortality, clinical signs, body weights, food consumption, organ weights, reproductive parameters, gross necropsy of selected tissues, and histological examination [all the selected tissues in high-exposure group; kidney (males) and liver in low- and mid-exposure groups]. The respiratory tract was not examined. The following parameters were used to assess toxicity in pups: mortality, clinical signs (examined twice daily), body weights (measured on lactation days 0, 4, 14, 21, and 28), sex ratio, gross necropsy (all tissues), and histological examination of grossly abnormal tissues.

The treatment did not increase mortality rates in FO and Fl adults. FO and Fl adults exposed to the low concentration had slightly increased relative and absolute liver weights; no other effects were observed in this group. FO adult males exposed to the mid-concentration had a slight increase in the incidence of staining in the anogenital area and FO and Fl adult males and females had an increased incidence of salivation. Statistically significant (p<0.05 or 0.01) changes in FO and Fl adults at the mid- and high-concentrations included decreased body weights relative to controls at some intervals during the pre-mating period, increased absolute (males) and relative (both sexes)

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Tcidney weight and increased absolute and relative (both sexes) liver weights. The depressions in body weights were <10% in the low-exposure females and sometimes reached >10% in high-exposure Fl females. Body weight gain in the FO and Fl females over the entire pre-mating period was significantly (p<0.05) depressed only at the high exposure, at which the depression was >10%. The body weight depression and decreased weight gain in the FO and Fl males during the pre-mating period was somewhat more pronounced than in the females, but may have been related in part to hyaline droplet nephropathy (below).

Histopathological examination revealed hypertrophy of central lobular hepatocytes in adult FO and Fl rats of both sexes exposed to the mid and high concentrations. Dilated renal tubular lumens with intraluminal granular casts predominantly at the corticomedullary junction were found in adult male FO and Fl rats exposed to these concentrations. Adult FO and Fl males from all exposure groups had intracytoplasmic granules/droplets in the proximal convoluted tubular epithelium of the kidney; the severity of this condition increased as exposure level increased. The description of the renal lesions and the staining characteristics of the granules/droplets (positive with the Mallory Heidenhain stain), and their occurrence only in the males, are consistent with hyaline droplet (alphaj^-globulin) nephropathy (U.S. EPA, 1991b). This endpoint is considered inappropriate for determination of RfDs (or RfCs) (U.S. EPA, 1991b).

Mean pup weights (mean of litter means) in the mid- and high-concentration Fl litters were significantly (p<0.05) decreased on day 0 of lactation; the effect at the mid-concentration was slight (w5% reduction). There were statistically significant (p<0.01) decreases in mean pup weight (mean of litter means) of high-exposure level pups in the Fl and F2 litters during lactation. No adverse reproductive effects were observed. This study identifies a NOAEL of 50 ppm (301 mg/m') and a LOAEL of 150 ppm (902 mg/m^) for liver, body weight and developmental effects in rats.

Subchronic oral studies (NTP, 1985; Robinson et al., 1991) report liver damage as the critical effect in rats and mice treated by gavage with 1,2-dichlorobenzene.

2) Derivation of provisional RfC

Based on the information summarized above, a provisional RfC can be derived from the two-generation study reported by Bio/dynamics (1989). That study reported liver effects (increased relative liver weight and hypertrophy of central lobular hepatocytes), and slight but significant pre-mating body weight depression in FO and Fl rats exposed to 902 mg/m^ 1/2-


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dichlorobenzene 6 hours/day 7 days/week, as well as decreased birth weight in Fl pups at 902 mg/m^; the NOAEL for systemic and developmental effects was 301 mg/m'. The study by Hollingsworth et al. (1958) reported a decrease in spleen weight but no histological changes in male guinea pigs and a 9% depression (relative to controls) in final body weight in male rats exposed to 560 mg/TO? 1,2-dichlorobenzene 7 hours/day, 5 days/week for 6 to 7 months; no other effects were seen. U.S. EPA (1987) considered the exposure concentration of 560 mg/m^ a LOAEL, but effects were minimal and therefore it could be regarded as a NOAEL. In the Hayes et al. (1985) study, a maternal LOAEL of 600 mg/m^ was identified for decreased body weight gain in rats exposed 6 hours/day during gestation days 6-15 and for body weight loss in rabbits during the first days of exposure (gestation days 6-8). In the same study, an exposure level of up to 2400 mg/m' did not induce developmental effects in rabbits and produced a slight delay in ossification in rats (NOAEL, 1200 mg/m') . The provisional RfC, based on the NOAEL of 3 01 mg/m' for liver effects and body weight depression in rats (Bio/dynamics, 1989) can be calculated as follows:

RfC = [NOAELHEC X L;^/LH]/UF

where

NOAELADJ = 301 mg/m' x 6/24 x 7/7 = 75.3 mg/m^.

^A/^H - blood/gas partition coefficient (rat/human) = 1 in the absence of data for 1,2-dichlorobenzene .

NOAELHEC = 75.3 mg/m'

UF = Uncertainty Factor = 3000 (3 for interspecies extrapolation using dosimetric conversion, etc., 10 for the protection of sensitive humans, 10 for the use of a subchronic study, and 10 for lack of complete database)

thus,

RfC = [75.3 mg/m']/3000 = 3E-2 mg/m^

Confidence in the key study is high because appropriate endpoints were examined in an adequate number of animals exposed for an appropriate time period and appropriate statistical analyses were performed. Confidence in the database is low due to the lack of information on possible upper respiratory effects in the supporting studies and the lack of a chronic study.

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Confidence in the provisional RfC is low reflecting low confidence in the database.

This provisional RfC calculated using the current methodology and more recent data (3E-2 mg/m^) is more conservative than the RfC listed in the HEAST (2E-1 mg/m')

REFERENCES:

ACGIH (American Conference of Governmental Industrial Hygienists). 1986. Documentation of the Threshold Limit Values and Biological Exposure Indices, 5th Ed. Cincinnati, OH. p. 178.

ACGIH (American Conference of Governmental Industrial Hygienists). 1991. Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices. ACGIH, Cincinnati, OH. p. 18, 39.

Bio/dynamics. 1989. An inhalation two-generation reproduction study in rats with ortho-dichlorobenzene. Submitted to Chemical Manufacturers Association, Washington, DC. TSCA Section 4 Submission, OTS Fiche #OTS0523028.

Dow Chemical Company. 1981. Ortho-dichlorobenzene: inhalation teratology probe study in rats and rabbits. TSCA 8D Submission, OTS Fiche #OTS0206148.

Hayes, W.C., T.R. Hanley, T.S. Gushow, K.A. Johnson and J.A. John. 1985. Teratogenic potential of inhaled dichlorobenzenes in rats and rabbits. Fund. Appl. Toxicol. 5: 190-202.

Hollingsworth, R.L., V.K. Rowe, F. Oyen, T.R. Torkelson and E.M. Adams. 1958. Toxicity of o-Dichlorobenzene. Arch. Ind. Health 17: 180-187.

NIOSH (National Institute for Occupational Safety and Health). 1990. NIOSH Pocket Guide to Chemical Hazards. U.S. Department of Health and Human Services. DHHS (NIOSH) Publications No. 90-117.

NTP (National Toxicology Program). 1985. Toxicology and carcinogenesis studies of 1,2-dichlorobenzene (o-dichlorobenzene) (CAS No. 95-50-1) in F344/N rats and B6C3F1 mice (gavage studies). NTP TR 255. NIH Publ. No. 86-2511.

OSHA (Occupational Safety and Health Administration). 1989. 29 CFR 1910. Air contaminants; Final Rule. Federal Register. 54(12): 2923-2960.

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U.S. EPA. 1987. Health Effects Assessment for Dichlorobenzenes. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Solid Waste and Emergency Response. ECAO-CIN-H079.

U.S. EPA. 1989. Interim Methods for Development of Inhalation Reference Doses. Office of Health and Environmental Assessment, Washington, DC. EPA 600/8-88/066F.

U.S. EPA. 1991a. Office of Health and Environmental Assessment Chemical Assessments and Related Activities. Office of Health and Environmental Assessment, Washington, DC. April, 1991. OHEA-1-127

U.S. EPA. 1991b. Alphaj^-Globulin: Association with Chemically Induced Renal Toxicity and Neoplasia in the Male Rat. Prepared for the Risk Assessment Forum, U.S. EPA, Washington, DC. EPA/625/3-91/019F.

U.S. EPA. 1992. Health Effects Assessment Summary Tables. Annual Update. FY-1992. Office of Research and Development, Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH. ECAO-CIN-821.

U.S. EPA. 1993a. Monthly Status Report of RfD/RfC and CRAVE Work Groups (As of 05/01/93). Office of Research and Development. Environmental Criteria and Assessment Office, Cincinnati, OH.

U.S. EPA. 1993b. Integrated Risk Information System (IRIS). Online. Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH.

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Attachment II.

Risk Assessment Issue Paper for: Derivation of a Provisional RfD and Evaluation of Carcinogenicity of 1,1-DICHLOROETHANE (CASRN 75-34-3)

INTRODUCTION

The following literature searches were conducted: TOXLINE (1988-1992), HSDB, RTECS, TSCATS, CASONLINE (1984-1990) and TOXLINE (1984-1990). OHEA documents listed in U.S. EPA (1991) and a toxicological profile for 1,1-dichloroethane (ATSDR, 1990) were also consulted for relevant information.

Inhalation and oral toxicity values for 1,1-dichloroethane are under discussion by the RfD/RfC Work Group (U.S. EPA, 1993a). U.S. EPA (1989a) proposed an RfD of lE-1 mg/kg/day for 1,1-dichloroethane based on a LOAEL of 109.8 mg/kg/day for renal tubular degeneration in a subchronic inhalation study in cats exposed to the chemical at a TWA concentration of 3,038 mg/m' 6 hours/day, 5 days/week for 26 weeks (Hofmann et al., 1971); an inhalation absorption factor of 0.5 was applied and an uncertainty factor of 1000 was used. U.S. EPA (1990) proposed an RfC of 5E-2 mg/m' for l, 1-dichloroethane based on a LOAEL„EC °f 518 mg/m' for elevated BUN and creatinine and kidney lesions in cats exposed to the chemical at a TWA concentration of 2,902 mg/m' 6 hours/day, 5 days/week for 23 weeks, the time at which renal toxicity became evident (Hofmann et al., 1971). An uncertainty factor of 10,000 was used.

The HEAST (U.S. EPA, 1992) lists an RfD for 1,1-dichloroethane of lE-1 mg/kg/day. This RfD is derived from U.S. EPA (1983, 1984) and is based on an inhalation study in rats by Hofmann et al. (1971). The derivation concluded that the NOAEL was 500 ppm (2,025 mg/m^, 6 hours/day, 5 days/week) 1,1-dichloroethane; no LOAEL was identified. The NOAEL was duration adjusted, multiplied by an absorption coefficient of 0.5 and by the ratio of the rat reference inhalation rate (0.22 m^/day) to a reference body weight (0.35 kg). An uncertainty factor of 1000 was applied (for inter- and intraspecies variation and extrapolation from a subchronic study). The HEAST (U.S. EPA, 1992) also lists an RfC for 1,1-dichloroethane of 5E-1 mg/m^. This RfC is derived from U.S. EPA (1983) and is based on an inhalation study in cats by Hofmann et al. (1971). The derivation concluded that the NOAEL was 500 ppm (2025 mg/m') 1,1-dichloroethane and the LOAEL was 1000 ppm (4050 mg/m', 6 hours/day, 5 days/week) for kidney damage. The NOAEL was duration adjusted, multiplied by the ratio of the cat inhalation rate (1.26 m'/day) to the cat body weight (3.3 kg) and multiplied


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lay the ratio of the human reference body weight (70 kg) to the human reference inhalation rate (20 m^/day). An uncertainty factor of 1000 was applied (for inter- and intraspecies variation and extrapolation from a subchronic study). This derivation is not consistent with current methodology for the development of inhalation RfCs (U.S. EPA, 1989b).

ACGIH (1991) has adopted a TLV-TWA of 200 ppm (810 mg/m^) with a notice of intended changes to 100 ppm (405 mg/m^) , and a TLV-STEL of 250 ppm (1010 mg/m^) . These values are aimed to protect workers against liver injury. The OSHA standard and NIOSH REL are 100 ppm (OSHA, 1989; NIOSH, 1990).

1,1-Dichloroethane was used in the past as a general anesthetic at a pressure of 0.026 atm, which is approximately equivalent to a concentration of 105,000 mg/m' (26,000 ppm)(Miller et al., 1965). Its use was discontinued when it was discovered that it induced cardiac arrhythmias at anesthetic doses (Browning, 1965).

1,1-Dichloroethane has a verified carcinogenicity classification of Group C (U.S. EPA, 1993b).

PHARMACOKINETICS

Little is known regarding the pharmacokinetics of 1,1-dichloroethane. A breath-holding study in humans determined that approximately 88% of the inhaled 1,1-dichloroethane was absorbed into the lung (Morgan et al., 1970). A subsequent study by the same investigators estimated a 1-minute retention coefficient in humans of 68% (Morgan et al., 1972). Quantitative inhalation data in animals were not available, but toxicity data indicates that pulmonary absorption occurs (ATSDR, 1990; U.S. EPA, 1983, 1985, 1990). Limited data suggest that 1,1-dichloroethane is well absorbed from the gastrointestinal tract of rats and mice (Mitoma et al., 1985). Results based primarily on in vitro studies suggest that the biotransformation of 1,1-dichloroethane is mediated by hepatic microsomal cytochrome P-450 system. In rat liver microsomes, 1,1-dichloroethane was dechlorinated more rapidly than 1,2-dichloroethane and the metabolites included acetic acid, chloroacetic acid, 2,2-dichloroethanol and trace amounts of dichloroacetic acid and chloroacetaldehyde (McCall et al., 1983; Loew et al., 1973; Salmon et al., 1981). By using a pharmacokinetics model, Sato and Nakajima (1987) calculated a respiratory clearance rate of 72 L/hour (41%) and a metabolic clearance rate of 105 L/hour (59%) for 1,1-dichloroethane in humans. In rats, oral administration of a dose of 700 mg/kg 1,1-dichloroethane resulted in excretion of 5% of the dose as COj and 86% as unchanged compound in the expired air (Mitoma et al., 1985). In mice, 70% of a dose of 1800 mg/kg was excreted


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unchanged in expired air, whereas 25% was accounted for as COj (Mitoma et al., 1985). Further information regarding pharmacokinetics of 1,1-dichloroethane was not located.

NONCARCINOGENIC EFFECTS

Acute Data

Smyth (1956) observed no deaths in rats exposed to 4,000 ppm (16,190 mg/m') 1,1-dichloroethane for 8 hours, but exposure to a concentration of 16,000 ppm (64,759 mg/m') for 8 hours was lethal. Browning (1965) reported that the lethal exposure level of 1,1-dichloroethane in mice was 17,500 ppm. Dow Chemical (1960) reported the results of single exposure studies of rats to 1,1-dichloroethane vapors. Dose- and time-related lethality was observed in male rats exposed to concentrations of 8,000 to 64,000 ppm 1,1-dichloroethane (32,380-259,036 mg/m' assuming 25''C and 760 mm Hg) for 0.1-7 hours. Autopsy of the animals that died revealed lung injury with slight liver and kidney pathology. Sax (1984) reported an oral LD50 of 725 mg/kg of l, l-dichloroethane in rats, whereas Dow Chemical (1960) reported that single oral doses of 2 g/kg induced no adverse reactions in rats, but autopsy showed some kidney injury.

Subchronic and Chronic Data

Groups of 10 Sprague-Dawley rats, 10 Pirbright-White guinea pigs, 4 "colored" rabbits and 4 cats were exposed to 0 or 500 ppm 1,1-dichloroethane (2024 mg/m', assuming 25'>C and 760 mm Hg) for 6 hours/day, 5 days/week for 13 weeks followed by a 10- to 13-week exposure period to 1000 ppm (4047 mg/m') (Hofmann et al., 1971). The TWA exposure concentration was 717 ppm (2902 mg/m') for cats and 750 ppm (3036 mg/m') for guinea pigs and rabbits (because effects were noticeable in cats after a total of 23 weeks, 23 weeks was used as the total duration in estimating the TWA for cats). Each group was composed of an equal number of males and females (2 each for cats and rabbits, 5 each for guinea pigs and rats). Behavior and body weight were monitored in all species. Hematologic and urinalysis values, SGPT, SGOT, serum urea and serum creatinine were monitored in rats, rabbits and cats. Sulfobromphthalein excretion was tested in rabbits and cats. It was not clearly specified what endpoints were tested in guinea pigs. After 13 weeks of treatment, none of the species tested showed any clinical or biochemical changes attributable to treatment with 1,1-dichloroethane and were therefore, exposed to 1000 ppm for an additional 10-13 weeks. All animals were necropsied, relative liver and kidney weights were determined, and the liver, kidneys, and occasionally other selected organs

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(not specified) were processed for histopathological examination. No effects were reported in treated rats, rabbits or guinea pigs. Following the increase in concentration to 1000 ppm, cats had reduced body weight gain and elevated serum urea and serum creatinine levels relative to controls. One cat was removed from exposure due to poor general condition after 10 weeks at 1000 ppm; for the remaining animals exposure terminated at week 13. At the end of the experiment, histopathological examination of the kidneys revealed renal tubular dilation and degeneration in 3 of the 4 treated cats. No information was provided regarding effects at the portal of entry (i.e., pulmonary effects). 1,2-Dichloroethane, which was also tested in this study, appeared to be considerably more toxic than 1,1-dichloroethane. Based on this study, a LOAEL of 2902 mg/m^ (TWA) for kidney effects in cats was derived. The TWA exposure of 3036 mg/m^ was a NOAEL for rats, guinea pigs and rabbits.

Dow Chemical (1990) conducted a multispecies subchronic inhalation study, but the results were reported only as an unpublished summary. Groups of 24 male and 36 female Wistar-derived rats, 2 female dogs and 3 male and 3 female rabbits were exposed to 0, 500 or 1000 ppm 1,1-dichloroethane (0, 2024 or 4047 mg/m', assuming 25»C and 760 mm Hg) 7 hours/day, 5 days/week for 6 months. Guinea pigs (7 males and 8 females) were exposed to 2024 mg/m' for 3 months. Hematologic parameters (PCV, hemoglobin, total and differential leucocyte counts) determined at 4 months of treatment and prior to termination at 6 months were not altered by exposure to 1,1-dichloroethane. Urinalyses performed at 5 months were unremarkable. Clinical chemistry values (alkaline phosphatase, urea nitrogen, SGPT) were within normal ranges. At necropsy, gross and microscopic examination of all major organs and tissues revealed no treatment-related adverse effects. The NOAEL for rats, dogs, and rabbits is 4047 mg/m^; the guinea pig NOAEL is 2024 mg/m^

Union Carbide (1947) provided information on Sprague-Dawley rats (12/sex/group) and mongrel dogs (1/sex/group) exposed to 0 or 1000 ppm 1,1-dichloroethane 7 hours/day for a total of 75 exposures over a 6-month period. The results, however, are of questionable significance since high mortality occurred in rats due to endemic lung infection (50% in controls, 51% in 1,1-dichloroethane groups). At the end of the 6-month period, the only effects reported in the single dog exposed to 1,1-dichloroethane were significantly reduced body weight gain throughout the study and marked lung congestion, but no other pathology. According to the investigators, the only effect in rats attributed to exposure to 1,1-dichloroethane was a significant decrease (p<0.004) in body weight gain in female rats.


800026

NCI (1978) conducted a range-finding oral study in which groups of 5 Osborne-Mendel rats/sex and 5 B6C3F1 mice/sex were gavaged for 6 weeks with 1,1-dichloroethane in corn oil followed by a 2-week observation period. The test material was administered 5 days/week at dose levels of 0, 562, 1000, 1780, 3160 or 5620 mg/kg/day in rats and 0, 1000, 1780, 3160, 5620 or 10,000 mg/kg/day in mice. In male rats, body weight decreased by 16% and 29% at 562 and 1000 mg/kg/day, respectively. In female rats, body weight decreased by 20% at 1780 and 3160 mg/kg/day and two animals died at the latter level. Body weight was not altered in mice, but two males and three females died at the 5620 raq/Ifiq/day dose level. No other endpoints were examined.

In a chronic oral study conducted by NCI (1978), Osborne-Mendel rats (50/sex/dose group) and B6C3F1 mice (50/sex/dose group) were administered 1,1-dichloroethane in corn oil 5 days/week for 78 weeks. An observation period of 33 weeks followed, after which all surviving animals were sacrificed and examinations for gross an microscopical organ pathology were made. The time-weighted average dosages over the 78-week treatment period were: 382 and 764 mg/kg/day for male rats, 475 and 950 mg/kg/day for female rats, 1442 and 2885 mg/kg/day for male mice, and 1665 and 3331 mg/kg/day for female mice. Twenty animals of each sex and species served as vehicle and untreated controls. Treatment-related effects were difficult to assess due to high mortality in rats due to pneumonia. Survival at the end of the study in the untreated control, vehicle control, low dose, and high dose groups was, respectively, 30, 5, 4, and 8% in male rats; 40, 20, 16, 18% in female rats; 35, 55, 62, and 32% in male mice; and 80, 80, 80 and 50% in female mice. In male rats, but not female rats, survival in both treated groups during the study was significantly lower (p<0.006) than in either the untreated control or vehicle treated group, although terminal survival rates between vehicle control and treated males were similar. In male mice, there was a significant association (significance not provided) between dosage and mortality and the trend for female mice was highly significant (p<0.001); these findings were due mainly to mortality in the high-dose groups. The possible cause of death in mice was not discussed, but according to the investigators (NCI 1978) it was not tumor-related. No treatment-related effects were observed in rats or mice regarding body weight, food consumption, appearance and behavior, or incidence of nonneoplastic lesions. Hematology and clinical chemistry parameters were not monitored. No NOAELs or LOAELs can be defined in this study due to the high mortality observed at the lowest dose tested.

Limited information on the oral toxicity of 1,1-dichloroethane is available in a two-stage carcinogenesis study in mice (Klaunig et al., 1986). Groups of 35 male B6C3F1 mice were administered 1,1-dichloroethane in the drinking water at 0,

For i n t e r n a l use only. DRAFT - Do not cite o r quote.

800027

835 or 2500 mg/L for up to 52 weeks following treatment with either 10 mg/L diethylnitrosamine (DENA) in the drinking water or deionized water for 4 weeks. The investigators estimated that the weekly dose of 1,1-dichloroethane was approximately 3.8 mg/g body weight (543 mg/kg/day) for the groups given the chemical at 2500 mg/L, but provided no information regarding the low-dose level. At sacrifice at the end of 24 weeks (10 mice/group) or 52 weeks (25 mice/group) of promotion, all tissues were examined for gross pathological lesions, and sections of the liver, kidneys and lungs were processed for light microscopy. Body weights in all 1,1-dichloroethane-treated groups were slightly lower than untreated controls, but the difference was not statistically significant. Treatment with 1,1-dichloroethane did not affect water intake or survival. No nonneoplastic lesions were reported in 1,1-dichloroethane-treated groups. In this study, the dose of 543 mg/kg/day represents a NOAEL for mice.

Developmental and Reproductive Toxicitv

Groups of 46, 16 and 19 pregnant Sprague-Dawley rats were exposed to 0, 3800 or 6000 ppm 1,1-dichloroethane (15,380 or 24,284 mg/m', assuming 25°C and 760 mm Hg) , respectively, for 7 hours/day on gestation days 6-15 (Schwetz et al., 1974). Food consumption was significantly decreased (p<0.05) during treatment at both concentration levels. Body weights were significantly reduced (p<0.05) in treated rats at both concentration levels on day 13 and in the 3800 ppm group on day 21 (other time points not examined). Treatment with 1,1-dichloroethane had no effect on maternal SGPT activity or gross appearance of the liver, but relative liver weight was significantly increased in nonpregnant rats 6 days after the last exposure. Exposure to 1,1-dichloroethane did not affect conception rate, number of implantations, litter size, incidence of fetal resorptions, fetal body measurements or incidence of gross or soft tissue anomalies. Exposure to 6000 ppm 1,1-dichloroethane caused a significant increase (p<0.05) in the incidence of delayed ossification of sternebrae, but the incidence at the 3800 ppm level was significantly lower than in controls. In this study, the exposure level of 15,38.0 mg/m' represents a maternal LOAEL and a developmental NOAEL for 1,1-dichloroethane. The developmental LOAEL is 24,284 mg/m^.

Studies of reproductive toxicity were not located.

SCENARIO FOR THE DERIVATION OF AN ORAL RfD

Relevant information is available from five studies for derivation of a provisional RfD for 1,1-dichloroethane. Three of these studies (Dow Chemical 1990; Hofmann et al., 1971; Schwetz

For i n t e r n a l u se o n l y . DRAFT - Do n o t c i t e o r q u o t e .

800028

et al., 1974) used the inhalation route of exposure; in studies conducted by NCI (1978) and Klaunig et al. (1986), the chemical was administered by the oral route. In the 78-week chronic oral study in rats and mice (NCI 1978) high mortality occurred at the lowest dose level tested (382 mg/kg/day for rats), therefore, neither NOAELs or LOAELs could be defined. In the 52-week drinking water study conducted by Klaunig et al. (1986) no adverse effects were observed in mice at 543 mg/kg/day and this dose level represented a NOAEL for 1,1-dichloroethane. However, the scope of this study was rather limited since only liver, kidney and lungs were examined histologically, and clinical chemistry and hematology values were not monitored. In the multispecies inhalation study conducted by Dow Chemical (1990)(reported only as an unpublished summary), a NOAEL of 2024 mg/m^ was identified for guinea pigs and a NOAEL of 4047 mg/m' was defined for rats, dogs and rabbits; all species were exposed 7 hours/day, 5 days/week for 3 to 6 months; these concentration exposure levels were the highest tested. The results of Dow Chemical (1990) are supported by data reported by Hofmann et al. (1971) who found no adverse effects in rats and rabbits exposed to TWA concentrations of 3036 mg/m' 1,1-dichloroethane (6 hours/day, 5 days/week) for 26 weeks. Hofmann et al. (1971), however, reported kidney lesions, and altered serum urea and creatinine in cats exposed to TWA of 2902 mg/m^ 1/1-dichloroethane for 23 weeks. In the inhalation study conducted by Schwetz et al. (1974) in rats exposed during pregnancy, a developmental NOAEL of 15,380 mg/m' was identified for 1,1-dichloroethane, the LOAEL was 24,284 mg/m'. Thus, it appears that cats, which were not tested in the Dow Chemical (1990) study, are the most sensitive species.

Based on the information summarized above, a provisional RfD might be calculated from the inhalation data in cats reported by Hofmann et al. (1971). In that study, one out of four cats showed kidney lesions after a total of 23 weeks of exposure (earliest monitoring time) to 1,1-dichloroethane. Two additional cats showed kidney lesions after 26 weeks of exposure. It does not seem appropriate to base this provisional RfD on a NOAEL for the first 13 weeks of exposure because the kidneys were not examined during this first exposure period. Lesions consisted of crystal precipitation and obstruction of the tubules, consistent with hydronephrosis, and tubule degeneration. The provisional RfD might be calculated as follows:

LOAELADJ = 2902 mg/m' X 6/24 X 5/7 = 518 mg/m^

Inhaled Dose = 518 mg/m' x [0.6739 mVday]/3.5 kg = 99.8 mg/kg/day

where:

For i n t e r n a l use o n l y . DRAFT - Do n o t c i t e o r q u o t e .

800029

0.6739 = Inhalation rate for a 3.5 kg cat; determined from an allometric relationship described in U.S. EPA (1987).

3.5= Cat body weight throughout the study estimated from graphic data in Hofmann et al. (1971).

The inhaled dose (LOAEL) of 99.8 mg/kg/day is lower than the lowest oral dose associated with early mortality in rats (382 ing/kg/day) in the NCI (1978) study. A default ratio of 1 was selected for oral:inhalation absorption factors given the lack of data.

thus,

RfD = inhaled dose/UF = [99.8 mg/kg/day]/10,000 =0.01 mg/kg/day

where:

UF = uncertainty factor (all five areas of uncertainty are involved including use of a LOAEL, interspecies extrapolation, protection of sensitive humans, use of a subchronic study, and for database limitations, including route-to-route extrapolation. Given that some areas of uncertainty may overlap, a maximum UF of 10,000 is applied).

The provisional RfD of 0.01 mg/kg/day for 1,1-dichloroethane would be one order of magnitude lower than that derived from the same data and currently under review by the RfD/RfC Work Group (U.S. EPA, 1989a). The difference is due to the following: U.S. EPA (1989a) considered a total exposure period of 26 weeks in estimating the TWA exposure; the inhalation rate for cats was estimated at 1.215 m'/day (Guyton, 1947); the cat body weight was estimated as 3 kg; and, an absorption factor of 50% was used.

If such a scenario would be used to define the RfD, confidence in the key study would be graded low because of the small number of animals used and because other than for the kidneys, limited information was provided regarding organs and tissues examined. Confidence in the database is low because adequate chronic oral studies were not available and because developmental data in only one species were located. Confidence in the provisional RfD would be low reflecting low confidence in the database and key study.

Caution is advised in using the provisional RfD for 1,1-dichloroethane. Insufficient pharmacokinetic data are available for accurately determining the absorption ratio for a route-to-route extrapolation. The use of an inhalation study to derive an oral Rfd may be obviated by the absence of the determination of

FoiT i n t e r n a l use o n l y . DRAFT - Do n o t c i t e o r q u o t e .

800030

portal-of-entry effects in the critical study. Occurrence of portal-of-entry effects would preclude the derivation of the RfD from this study. Additionally, the Hofmann et al. (1971) cat study is also, at best, marginal for use in a risk assessment. Therefore, if this provisional RfD is chosen, this office will not be able to attest to its scientific accuracy and use.

CARCINOGENICITY

1,1-dichloroethane has been classified as a group C, possible human carcinogen by the Carcinogenic Risk Assessment Verification Endeavor (CRAVE) Work Group. Based on available data, an oral quantitative estimate cannot be provided at this time. Upon receipt of the NCI, 1978 raw data, the CRAVE Work Group will reevaluate an oral quantitative estimate. In the meantime, please consult the IRIS database (U.S. EPA, 1993b) for a qualitative assessment of 1,1-dichloroethane.

REFERENCES:

ACGIH (American Conference of Governmental Industrial Hygienists). 1986. Documentation of Threshold Limit Values and Biological Exposure Indices for Chemical Substances in the Workroom Air, 5th ed., Cincinnati, OH, p. 184.

ACGIH (American Conference of Governmental Industrial Hygienists). 1991. Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices. ACGIH, Cincinnati, OH. p. 18, p. 39.

ATSDR (Agency for Toxic Substances and Disease Registry). 1990. Toxicological Profile for 1,1-Dichloroethane. ATSDR, U.S. Public Health Service, Atlanta, GA. NTIS PB\91\180539.

Browning, E. 1965. Dichloroethane. Tn: Toxicity and Metabolism of Industrial Solvents. Elsevier Publishing Co., Amsterdam, pp. 247-252.

Dow Chemical Company. 1960. Results of range finding toxicological tests on 1,1-dichloroethane. TSCA submission OTS Fiche #OTS0515949.

Dow Chemical Company. 1990. Six month inhalation study with 1,1-dichloroethane. Letter to Syracuse Research Corporation, February 14, 1990.

Guyton, A.C. 1947. Measurement of the respiratory volumes of laboratory animals. Am. J. Physiol. 150: 70-77.


800031

Hofmann, H.T., H. Birnstiel and P. Jobst. 1971. On the inhalation toxicity of 1,1-dichloroethane. Arch. Toxicol. 27: 248-265. (English translation)

Klaunig, J.E., R.J. Ruch and M.A. Pereira. 1986. Carcinogenicity of chlorinated methane and ethane compounds administered in drinking water to mice. Environ. Health Perspec. 69: 29-93.

Loew, G., J. Trudell and H. Motulsky. 1973. Quantum chemical studies of the metabolism of a series of chlorinated ethane anesthetics. Mol. Pharmacol. 9: 152-162.

McCall, S.N., P. Jurgens and K.M. Ivanetich. 1983. Hepatic microsomal metabolism of dichloroethanes. Biochem. Pharmacol. 32: 207-213.

Miller, K.W., W.D.M. Paton and E.B. Smith. 1965. Site of action of general anesthetics. Nature 206: 574-577.

Mitoma, C., T. Steeger, S.E. Jackson, K.P. Wheeler, J.H. Rogers and H.A. Milman. 1985. Metabolic disposition study of chlorinated hydrocarbons in rats and mice. Drug Chem. Toxicol. 8: 183-194.

Morgan, A., A. Black and D.R. Belcher. 1970. The excretion in breath of some aliphatic halogenated hydrocarbons following administration by inhalation. Ann. Occup. Hyg. 13: 219-233.

Morgan, A., A. Black and D.R. Belcher. 1972. Studies on the absorption of halogenated hydrocarbons and their excretion in breath using '*C1 tracer techniques. Ann. Occup. Hyg. 15: 273-282.

NCI (National Cancer Institute). 1978. Bioassay of 1,1-dichloroethane for possible carcinogenicity. NCI/NTP TR 066. DHEW Publ. No. (NIH) 78-1316.

NIOSH (National Institute for Occupational Safety and Health). 1990. NIOSH Pocket Guide to Chemical Hazards. U.S. Department of Health and Human Services. DHHS (NIOSH) Publication No. 90-117.

OSHA (Occupational Safety and Health Administration). 1989. 29CFR 1910. Air Contaminants; Final Rule. Federal Register. 54(12): 2923-2960.

Salmon, A.G., R.B. Jones and W.C. Mackrodt. 1981. Microsomal dechlorination of chloroethanes: Structure-reactivity relationships. Xenobiotica 11: 723-734.


800032

Sato, A. and T. Nakajima. 1987. Pharmacokinetics or organic solvent vapors in relation to their toxicity. Scand. J. Work Environ. Health 13: 81-93.

Sax, N.I., Ed. 1984. Dangerous Properties of Industrial Materials, 6th ed. Van Nostrand Reinhold Co., NY. pp. 1362-1363.

Schwetz, B.K., K.L. Leong and P.J. Gehring. 1974. Embryo- and fetotoxicity of inhaled carbon tetrachloride, 1,1-dichloroethane and methyl ethyl ketone in rats. Toxicol. Appl. Pharmacol. 28: 452-464.

Smyth, H.F. Jr. 1956. In: Handbook of Toxicology, Vol. 1, W.S. Spector, Ed. pp. 92-95.

Union Carbide Corporation. 1947. Repeated exposure of rats and dogs to vapors of eight chlorinated hydrocarbons. TSCA Submission OTS#0515559.

U.S. EPA. 1983. Drinking Water Criteria Document for 1,1-Dichloroethane. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Drinking Water, Washington, DC. ECAO-CIN-303.

U.S. EPA. 1984. Health Effects Assessment for 1,1-Dichloroethane. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Emergency and Remedial Response, Washington, DC. ECAO-CIN-H027.

U.S. EPA. 1985. Health and Environmental Effects Profile for Dichloroethanes. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Solid Waste and Emergency Response, Washington, DC. ECAO-CIN-P139.

U.S. EPA. 1987. Recommendation for and Documentation of Biological Values for Use in Risk Assessment. Prepared by Environmental Criteria and Assessment Office, Office of Health and Environmental Assessment, Cincinnati, OH for the Office of Solid Waste and Emergency Response, Washington DC. ECAO-CIN-554.

U.S. EPA. 1989a. Oral RfD Verification Meeting Notes of 9/21/89 (with attached summary sheet). RfD and RfC Work Group. Office of Health and Environmental Assessment, Washington, DC. (Available from: Environmental Criteria and Assessment Office, Cincinnati, OH).


800033

U.S. EPA. 1989b. Interim Methods for Development of Inhalation Reference Doses. Office of Health and Environmental Assessment, Washington, DC. EPA 600/8-88/066F.

U.S. EPA. 1990. Inhalation RfC Verification Meeting Notes of 4/19/90 (with attached summary sheet). RfD and RfC Work Group. Office of Health and Environmental Assessment, Washington, DC. (Available from: Environmental Criteria and Assessment Office, Cincinnati, OH).

U.S. EPA. 1991. Office of Health and Environmental Assessment Chemical Assessments and Related Activities. Office of Health and Environmental Assessment, Washington, DC. April, 1991. OHEA-1-127.

U.S. EPA. 1992. Health Effects Assessment Summary Tables. Annual FY 1992. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office for the Office of Emergency and Remedial Response, Washington, DC. NTIS No. PB92-921100.

U.S. EPA. 1993a. Monthly Status Report of RfD/RfC and CRAVE Work Groups (As of 05/01/93). Office of Research and Development. Environmental Criteria and Assessment Office, Cincinnati, OH.

U.S. EPA. 1993b. Integrated Risk Information System (IRIS). Online. Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH.


800034

Attachment III.

Risk Assessment Issue Paper for: Provisional Inhalation Slope Factor for

1,1-DICHLOROETHYLENE (CASRN 73-35-4)

The important issue pertains to the appropriate slope factor for use in Superfund risk assessments. Because the slope factor presented in the HEAST is based on absorbed and metabolized dose, it is not the proper cancer toxicity value for use in Superfund risk assessments. The proper inhalation cancer toxicity value to use when the slope factor is based on metabolized dose has previously been addressed. An inhalation exposure cancer toxicity value, analogous to an exposure slope factor, of 1.75E-1 (mg/kg/day)', was calculated for 1,1-dichloroethylene directly from the unit risk. The inhalation exposure cancer toxicity value was obtained by multiplying the unit risk in air by 70 kg (the reference human body weight) and by 1000 (/xg/mg) , and dividing the result by 20 m'/day (the reference human inhalation rate).

The HEAST (U.S. EPA, 1992) presents for 1,1-dichloroethylene an inhalation slope factor of 1.2E+0 (mg/kg/day)''. The unit risk is verified and available on IRIS (U.S. EPA, 1993); however, all inhalation slope factors have been removed from IRIS. An earlier version of IRIS presented the inhalation slope factor that is currently presented in the HEAST.

The slope factor of 1.2E+0 (mg/kg/day)' based on internal dose is rounded from 1.16 (mg/kg/day)'' calculated by U.S. EPA (1985) from the incidence of kidney tumors in male mice exposed by inhalation to 0, 10 or 25 ppm 1,1-dichloroethylene 4 hours/day, 4-5 (average 4.5) days/week for 52 of a total of 121 weeks (Maltoni et al., 1977, 1985). The carcinogenicity of 1,1-dichloroethylene is believed to result from macromolecular binding of its metabolites. This information was based on the relationship between exposure and metabolic dose for 1,1-dichloroethylene, therefore, U.S. EPA (1985) based risk estimation on metabolized dose. In a study of the fate of C'*-1,1-dichloroethylene, McKenna et al. (1977) exposed mice to 10 ppm for 6 hours and estimated, from recovery of radioactivity in expired air, urine, feces and carcass, that 0.186 mg/mouse had been absorbed and metabolized. U.S. EPA (1985) concluded that, at the exposure concentrations used in the cancer study, the entire absorbed dose was metabolized, and the rate of metabolism was constant and proportional to the exposure concentration. Assuming that mice in the cancer and pharmacokinetic studies absorbed and metabolized 1,1-dichloroethylene in an identical manner, and by adjusting for differences in duration of exposure (4 hours/day in the cancer study and 6 hours/day in the


800035

pharmacokinetic study) U.S. EPA (1985) estimated that the mice in the cancer study exposed to 10 and 25 ppm absorbed and metabolized 0.124 and 0.309 mg/day, respectively.

U.S. EPA (1985) assumed that the ratio of the total amount (in mg) metabolized by humans to the total amount metabolized by mice is a function of the ratio of the body surface area of humans to the body surface area of mice, which is approximated by the expression

(70/0.035)°*'' = 159

where 70 is the reference human body weight (in kg) and 0.035 is the body weight of the mice (in kg) in the cancer study. The mouse metabolized doses estimated in the previous paragraph are multiplied by 159 and adjusted to equivalent continuous and lifetime exposure (multiplied by 4.5/7 days and by 52/121 weeks) to estimate equivalent human metabolized doses of 5.44 and 13.60 mg/day for 10 and 25 ppm, respectively. Dividing these doses by 70 kg yields equivalent human metabolized doses of 0.078 and 0.195 mg/kg/day, respectively.

U.S. EPA (1985) applied the multistage model to the tumor incidence data (0/126, 0/25 and 28/119) and the equivalent human metabolized doses (0, 0.078 and 0.195 mg/kg/day) estimated for the experimental exposure concentrations (0, 10 and 25 ppm, respectively) and computed a slope factor for humans of 1.16 (mg/kg/day)-'.

As noted above, U.S. EPA (1985) estimated a human equivalent metabolized dose of 0.078 mg/kg/day for the experimental exposure concentration of 10 ppm. By adjusting the 10 ppm concentration for intermittent exposure (4.5 days/week and 52/121 weeks), an equivalent continuous lifetime exposure concentration of 0.46 ppm was estimated. If 0.46 ppm is equivalent to 0.078 mg/kg/day, it follows that

(0.078 mg/kg/day)/O.46 ppm = 0.17 (mg/kg/day)/ppm.

The unit risk, therefore, can be expressed as

1.16 (mg/kg/day)'' x 0.17 (mg/kg/day)/ppm = 2.0E-1 (ppm)'

or as

2.0E-4 (ppb)'

By applying assumptions of the ideal gas law and the molecular weight for 1,1-dichloroethylene (96.95), the unit risk can also be expressed as


800036

2.0E-4 (ppb)'' X 24.45/96.95 = 5.0E-5 (.Hg/m^)'\

which appears on IRIS (U.S. EPA, 1993).

REFERENCES:

Maltoni, C , G. Cotti, L. Morisi and P. Chieco. 1977. Carcinogenicity bioassays of vinylidene chloride. Research plan and early results. Med. Lav. 68(4): 241-262.

Maltoni, C., G. Lefemine, P. Chieco, G. Cotti and V. Patella. 1985. Experimental research on vinylidene chloride carcinogenesis. Bo. 3 Princeton, NJ: Princeton Scientific Publishers.

McKenna, M.J., P.G. Watanabe and P.G. Gehring. 1977. Pharmacokinetics of vinylidene chloride in the rat. Environ. Health Perspect. 21: 99-105.

U.S. EPA. 1985. Health Assessment Document for Vinylidene Chloride. Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Research Triangle Park, NC. EPA 600/8-83-031F.

U.S. EPA. 1992. Health Effects Assessment Summary Tables. Annual FY-1992. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office for the Office of Emergency and Remedial Response, Washington, DC. NTIS No. PB92-921100.

U.S. EPA. 1993. Integrated Risk Information System (IRIS). Online. Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH.

For i n t e r n a l u se o n l y . DRAFT - Do n o t c i t e o r quo te . -22-

800037

Attachment IV.

Risk Assessment Issue Paper for: Evaluation of Carcinogenicity for 4-METHYL-2-PENTANONE

(METHYL ISOBUTYL KETONE) (CASRN 108-10-1)

INTRODUCTION

This chemical is not the subject of an ATSDR toxicological profile and carcinogenicity information is not listed on IRIS (U.S. EPA, 1993a), the CRAVE Status Report (U.S. EPA, 1993b) or on the HEAST (U.S. EPA, 1992). The U.S. EPA (1987) has prepared a Health Effects Assessment document on methyl isobutyl ketone (U.S. EPA, 1987). A TOXLINE search was completed to determine if any additional data were published between 1986 and 1991. A TSCATS search was also conducted.

CARCINOGENICITY

No information on the carcinogenicity of 4-methyl-2-pentanone was located in the HEA (U.S. EPA, 1987) or on the updated literature searches. Also, lARC has not reviewed 4-methyl-2-pentanone, and this chemical has not been scheduled for testing by the NTP (1991).

WEIGHT-OF-EVIDENCE CLASSIFICATION

Because no carcinogenicity data were located, U.S. EPA (1987) placed 4-methyl-2-pentanone into weight-of-evidence classification group D: not classifiable as to human carcinogenicity.

DERIVATION OF ORAL SLOPE FACTOR

According to U.S. EPA (1986) guidelines, classification of a chemical in weight-of evidence Group D precludes quantitative risk assessment.

REFERENCES:

NTP (National Toxicology Program). 1991. Management Status Report. 07/09/91.

U.S. EPA. 1986. Guidelines for Carcinogen Risk Assessment. Federal Register 51 (185): 33992-34003.


800038

U . S . EPA. 1987. Health Effects Assessment for Methyl Isobutyl Ketone. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Solid Waste and Emergency Response, Washington, D.C. ECA0-CIN-H081.

U.S. EPA. 1992. Health Effects Assessment Summary Tables. Annual FY-1992. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office for the Office of Emergency and Remedial Response, Washington, DC. NTIS PB92-921100.

U.S. EPA. 1993a. Integrated Risk Information System (IRIS). Online. Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH.

U.S. EPA. 1993b. Monthly Status Report of CRAVE Work Group (as of 05/01/93). Office of Research and Development. Environmental Criteria and Assessment Office, Cincinnati, OH.


800039

j^ttachment V.

Risk Assessment Issue Paper for: Evaluation of Systemic Toxicity after Oral Exposure to

N-BUTYLBENZENE (CASRN 104-51-8), SEC-BUTYLBENZENE (CASRN 135-98-8),

TERT-BUTYLBENZENE (CASRN 98-06-6) and N-PROPYLBENZENE (CASRN 103-65-1)

We have search the available literature on sec- and tert-butyl benzene for experimental data appropriate for use in calculating an oral RfD for these chemicals. Unfortunately, other than acute LDSO's and acute irritation data, no toxicology data were found from which an oral RfD could be identified. Oral RfDs for n-butyl benzene and propylbenzene could not be calculated because there were no appropriate data available in the searches for either of these chemicals. Only acute studies and studies of mixtures were available.

There are four saturated short-chain alkyl benzenes for which there are verified oral RfDs. These are summarized below:

Compound Oral RfD rma/ka/dav)

Critical Effect

Ethylbenzene

Toluene (methylbenzene)

Xylenes, mixed (dimethylbenzene)

Cumene (isopropylbenzene)

(U.S.EPA, 1993)

1 E-1

2 E-1

2 E+0

4 E-2

liver and kidney toxicity

changes in liver and kidney weight

hyperactivity, decreased body weight and increased mortality

increased average kidney weight

We recommend that the oral RfD for cumene be selected as a surrogate for sec- and tert-butyl benzene, primarily because it has the most conservative oral RfD of the four alkylbenzenes and it is has the most similar alkyl chain length (3) to the sec- and tert-butyl benzene. Chain length is believed to be an important factor in the toxicity of alkyl benzenes. In addition, of the four, only cumene has an acute oral LD50 which is lower than that measured for tert-butyl benzene (2.91 versus 3.5-4.4 g/kg) in rats.

For i n t e r n a l use only. DRAFT -25-

- Do not c i t e o r quote .

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REFERENCES:

American Petroleum Institute. 1989. Inhalation reproduction range-finding study in mated rats with C9 aromatic hydrocarbons. EPA/OTS; Doc #86-890000229.

Haider, CA., C.E. Holdsworth, B.Y. Cockrell and V.J. Piccirillo. 1985. Hydrocarbon nephropathy in male rats: Identification of the nephrotoxic components of unleaded gasoline. Toxicol. Indus. Hlth. 1: 67-88.

Int'l. Research & Development Corp. 1988. Inhalation developmental toxicity study in mice with C9 aromatic hydrocarbons (final report) with cover letter dated 042688. EPA/OTS; Doc #FYI-AX-0588-0605.

Int'l. Research & Development Corp. 1989. Range-finding inhalation toxicity study in mice with C9 aromatic hydrocarbons. EPA/OTS; Doc #86-890000223.

Int'l Research & Development Corp. 1989. Three generation reproduction/fertility study in rats with C9 aromatic hydrocarbons (volume 1-3) (draft) with attached appendix and cover letter dated 051589. EPA/OTS; Doc #FYI-OTS-0589-0693.

Nielson, G.D. and Y. Alarie. 1982. Sensory irritation and respiratory stimulation by airborne benzene and alkylbenzenes: Prediction of safe industrial exposure levels and correlation with their thermodynamic properties. Toxicol. Appl. Pharmacol. 65: 459-477.

Pyykko, K., S. Paavilainen, T. Metsa-Ketela and K. Laustiola. 1987. The increasing and decreasing effects of aromatic hydrocarbon solvents on pulmonary and hepatic cytochrome P-450 in he rat. Pharmacol. Toxicol. 60: 288-293.

U.S. EPA. 1987. Results of range-finding toxicological tests on sec-butylbenzene. EPA/OTS; Doc #86-870002172.

U.S. EPA. 1987. Acute oral, percutaneous and inhalation toxicity, skin and eye irritancy and skin sensitization potential of tertiary butyl benzene. EPA/OTS; Doc #86-870001648.

U.S. EPA. 1987. Acute toxicological properties and industrial handling hazards of tert-butylbenzene. EPA/OTS; Doc #86-870002061.

U.S, EPA. 1987. Oral tert-butyl-benzene testing in male rats. EPA/OTS; Doc # 86-870000981.

For i n t e r n a l use o n l y . DRAFT - Do no t c i t e o r q u o t e .

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U.S. EPA. 1987. Toxicity studies of tert-butylbenzene and hexamethylene diisocyanate with cover letter dated 073087. EPA/OTS; Doc #86-870001306.

U.S. EPA. 1993. Integrated Risk Information System. Online, Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH.


800042

Attachment VI.

Risk Assessment Issue Paper for: Feasibility of Developing an Oral RfD for

1,1,2,2-TETRACHLOROETHANE (CASRN 79-34-5) by Analogy to CI8-l,2-DICHLOROETHYLENE (CASRN 156-59-2)

The following literature was reviewed for data on subchronic and chronic oral toxicity of 1,1,2,2-tetrachloroethane that might be relevant to the derivation of an oral RfD:

ATSDR Toxicological Profile on 1,1,2,2-tetrachloroethane (ATSDR, 1989)

Drinking Water Health Advisory for 1,1,2,2-Tetrachloroethane (U.S. EPA, 1987)

The TOXLINE literature data base was searched for the period 1988-1992, but no new data that was directly relevant to the derivation of the RfD for 1,1,2,2-tetrachloroethane was identified.

We do not recommend using the RfD for cis-1,2-dichloroethylene as a surrogate RfD for 1,1,2,2-tetrachloroethane because of differences in critical effects and the apparent greater toxicity of 1,1,2,2-tetrachloroethane.

The provisional oral RfD for cis-l,2-dichloroethylene of lE-2 mg/kg-day is based a subchronic NOAEL and LOAEL of 32 and 97 mg/kg-day for decreased hematocrit and hemoglobin in rats (McCauley et al., n.d.; U.S. EPA, 1992). An uncertainty factor of 3000 was applied to the NOAEL. Confidence in the data base and RfD is classified as "low" because of lack of corroborating studies and lack of developmental, reproductive and chronic toxicity studies. Based on this limited data base, the critical effect of cis-l,2-dichloroethylene is assumed to be hematologic. Given that 1) adverse effects occur in animals exposed to dosages of 1,1,2,2-tetrachloroethane less than the NOAEL for cis-1,2-dichloroethylene and 2) critical toxic effects of 1,1,2,2-tetrachloroethane may not be the same as critical effects of cis -1,2-dichloroethylene (hematologic), use of the RfD for cis-1,2-dichloroethylene as an RfD for 1,1,2,2-tetrachloroethane is not appropriate.

REFERENCES;

ATSDR (Agency for Toxic Substances and Disease Registry). 1989. Toxicological Profile for 1,1,2,2-Tetrachlorethane. U.S. Public Health Service, Atlanta, GA. PB/90/182148/AS.

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McCauley, P.T., M. Robinson, L.W. Condie and M. Parnell. n.d. The effects of subacute and subchronic oral exposure to cis-1,2-dichloroethylene in rats, (cited in U.S. EPA, 1990).

U.S. EPA. 1987. Drinking Water Health Advisory for 1,1,2,2-Tetrachloroethane Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Drinking Water, Washington, DC. ECAO-CIN-W026. External Review Draft.

U.S. EPA. 1992. Health Effects Assessment Summary Tables. Annual FY 1992. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office for the Office of Emergency and Remedial Response, Washington D.C. NTIS No. PB92-921100.


800044

Attachment VII.

Risk Assessment Issue Paper for: Oral RfD and Inhalation RfC Derivation Issues for

TETRAHYDROFURAN (CASRN 109-99-9)

This memo clarifies the issues surrounding the development of an oral RfD for tetrahydrofuran. In short, there is at present insufficient data from oral exposure to tetrahydrofuran on which to derive an oral RfD. In the one oral study that we have been able to find, Sprague-Dawley•rats were given up to 1 g/L tetrahydrofuran in their drinking water (Komsta et al., 1988) for 4 weeks. Rats treated at the highest dose (111 mg/kg/day) showed a slightly higher incidence of mild to minimal histologic changes in the liver compared to control rats. No acanthosis or irritation were reported. No statistical tests for significance were performed on the data. No other toxic effects of exposure were reported, although it is not clear what, if any, other observations were made. Given the relatively short duration of this study and the limited toxicological assessment of oral exposure to tetrahydrofuran, it is not recommended that the oral data be used to derive an oral RfD.

The toxicological data available to us for consideration of development of an oral RfD for tetrahydrofuran is primarily by inhalation exposure. Several attempts have been made to derive an oral RfD based on inhalation exposure to tetrahydrofuran. Each of these derivations have limitations that may preclude their use for the Agency consensus of a verified RfD.

SCENARIO 1: The original RfC summary sheet proposed using the Katahira (1982) study as a basis for developing an RfC. Male Sprague-Dawley rats were exposed to 0, 100, 200, 1,000 or 5,000 ppm (0, 294, 590, 2,950 or 14,746 mg/m') for 4 hours/day, 5 days/week for 12 weeks. Several statistically significant changes in hematological and serum chemistry parameters were observed at 1,000 and 5,000 ppm exposure concentrations. These changes included increased SOT, SGPT, total cholesterol and total bilirubin along with decreased leukocyte count and serum glucose. In addition a decrease in body weight was observed in the high-exposure group. The biochemical changes are indicative of liver damage and dysfunction. Therefore, a NOAEL of 200 ppm (NOAELHEC; = 70 mg/m') and a LOAEL of 1,000 ppm (LOAELHEC = 351 mg/m') were identified.

Since the effects are extrarespiratory, and portal of entry effects are reasonably expected not to occur upon exposure to tetrahydrofuran (based on examination of the total database), a route-to-route extrapolation could be performed. However, there are no physiologically-based/pharmacokinetic (PBPK) data to


800045

estimate the amount of absorption from the inhalation route to the extrarespiratory pool. A typical default assumption in the past was to use a 50% absorption factor. However, such a selection is purely arbitrary and is not based on any appropriate experimental data. In no way can such an assumption be used with confidence to calculate an equivalent oral dose in mg/kg/day. Such a calculation (using default values of a total daily minute volume of 20 m' for a 70 kg adult) would yield an equivalent NOAEL oral dose of 10 mg/kg/day. A minimum uncertainty factor of 1000 would need to be applied to this calculation. Given the lack of data, the uncertainty factor would most likely be higher (up to 10,000).

The Katahira (1982) study was performed in a small, acute-sized rectangular chamber in which compressed air was passed through an impinger containing tetrahydrofuran. This was the only source of ventilation for the animals regardless of chamber or group size. Furthermore, tetrahydrofuran is a volatile compound which can evaporate readily and by purging air through an impinger containing a varying amount of tetrahydrofuran can markedly accelerate the rate of loss. It is not clear from the method description how a consistent test atmosphere was created or controlled and refreshed during each exposure period nor whether separate chambers were available for each exposure group. These methodological questions pertaining to the conduct of Katahira's study limit its utility when attempting to establish an RfC for tetrahydrofuran. However, this study does describe the irritant and anesthetic effects of tetrahydrofuran and later acclimation to these effects as well as the extrarespiratory hepatic effects seen in other reports as described below.

SCENARIO 2: The use of the Katahira (1982) study is further compromised by the results of the Chhabra et al. (1990) study and the attending Grumbein (1988) pathological report. This study and report is currently being proposed as co-critical studies for the development of the RfC. This study was conducted by the National Toxicology Program and the documentation and characterization of the test atmosphere generation, chamber and analytical systems was properly conducted, thereby surplanting the use of the Katahira (1982) study as the basis for deriving the RfC. Furthermore, sampling confirmed that the test atmospheres were distributed uniformly throughout each exposure chamber, within 1% of the target value for each group. Fischer 344/N rats and B6C3F1 mice (10 sex/species/group) were exposed to 0, 66, 200, 600, 1,800, and 5000 ppm (0, 195, 590, 1770, 5,309 and 14,746 mg/m') for 6 hours/day, 5 days/week for 13 weeks. The animals were observed for clinical signs of toxicity, changes in body weight, morbidity and mortality. Hematological and clinical chemistry tests were performed at necropsy on rats only. At termination a complete necropsy was performed with complete

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histopathological examination of all major tissues, including the nasal cavity, turbinates, trachea, mainstem bronchi and lungs.

Rats exposed to 5000 ppm tetrahydrofuran had increased erythrocyte counts, packed cell volume, hemoglobin and mean corpuscular volume. BUN and creatinine levels were decreased, while bile acids were increased. Thymus and spleen weights were depressed in both sexes while liver weights were increased in the females at this highest concentration. The NOAEL for rats is established as 1800 ppm (NOAELHEC - 948 mg/m^) .

Mice were found to have significantly decreased spleen weights in both sexes at 5000 ppm. In males, thymic weights were significantly decreased and liver weights increased at 600, 1800 and 5000 ppm. Liver weights were significantly increased in females at 1800 and 5000 ppm. Both sexes exposed to 5000 ppm tetrahydrofuran exhibited a high incidence of hepatic lesions (minimal to mild centrilobular cytomegaly or hypertrophy). Based on these data a NOAEL for mice was established at 600 ppm (NOAELHEC = 316 mg/m') and a LOAEL of 1800 ppm (LOAELHEC = 948 mg/m') .

Based on the results of this subchronic NTP study, mice are clearly the more susceptible specie to the effects of exposure to tetrahydrofuran than were rats. The final report on the current NTP chronic inhalation bioassay should be available in 1993. Results from the chronic study should buttress the current data base, thereby increasing the level of confidence for the RfC derivation. Currently, the RfD/RfC Work Group is concerned about the potential effect at the thymus. These data are currently being reviewed and may affect the disposition of the RfC for tetrahydrofuran.

As stated above for the Katahira study, the effects of exposure to tetrahydrofuran are extrarespiratory, and portal of entry effects are reasonably expected not to occur. A route-to-route extrapolation could be performed, however, there are no PBPK data to estimate the amount of absorption from the inhalation route to the extrarespiratory pool. A typical default assumption in the past was to use a 50% absorption factor. However, such a selection is purely arbitrary and is not based on any appropriate experimental data. In no way can such an assumption be used with confidence to calculate an equivalent oral dose in mg/kg/day. Such a calculation (using default values of a total daily minute volume of 20 m' for a 70 kg adult) would yield an equivalent NOAEL oral dose of 45 mg/kg/day (based on a mouse NOAEL of 600 ppm). A minimum uncertainty factor of 1000 would need to be applied to this calculation. Given the lack of data, the uncertainty factor would most likely be higher (up to 10,000).


800047

The use of the inhalation exposure data to derive an oral RfD for tetrahydrofuran is problematic at best. Although, the inhalation data base is relatively strong and has been given a medium confidence level, the NTP chronic inhalation exposure will not be available until 1993. Furthermore, no PBPK data are available to assess the equivalent oral dose that the experimental species would receive upon inhalation exposure to tetrahydrofuran. If you choose to use the inhalation data briefly described above to derive an equivalent oral dose to tetrahydrofuran, do so with caution. My advice would be to wait until thymus effect issue is resolved by the RfD/RfC Work Group, since the NOAEL may be found to lower than is currently proposed.

REFERENCES:

Chhabra, R.S., M.R. Elwell, B. Chou, R.A. Miller, and R.A. Renn. 1990. Subchronic toxicity of tetrahydrofuran vapors in rats and mice. Fund. Appl. Toxicol. 14(2): 338-345.

Grumbein, S. 1988. Pathology working group chairperson's report: 13-week subchronic toxicity test by inhalation of tetrahydrofuran (C60560b) in Fisher 344 rats and B6C3F1 mice. Prepared by Pahology Associates, Inc. Submitted to National Toxicology Program.

Katahira, T. 1982. Experimental studies on the toxicity of tetrahysrofuran. Osaka-Shiritsu Daigaku Igaku Zasshi. 31: 221-239 (Translation).

Komsta, E., I. Chu, V.E. Secours, V.E. Valli, D.C. Villeneuve. 1988. Results of a short-term toxicity study for three organic chemicals found in niagara River drinking water. Bull. Environ, contam. Toxicol. 41(4): 515-522.


800048

Attachment VIII.

Risk Assessment Issue Paper for: Evaluation of the Inhalation Concentration for

1,1,1-TRICHLOROETHANE (CASRN 71-55-6)

The RfC for 1,1,1-trichloroethane listed in the HEAST (U.S. EPA, 1992) is lE+0 mg/m^, based on a NOAEL of 500 ppm in a 6-month study in guinea pigs conducted by Torkelson et al. (1958). In the HEAST (U.S. EPA, 1992), this risk assessment is cited to the HEA on 1,1,1-trichloroethane (U.S. EPA, 1984). However, the risk assessment in the HEA is actually based on studies by Prendergast et al. (1967) for subchronic, and Quast et al. (1978) for chronic inhalation exposure. A footnote in an earlier version (U.S. EPA, 1991) of the HEAST (omitted from the present version) revealed that the assessment shown in the HEAST was changed to be consistent with the derivation of the oral RfD. The oral RfD was originally based on an oral NCI bioassay (NCI, 1977). Later derivations were based on a 90-day inhalation study in mice (McNutt et al., 1975) and, subsequently, the 6-month study in guinea pigs (Torkelson et al., 1958). The RfD Summary Sheet in which the oral RfD based on the 6-month guinea pig inhalation study was derived pointed out that a chronic inhalation study in progress at that time (Quast et al., 1988) would probably be a better basis for RfD derivation than the guinea pig study when published. However, an oral RfD based on this study was never derived. The RfD was eventually withdrawn from IRIS on 7/16/91 and remains under review at this time (U.S. EPA, 1993). An RfC based on a preliminary version of the Quast et al. (1988) study was not verified due to requests for more data regarding the reported liver lesions and the suggestion that neurological effects in humans might be a more sensitive endpoint (U.S. EPA, 1988). A subsequent RfC was based on neurological endpoints in acutely exposed humans (Mackay et al., 1987), but was not verified because the Work Group had strong reservations regarding use of a 3.5-hour study to derive an RfC and questioned whether neurotoxicity was really the critical effect for prolonged exposure (U.S. EPA, 1990). The Work Group also requested further review of several studies, including Prendergast et al. (1967) and McNutt et al. (1975). No further actions have been taken (U.S. EPA, 1993). The goal of the current task is to examine the merits of continuing to use the RfC in the HEAST for Superfund work pending outcome of review by the Work Group. In order to perform this task, the RfC in the HEAST was compared to the latest RfC reviewed by the Work Group and some of the other possibilities mentioned above.


800049

1) RfC derived in HEAST (U.S. EPA, 1992)

The RfC listed in the HEAST is lE+0 mg/m'. This RfC was calculated using outdated methodology, as described in Table 1. Application of the current methodology to the same data produces an RfC of 2E+0 mg/m'. This derivation is also shown in Table 1. The primary problem with this RfC derivation is that only one dose level (500 ppm = 2728 mg/m') was tested in the 6-month study by Torkelson et al. (1958), making this dose a free-standing NOAEL. Although the authors reported additional studies in which animals were exposed to 1000, 2000 or 10,000 ppm (5456, 10,912 or 54,560 mg/m') of 1,1,1-trichloroethane for 3 months, these were all discrete studies conducted independently. These studies showed that exposure to 2000 ppm for 30 minutes/day or 1000 ppm for 3 hours/day produced effects on the liver (fatty changes/ increased liver weight) and lungs (irritation/inflammation) of exposed guinea pigs. However, the short daily exposure times may not be appropriate for assessing chronic continuous exposure. Adams et al. (1950) found significant reductions in body weight gain (growth reduced to 65-82% of that in controls) among guinea pigs exposed to 650 ppm (3546 mg/m') of 1,1,1-trichloroethane for 57-93 days (7 hours/day, 5 days/week), and this dose level was chosen as the LOAEL for 1,1,1-trichloroethane in the HEAST derivation. However, this effect on body weight was not replicated in the high-dose studies performed by Torkelson et al. (1958). In the Adams et al. (1950) study, liver effects were seen only at doses of ^3000 ppm (16,368 mg/m') .

2) Last RfC considered by Work Group

A proposed RfC of 9E-1 mg/m' was derived from neurological endpoints (performance in psychomotor tasks) in an acute human study (MacKay et al., 1987). Using current guidelines for applying uncertainty factors this RfC would be 3E+0 mg/m^, as shown in Table 1. This RfC derivation was not well received by the Work Group, primarily due to the very brief duration of exposure (U.S. EPA, 1990), so it would probably be best to avoid using this proposed RfC.

3) Other possibilities

RfCs derived from other studies are shown in Table 1, grouped by critical endpoint. The two possibilities for critical endpoint supported by the data are liver alterations and neurotoxicity (fetotoxic effects have been reported, but only at much higher doses). Studies previously considered by the Work Group for derivation of an RfC (or RfD by route-to-route extrapolation) based on liver effects included chronic studies by Quast et al. (1978, 1988) and a subchronic study by McNutt et al. (1975). A subchronic study by Calhoun et al. (1981) also appears to merit consideration. Choice of liver histopathology as the


800050

critical effect is supported by numerous animal studies that reported mild changes in the liver as an effect of chronic or subchronic 1,1,1-trichloroethane exposure (Adams et al., 1950; Calhoun et al., 1981; McNutt et al., 1975; Quast et al., 1978, 1988; Torkelson et al., 1958) and by case reports of fatty liver disease in workers whose primary chemical exposure was to 1,1,1-trichloroethane (Hodgson et al., 1989).

NOTE: The exercise that follows proposing calculated RfCs derived from specific studies is not intended to propose alternative ways of calculating an RfC, but to give a sense of the appropriateness of using default criteria as presently published in HEAST. This is purely an illustrative exercise and does not construe or describe the method that the Work Group utilizes to establish an RfC or an RfD.

The study by Quast et al. (1988) was a thorough, well-conducted chronic 2-year toxicity study using sufficient numbers of male and female animals of two species (rats and mice). The high-dose of 1500 ppm (8184 mg/m^) was designated to be a LOAEL based on microscopic changes in the liver of male and female rats (visible at interim sacrifices at 6-18 months, but obscured by geriatric changes at final sacrifice at 24 months). The observed change in the liver consisted of an accentuation of the normal hepatic lobular pattern, with altered cytoplasmic staining in the cells surrounding the central vein making hepatocytes in the portal region appear reduced in size. The only other effect reported was reduced body weight of female rats in both the 500 and 1500 ppm groups for much of the study. Although statistically significant, this effect appeared to be slight in both groups (<7%). The authors considered the change to be treatment-related only in the high-dose group. The RfC originally derived from this study was lE+1 mg/m'. Using current methodology, the RfC would be 2E+1 mg/m', derived as shown in Table 1.

The earlier study by Quast et al. (1978) was a chronic study in which rats were exposed to 0, 875 or 1750 ppm (0, 4774 or 9548 mg/m') of 1,1,1-trichloroethane for 12 months and observed for an additional 12 months. Analyses included hematology, serum chemistry, urinalysis, body and organ weights and gross and microscopic examination. The only effect considered to be exposure-related by the authors was an increased incidence of focal hepatocellular alterations in female rats exposed to 1750 ppm. An RfC of 3E+1 mg/m' could be derived from this study as shown in Table 1.

The study reported by Calhoun et al. (1981) was similar to those performed by Quast et al. (1978, 1988), but only 3 months in duration. In this study, the LOAEL of 2000 ppm (10,912 mg/m') produced mild liver alterations (fatty changes in female rats and


800051

reduced liver glycogen levels in rats of both sexes). Mild nasal olfactory epithelium degeneration was also reported, but has not been confirmed by other studies (Quast et al., 1988) that examined the complete respiratory tract. No effects were reported at 1000 ppm (5456 mg/m^) . Table 1 shows that the RfC derived from this study could be 3E+0 mg/m'.

The study by McNutt et al. (1975) concentrated on investigation of histopathology, especially of the liver, in male mice exposed to 0, 250 or 1000 ppm (0, 1364 or 5456 mg/m^) of 1,1,1-trichloroethane continuously for 14 weeks. The study used a large number of mice and monitored changes throughout the study period with frequent interim kills. Liver effects in mice exposed to 1000 ppm included increases in absolute and relative liver weight, liver triglycerides and liver lesions (in the centrilobular region, swelling of hepatocytes, vacuolization, extensive cytoplasmic alterations, increased lipid and triglyceride content, vacuolar degeneration and, after 10 weeks, necrosis of individual hepatocytes). In general, the changes found in the livers of mice exposed to 250 ppm were minimal (occasional mild ultrastructural variations after 10 weeks of exposure), although two observations of vacuolar degeneration and one of focal necrosis were noted. Exposure-related lesions were not found in other organs (heart, lung, brain, intestine, kidney or pancreas). The RfC derived from this study would be 5E+0 mg/m^, as shown in Table 1.

The RfCs based on liver changes varied over one order of magnitude, with the subchronic studies suggesting RfCs of 3-5 mg/m' and the chronic studies suggesting RfCs of 20-30 mg/m'. A problem with all of these RfCs, which were based on studies in rats and mice, is that there is evidence showing that guinea pigs are more sensitive than either of these species to 1,1,1-trichloroethane toxicity (Torkelson et al., 1958). Ideally, the RfC would be based on effects in the most sensitive species. This could be compensated for by raising the uncertainty factor for interspecies extrapolation from 3 to 10 for the rat and mouse studies, reducing the RfCs to 5-8 mg/m' in the chronic studies and 1 mg/m' in the subchronic studies. There is also a concern that liver effects are not the most critical effects of long-term exposure to 1,1,1-trichioroethane. Studies by Rosengren et al. (1985) and Karlsson et al. (1987) have revealed exposure-related neurochemical changes in the brains of gerbils that suggest that 1,1,1-trichloroethane can produce permanent damage to the brain at relatively low concentrations.

Rosengren et al. (1985) exposed groups of 4 male and 4 female Mongolian gerbils to concentrations of 70, 210 or 1000 ppm (382, 1146 or 5456 mg/m') of 1,1,1-trichloroethane vapor continuously for 3 months. Each exposure group was matched with a control group of 4 male and 4 female sex-matched littermates.


800052

All animals were maintained for an additional 4 months prior to sacrifice. Upon sacrifice, the brain was weighed, dissected and used for biochemical analyses. No deaths occurred during the study and no effects on body weight were found. Brain weight was significantly reduced in the high-dose group, although the difference from controls was slight (2.5% reduction). Significantly increased concentrations of glial fibrillary acidic (GFA) protein were found in the sensorimotor cerebral cortex of mid- and high-dose gerbils. The increase was roughly 33% in both groups. GFA protein levels were not increased in the frontal cerebral cortex or the occipital cerebral cortex. Brain concentrations of S-100 protein and total protein were unaffected by exposure. GFA protein is the main protein subunit of astroglial filaments and is used by neurobiologists as a marker for demonstrating formation of astroglial fibrils in response to brain injury. S-100 protein is also used as a marker for astroglial cell increase in response to brain injury, but is found in both protoplasmic and fibrillary astrocytes. The increase in GFA protein in this study suggests the occurrence of astrogliosis in the sensorimotor cerebral cortex, and astrogliosis is evidence of damage to the central nervous system. The fact that the effect was found 4 months after the end of exposure suggests it is irreversible. Failure to observe an increase in S-100 could have been due to a shift from protoplasmic to fibrillary astrocytes in response to 1,1,1-trichloroethane exposure. It should be noted, however, that the related compounds trichloroethylene and tetrachloroethylene both produced increases in S-100 as well as GFA protein.

In a study conducted similarly to Rosengren et al. (1985), Karlsson et al. (1987) found that 1,1,1-trichloroethane at 70 ppm significantly reduced DNA concentrations in 3 of 9 brain areas investigated (posterior cerebellar hemisphere, anterior cerebellar vermis and hippocampus), but not the sensorimotor cerebral cortex affected in the study by Rosengren et al. (1985) . Reduced DNA content suggests decreased cell density due to either induced cell death or inhibition of nonneuronal cell acquisition. RfCs derived from these studies, shown in Table 1, would be lower than those based on liver effects (0.1-1 mg/m') . However, the reliability of these neurochemical changes as markers for physical damage to the brain is uncertain. Histopathology studies were not done to confirm that cell damage had occurred. These studies were also limited by failure to investigate other endpoints (e.g., hepatotoxicity). This is especially problematic because no other toxicity data are available for gerbils exposed to 1,1,1-trichloroethane. In addition, the studies were limited by small group sizes and failure to perform analyses immediately following exposure. The Karlsson et al. (1987) study was further limited by inclusion of only a single dose level. Although the fact that other studies have not found brain lesions following 1,1,1-trichloroethane exposure might seem to discredit these

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results, that is not the case because the routine histopathology techniques used in the available studies may not have been adequate to detect the lesions. The inconsistency in affected brain area between the two studies is a point of concern, however.

One other study considered in previous RfC/RfD derivations was conducted by Prendergast et al. (1967). In one experiment, rats, guinea pigs, rabbits, dogs and monkeys were inteirmittently (8 hr/d, 5 d/wk) exposed to 12,060 mg/m' for 6 weeks, and in another these same species were exposed continuously to 754 or 2059 mg/m' for 90 days. The only noteworthy effect was reduced body weight gain in rabbits and dogs in both the intermittent exposure experiment and the high-dose group of the continuous exposure experiment. This apparent effect was not evaluated statistically, however, and group sizes were very small (only 3 rabbits and 2 dogs were included in each group). Therefore, derivation of an RfC from this study would not appear to be appropriate.

Conclusion:

There are many issues to be resolved regarding the RfC for 1,1,1-trichloroethane, including such basic considerations as critical effect and study to use. Although the RfC in the HEAST is not based on a strong foundation and was calculated using outdated methodology, it is similar to, but more conservative than, most of the other possibilities in the data base. Therefore, it would appear to be appropriate to keep using the value in the HEAST (lE+0 mg/m') as the RfC for 1,1,1-trichloroethane until the important outstanding issues are settled by the RfD/RfC Work Group. Alternatively, the value calculated from the same data using the current methodology (2E+0 mg/m') could be used. Please note that these two numbers are not substantially different given the definition of the RfC that states that the value is accurate "...within an order of magnitude".


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Table 1 . Calculated RfC Derivat ions Under Consideration fo r 1,1,1-Trtchloroethane

Study Species Effect Exposure Level (mg/m')

HEC (mg/iir')

UF/MF Calculated RfC (rog/m')

Torkelson et al., 1958*; guinea pig Adams et al.. 1950' [derivation in HEAST]

Torlcetson et al., 1958*; guinea pig Adams et al., 1950*" [derivation using current methodology]

MacKay et al., 1987 human

Quast et al., 1988

Quast et al., 1978

rat

rat

Calhoun et al., 1981 rat

McNutt et al., 1975 mouse

Rosengren et al., 1985 gerbil

Karlsson et al., 1987 gerbil

reduced body weight gain

reduced body weight gain

altered performance in some neurological tests

liver alterations

liver alterations

liver alterations

liver alterations

neurochemical changes suggesting physical damage to brain

neurochemical changes suggesting physical damage to brain

0 2728° N 3546" L

0 2728° N 3546" L

tf 950 L 1900

tf 818 2728 N 8184 L

0° 4774 N 9548 L

0" 5456 H 10912 L

0 ' 1364 N 5456 L

O" 382 N 1146 L 5456

0' 382 L

0* 1061 1383

0* 568 739

tf 950 1900

tf" 146 487 1461

tf" 852 1705

(T 974 1949

0* 1364 5456

0* 382 1146 5456

0" 382

N L

N L

L

N L

N L

N L

N L

N L

L

lOOO'/l

300^/1

300^/1

30"/1

30"/1

300Vl

300Vl

300^/1

300071

1E+0

2E+0

3E«0

2E+1

3E*1

3E+0

5E+0

1E+0

1E-1

00 o o o

•Source of NOAEL. 'Source of LOAEL. °7 hrs/day, 5 day/weeic for 6 months "7 hrs/day, 5 day/week for 2-3 months *HEC calculated as the product of the duration-adjusted exposure level and the ratio of guinea pig inhalation rate(0.23 nr'/day):body Height(0.43 kg).


divided by the ratio of human inhalation rate(20 mVday):body weight(70 kg). "UF calculated from factors of 10 for subchronic study, 10 for interspecies differences and 10 to protect sensitive individuals. 'NEC calculated as the product of the duration-adjusted exposure level and the blood:gas partition coefficient ratio (LA/LH). Since values for L^/LH were not available, a default value of 1 was used.

"XJF calculated from factors of 10 for subchronic study, 3 for interspecies differences and 10 to protect sensitive individuals. "3.5 hrs HlEC • exposure concentration for this acute human study. *Vr calculated from factors of 3 for use of a minimal LOAEL, 10 for use of an acute study and 10 to protect sensitive individuals. '6 hrs/day, 5 days/week for 2 years "HEC calculated as the product of the duration-adjusted exposure level and the blood:gas partition coefficient ratio (L^/LH). L^/LH > 5.67/2.53 -2.24. Since L^/LH > U the default value of L«/LH • 1 is used. "UF calculated from factors of 3 for interspecies differences and 10 to protect sensitive individuals. *6 hrs/day, 5 days/week for 1 year "6 hrs/day, 5 days/week for 3 months *24 hrs/day, 7 days/week for 3 months "UF calculated from factors of 10 for use of a LOAEL, 10 for subchronic study, 3 for interspecies differences and 10 to protect sensitive individuals.

00 o o o ^ For i n t e r n a l use o n l y . DRAFT - Do n o t c i t e o r quo te . a> -41-

REFERENCES;

Adams, E.M., H.C. Spencer, V.K. Rowe and D.D. Irish. 1950. Vapor toxicity of 1,1,1-trichloroethane (methylchloroform) determined by experiments on laboratory animals. Ind. Hyg. Occup. Med. 1: 225-236.

Calhoun, L.L., F.J. Quast, A.M. Schumann et al. 1981. Chlorothene VG: Preliminary studies to establish exposure concentrations for a chronic inhalation study with rats and mice. Toxicology Research Laboratory, Health and Environmental Sciences, The Dow Chemical Company, Midland, MI. (Unpublished study)

Hodgson, M.J., A.E. Heyl and D.H. Van Thiel. 1989. Liver disease associated with exposure to 1,1,1-trichloroethane. Arch. Intern. Med. 149(8): 1793-1798.

Karlsson, J.E., L.E. Rosengren, P. Kjellstrand and K.G. Haglid. 1987. Effects of low-dose inhalation of three chlorinated aliphatic organic solvents on deoxyribonucleic acid in gerbil brain. Scand. J. Work Environ. Health. 13: 453-458.

MacKay, C.J., L. Campbell, A.M. Samuel et al. 1987. Behavioral changes during exposure to 1,1,1-trichloroethane: Time-course and relationship to blood solvent levels. Am. J. Ind. Med. 11: 223-240.

McNutt, N.S., R.L. Amster, E.E. McConnell and J. Morris. 1975. Hepatic lesions in mice after continuous inhalation exposure to 1,1,1-trichloroethane. Lab. Invest. 32(5): 642-654.

NCI (National Cancer Institute). 1977. Bioassay of 1,1,1-trichloroethane for possible carcinogenicity. NCI Carcinogen. Tech. Rep. Ser. 3. NTIS PB265082.

Prendergast, J.A., R.A. Jones, L.J. Jenkins, Jr. and J. Siegel. 1967. Effects on experimental animals of long-term inhalation of trichloroethylene, carbon tetrachloride, 1,1,1-trichloroethane dichlorodifluoromethane, and 1,1-dichloroethylene. Toxicol. Appl. Pharmacol. 10: 270-289.

Quast, J.F., L.W. Rampy, M.G. Balmer, B.K.J. Leong and P.J. Gehring. 1978. Toxicologic and carcinogenic evaluation of a 1,1,1-trichloroethane formulation by chronic inhalation in rats. Toxicology Research Laboratory, Health and Environmental Research, The Dow Chemical Company, Midland, MI. (Unpublished study)

Quast, J.F., L.L. Calhoun and L.E. Frauson. 1988. 1,1,1-Trichloroethane formulation: A chronic inhalation toxicity and


800057

oncogenicity study in Fischer 344 rats and B6C3F1 mice. Fund. Appl. Toxicol. 11: 611-625.

Rosengren, L.E., A. Aurell, P. Kjellstrand and K.G. Haglid. 1985. Astrogliosis in the cerebral cortex of gerbils after long-term exposure to 1,1,1-trichloroethane. Scand. J. Work Environ. Health. 11: 447-456.

Torkelson, T.R., F. Oyen, D.D. McCollister and V.K. Rowe. 1958. Toxicity of 1,1,1-trichloroethane as determined on laboratory animals and hximan subjects. Am. Ind. Hyg. Assoc. J. 19: 353-362.

U.S. EPA. 1984. Health Effects Assessment for 1,1,1-trichloroethane. Prepared by Environmental Criteria and Assessment Office, Office of Health and Environmental Assessment, Cincinnati, OH. EPA/540/1-86-005.



U.S. EPA. 1991. Health Effects Assessment Summary Tables. Annual FY-1991. Office of Research and Development, Office of Emergency and Remedial Response, Washington, DC. NTIS PB91-921100.


U.S. EPA. 1993. Quarterly Status Reports of RfD/RfC Work Group (As of 5/01/93). Office of Research and Development. Environmental Criteria and Assessment Office, Cincinnati, OH.

For internal use o n l y . DRAFT - Do n o t c i t e o r q u o t e . -43-

800058

Attachment IZ.

Risk Assessment Issue Papers for Evaluation of Systemic Toxicity and Carcinogenicity of;

HEXADECANOIC ACID (CASRN 75-10-3)

INTRODUCTION

The following computer searches were conducted for hexadecanoic acid: TOXLIT 1965-1991, TOXLINE 1981-1991, MEDLINE 1980-1991, CANCER 1963-1991, ETIC, HSDB, and RTECS. The TOXLIT, TOXLINE, MEDLINE, AND CANCER database searches were limited to only include oral data. A search of inhalation data on TOXLINE and a TSCATS search have been conducted. No information was located in TSCATS. The following sources were examined for information on the noncarcinogenic and carcinogenic effects of hexadecanoic acid OHEA CARA list (U.S. EPA, 1991), IRIS status reports (U.S. EPA, 1993a,b,c) and NTP status report (NTP, 1991). This compound has not beeun the subject of an ATSDR toxicological profile. In addition, there are no NIOSH REL (NIOSH, 1990), ACGIH TLV (ACGIH, 1991), or OSHA PEL (OSHA, 1989) values for hexadecanoic acid.

Hexadecanoic acid is a long hydrocarbon chain carboxylic acid. This 16-carbon saturated fatty acid is found in practically all vegetable oils and animal fats. Palmitic acid is a synonym for hexadecanoic acid (Anonymous, 1987).

NONCARCINOGENIC EFFECTS FOLLOWING INHALATION EXPOSURE AND DERIVATION OF RfC

No information on the noncarcinogenic effects in humans and/or animals following inhalation of hexadecanoic acid were located. However, there is some information on the toxicity of airborne lauric acid. Laurie acid is a 12-carbon saturated fatty acid. In a NIOSH Health Hazard Evaluation report (as reviewed in Anonymous, 1987), 7 workers reported eye, nose, throat, and skin irritation following exposure to airborne lauric acid. The workers were involved in the flaking and bagging operation at a manufacturing facility. It is not known if hexadecanoic acid would have similar irritative effects. A route-to-route extrapolation from oral data is not recommended because of the possibility of portal-of-entry effects and the lack of comparative toxicokinetic data.


800059

NONCARCINOGENIC EFFECTS FOLLOWING ORAL EXPOSURE AND DERIVATION OF MS.

There is an abundance of literature on the role of saturated fatty acids in the etiology of coronary heart disease. It is believed that a diet high in saturated fat will increase an individual's risk of coronary heart disease. However, a number of other factors can also contribute to the increased risk of coronary heart disease; other factors include dietary cholesterol, sugar, protein, and fiber and nondietary factors such as cigarette smoking, exercise, and heredity. Saturated fatty acids have been shown to be active in elevating plasma cholesterol and triglyceride levels. There have been a number of studies which compared the ability of several saturated fatty acids to raise cholesterol and triglyceride levels. In a rat study conducted by Renaud (1968), groups of male Holtzman rats (6-7/group) were fed high fat diets containing 32% butter and 5% either caprylic acid, lauric acid, myristic acid, hexadecanoic acid, or stearic acid. The American Institute of Nutrition (1977) recommends a diet containing 5% corn oil for rats. Of the fatty acids tested, hexadecanoic acid had the greatest ability to increase serum cholesterol and triglyceride levels. Because of the interplay of a number of dietary and nondietary factors on plasma cholesterol and triglyceride levels, it is difficult to determine what level of hexadecanoic acid would increase serum cholesterol to a level that would result in increased risk of coronary heart disease. Thus, it is recommended that an RfD for hexadecanoic acid not be derived.

CARCINOGENIC EFFECTS

No information on the carcinogenicity of inhaled hexadecanoic acid was located.

No relevant information of the carcinogenicity of ingested hexadecanoic acid was located. In Anonymous (1987), a subchronic study conducted by Herting et al. (1959) is discussed in the carcinogenicity section. A review of this study follows. Groups of male and female Holtzman rats (48-72/group) were fed a diet containing 50% hexadecanoic acid [using a food factor of 0.05 (U.S. EPA, 1986), this is equivalent to a dose of 25 mg/kg/day] and 4% corn oil or a control diet for 24 weeks (Herting et al., 1959). The control diet contained 4% corn oil and 10% triacetin. After 24 weeks, the hexadecanoic acid treated group was switched to a diet containing 20% corn oil. There was no change in the control diet. Histopathological examination of the fat attached to the adrenal, kidney, stomach, testis, and ovaries was conducted. Interim sacrifices occurred after 8, 16, and 24 weeks. An increased incidence (3/6, 4/6, 4/5 for 8, 16, and 24 week sacrifices, respectively) of lipogranulomas in the fat associated

For i n t e r n a l use o n l y . DRAFT - Do n o t c i t e o r quo te , -45-

800060

with the testis or ovaries was observed in the rats receiving hexadecanoic acid. No lipogranulomas were observed in the rats receiving hexadecanoic acid. Eight weeks after the hexadecanoic acid treated rats were switched to the corn oil diet, there was a decrease in the incidence (2/5) and severity of lipogranulomas. No lipogranulomas were observed 16 weeks (2 rats examined) or 24 weeks (1 rat examined) after the removal of hexadecanoic acid from the diet.

GENOTOXICITY

There is no infoirmation on the genotoxicity of hexadecanoic acid.

WEIGHT-OF-EVIDENCE CLASSIFICATION

The lipogranulomas observed in the Herting et al. (1959) study can not be considered carcinogenic endpoints. In addition, only adipose tissue was examined in this study. Thus the Herting et al. (1959) study is inadequate for the assessment of carcinogenicity of hexadecanoic acid. Based on inadequate animal data and no human data, hexadecanoic acid is classified in U.S. EPA (1986) weight-of-evidence group D, not classifiable as to human carcinogenesis.

DERIVATION OF INHALATION AND ORAL SLOPE FACTORS

According to U.S. EPA (1986) guidelines, classification of a compound in weight-of-evidence Group D precludes quantitative risk assessment.

REFERENCES;

ACGIH (American Conference of Governmental Industrial Hygienists). 1991. Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices 1991-1992. ACGIH, Cincinnati OH.

American Institute of Nutrition. 1977. Report of the American Institute of Nutrition Ad Hoc Committee on standards for Nutritional Studies. J. Nutr. 107: 1340-1348.

Anonymous. 1987. Final report on the safety assessment of oleic acid, lauric acid, palmitic acid, myristic acid, and stearic acid. J. Am. Coll. Toxicol. 6: 321-401.

For internal use only. DRAFT - Do not cite or quote. -46-

800061

Herting, D.C, P.L. Harris, and R.C. Grain. 1959. Lipogranuloma from dietary saturated fats: Production and Reversal. Toxicol. Appl. Pharmacol. 1: 505-514.

NIOSH (National Institute for Occupational Safety and Health. 1990. NIOSH Pocket Guide to Chemical Hazards. U.S. Department of Health and Human Services, NIOSH, Cincinnati OH.

NTP (National Toxicology Program). 1991. Chemical Status Report (07/09/91). National Toxicology Program, Research Triangle Park, NC.

OSHA (Occupational Safety and Health Administration). 1989. Air Contaminants; Final Rule. 29 CFR Part 1910. Fed. Reg. 54.

Renaud, S. 1968. Thrombotic, atherosclerotic and lipemic effects of dietary fats in the rat. Angiology 20: 657-669.

U.S. EPA. 1986. Guidelines for Carcinogen Risk Assessment. Fed. Reg. 51: 3392-34003.

U.S. EPA. 1991. Chemical Assessment and Related Activities. Prepared by Technical Information Staff, Office of Health and Environmental Assessment for Office of Health and Environmental Assessment, Washington, DC. April, 1991.

U.S. EPA. 1993a. Monthly status report of the RfD/RfC Work Group-RfC (as of 05/01/93). Office of Research and Development. Environmental Criteria and Assessment Office, Cincinnati, OH.

U.S. EPA. 1993b. Monthly status report of the RfD/RfC Work Group-RfD (as of 05/01/93). Office of Research and Development. Environmental Criteria and Assessment Office, Cincinnati, OH.

U.S. EPA. 1993c. Monthly status report of the CRAVE Work Group (as of 05/01/93). Office of Research and Development, Environmental Criteria and Assessment Office, Cincinnati, OH.


800062

TETRAMETHYLCYCLOHEZANE

The following searches for tetramethylcyclohexane were conducted: TOXLINE (1965-1991), TOXLIT (1965-1991) and CHEMLINE. No information was located on TSCATS. Because the request did not specify which isomers, the literature searched included all isomers (including mixtures of isomers) of tetramethylcyclohexane. No EPA or ATSDR documents have been prepared on this compound. Only one relevant study was identified (Johannsen and Levinskas, 1987).

ORAL RfD

In an acute study, Johannsen and Levinskas (1987) administered single gavage doses of various isomers of tetramethylcyclohexane to Sprague-Dawley rats. The isomers tested were cis-1,1,3,5-; trans-1,1,3,5-; i:i mixture of cis-1,1,3,5- and trans-1,1,3,5-; cis,trans-l,2,3,4-; cis,trans-1,2,3,5-; cis,trans-l,2,4,5-; and cis,trans-1,1,2,3-tetramethylcyclohexane. The animals were observed for 14 days following the dosing. Lethality was the only endpoint assessed. In terms of the incidence of mortality, no statistically significant differences between the isomers were observed. Doses as high as 15,380 mg/kg were not associated with a statistically significant increase in the incidence of death.

Johannsen and Levinskas (1987) also exposed groups of 15 male and 15 female Sprague-Dawley rats to 0, 3000, 10,000 or 30,000 ppm (0, 300, 1000, and 3000 mg/kg/day, authors' estimate) of a mixture of cis- and trans 1,1,3,5-tetramethylcyclohexane (50% cis and 50% trans) in the diet for 90 days. Groups of 4 male and 4 female beagle were similarly exposed to 0, 100, 300, or 1000 ppm (2.5, 7.5, or 25 mg/kg/day, authors' estimate) tetramethylcyclohexane. In rats, no effects on survival, body weight or blood chemistry (BUN, glucose, serum alkaline phosphatase, SGPT), hematology (hemoglobin, hematocrit, and red and white blood cell count), or urinalysis parameters were observed. An increase in absolute liver weight was observed in males exposed to the highest dose. The only histopathological alteration (major organs and tissues examined) observed was renal lesions consisting of protein resorption droplets in the proximal convoluted tubules in all treated male rats. In the dogs, no treatment related effects on survival, body and organ weights, blood chemistry, hematology, and urinalysis parameters, and histopathology were observed.

Dr. Johannsen was contacted regarding the kidney lesions observed in the male rats. Dr. Johannsen stated that Monsanto dropped the project after the completion of the subchronic study.

For i n t e r n a l u se o n l y . DRAFT - Do n o t c i t e o r q u o t e .

800063'

and thus, further research was not conducted to determine if the lesions were caused by a2„-globulin accumulation. The description of nephrotoxicity observed in the male rats is consistent with that of 02„-globulin nephropathy observed in male rats exposed to other branched chain alkanes (Swenberg et al., 1989). These data suggest that exposure to 1,1,3,5-tetramethylcyclohexane may induce a2j,-globulin nephropathy. Because aj^-globulin is a male rat specific protein, 02„-globulin nephropathy would not be expected to occur in other species. Thus, tetramethylcyclo-hexane-induced nephrotoxicity in male rats is not considered a critical endpoint. The NOEL in dogs (25 mg/kg/day) was selected as the basis of the RfD. A 3000 uncertainty factor is applied to the NOEL to yield an RfD of 8 x 10'̂ mg/kg/day. The areas of uncertainty associated with the RfD derived from this NOEL include use of a less than chronic study (10), interspecies differences (10), variation in sensitivity among individuals (10), and an incomplete database (3).

Confidence in the study is medium because it is a subchronic study that defined a free standing NOEL. Confidence in the database is low because there were no chronic or reproductive/ developmental studies. Resulting confidence in the RfD is low.

SLOPE FACTOR

No information was located on the carcinogenicity of tetramethylcyclohexane, thus, a slope factor cannot be derived at this time. Based on the lack of carcinogenicity data, tetramethylcyclohexane is classed in U.S. EPA weight-of-evidence group D, not classifiable to human carcinogenicity (U.S. EPA, 1986),

DERMAL TOXICITY DATA

No data on the dermal toxicity of tetramethylcyclohexane were located. Without evidence to suggest route-specific differences in the toxicity of a compound, it is the U.S. EPA's position that the toxicity manifested via one route of exposure is relevant to considerations of any other route of exposure (U.S. EPA, 1993). There are no data on tetramethylcyclohexane in which to determine if there is route-specific toxicity; the toxicity studies located for tetramethylcyclohexane involve oral exposure. In the absence of conflicting data, it is possible to use the oral toxicity data for dermal risk assessment.


"""" 800064

REFERENCES;

Johannsen, F.R., G.J. Levinskas. 1987. Acute and subchronic toxicity of tetramethylcyclohexanes. J. Appl. Toxicol. 7:245-248.

Swenberg, J.A., B. Short, S. Borghoff, et al. 1989. The comparative pathobiology of 02„-globulin nephropathy. Toxicol. Appl. Pharmacol. 97:35-46.

U.S. EPA. 1986. Guidelines for Carcinogen Risk Assessment. Fed. Reg. 51:3392-34003.

U.S. EPA. 1993. Integrated Risk Information System. Online. Oral RfD Background Document. Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH.


800065

TRIBROMOPHENOL

There are 6 possible isomers for tribromophenol but there cannot be a 1,2,4-isomer since position 1 in the phenyl ring corresponds to the hydroxy1 group. In order to avoid further delay we have reviewed available literature on tribromophenols as a class and also on any specific isomer for which information was available.

No EPA document on tribromophenol or individual isomers was identified. Furthermore, tribromophenol has not been the subject of an ATSDR toxicological profile.

The following computer searches were conducted for tribromophenol: TOXLINE and TOXLIT (1981-91), HSDB, and RTECS. The only isomer for which data were available was 2,4,6-tribromophenol. These data, summarized below, were considered inadequate for derivation of an RfC.

Albino rats (5/sex/group) were exposed to 2,4,6-tribromophenol at target concentrations of 0, 0.1, or 1.0 mg/L (0, 100, or 1000 mg/m , respectively) 6 hours/day, 5 days/week for 3 weeks (IBT, 1977). Particle size was not reported. End points monitored included mortality, body weight gain, and general behavior. Hematologic and clinical chemistry studies, and urinalysis were performed in selected animals from all groups. At the end of the study, all survivors were subjected to gross necropsy. Selected tissues and organs from rats in the control and high exposure groups were processed for microscopical evaluation. Two rats in the high exposure groups died after 2 weeks of exposure; the cause of death was not reported. Animals in both the low and high exposure groups showed hypoactivity, salivation, lacrimation and red nasal discharge. Body weight gain in both low-and high-exposure females and in high-exposure males was significantly lower than in controls. Results from blood tests and urinalyses conducted on samples obtained at sacrifice were unremarkable. At necropsy, 9/10 rats in the high-exposure group were considered emaciated. Gross alterations were restricted to the high-exposure groups, and consisted of discoloration of the kidney in one male and liver fibrosis in one female. Histopathological examination of tissues of the high-exposure groups (low-exposure groups were not examined) revealed dilation of renal tubules in 3/5 rats of each sex, and an area of submassive hepatic necrosis in one female. No other histological changes attributed to the test material were observed. A NOAEL was not defined in this study.

Charles River rats (5/sex) were exposed for 4 hours to dusts of 2,4,6-tribromophenol and observed for 14 days after the exposure (IBT, 1976). The exposure concentration was 1.63 mg/L


800066

(1630 mg/m') ; there was no mention of a control group being used. There were no deaths during the exposure period or during the 14-day observation period. Ptosis was observed after 10 minutes of exposure, but subsided once exposure ceased. Red nasal discharge lasting from 8 to 18 hours was noticed in all animals at the end of the exposure period.

In a study conducted by IRDC (1974a), CD rats (5/sex) were exposed to dusts of 2,4,6-tribromophenol at a concentration level of approximately 50 mg/L (50,000 mg/m') for 4 hours and observed for 14 days after the exposure period; no controls were used. No deaths occurred during the study. Body weight gain was not affected by exposure to 2,4,6-tribromophenol. During the 4-hour exposure periods the rats exhibited decreased motor activity, eye squint, slight dyspnea, erythema and ocular porphyrin discharge. Additional signs of toxicity starting at 24 hours included diarrhea and clear nasal discharge. No compound-related effects were observed at necropsy. Histopathological examination was not performed.

IRDC (1978) conducted a pilot developmental toxicity study with 2,4,6-tribromophenol. In this study, CD pregnant rats (5/dose level) were administered 0, 10, 30, 100, 300, 1000, or 3000 mg 2,4,6-tribromophenol/kg/day by gavage in corn oil on gestation days 6 through 15. On day 20 the rats were sacrificed and the uterine contents examined. There was no mortality or adverse clinical signs in rats receiving ^1000 mg 2,4,6-tribromophenol/kg/day. All animals in the 3000 mg/kg/day group died after one day of treatment. No significant compound-related effects were observed regarding the number of viable and nonviable fetuses, resorptions, implantations, corpora lutea, or maternal body weights in females treated with <300 mg 2,4,6-tribromophenol/kg/day relative to controls. A slight decrease in maternal body weight gain between gestation days 6 and 12, an increase in post implantation losses, and a slight decrease in the number of viable fetuses were reported in the 1000 mg/kg/day dose group. Fetuses were not examined for malformations.

Dow Chemical Company (1946) reported that oral doses of 3000 mg 2,4,6-tribromophenol/kg killed guinea pigs, but doses of 1000 mg/kg did not. In addition, they reported that a 10% solution (vehicle not reported) produced slight skin irritation in rabbits. Further details were not available.

A combined oral LDjo of 5012 mg/kg (4178-6013 mg/kg) was reported in male and female Spartan rats administered 2,4,6-tribromophenol in 0.5% Methocel (IRDC, 1974b). Deichmann and Keplinger (1981) indicated that the oral LDjo for 2,4,6-tribromophenol as sodium salt in rats (strain not specified) is somewhat less than 2000 mg/kg.


800067

Pharmacokinetic data were obtained in male and female Holzman rats (2-3/group) given a single oral dose of 4-5 mg 14C-2,4,6-tribromophenol/kg by gavage in ethanol and monitored for up to 96 hours after dosing (Velsicol Chemical Corporation, 1977). Forty-eight hours after treatment, the amount of 14C remaining in each of 11 major tissues did not exceed 0.005% of the administered radioactivity, and only the liver, lungs and kidneys had detectable residues. Blood 14C peaked 1 hour after dosing and the retention half-life in blood was 2.03 hours. Retention in other tissues ranged from 1.45 to 2.3 hours. Results from repeated dosing suggested that the distribution of 2,4,6-tribromophenol (or metabolites) in the body is limited to the plasma or extracellular fluid. Forty-eight hours after dosing, the total excretion of 14C ranged from 50.3 to 91.2% of the dose in the urine and from 3.9 to 13.7% in the feces.

Tribromophenols have not been evaluated for carcinogenic potential. Based on the lack of data available, tribromophenols can be assigned to EPA weight-of-evidence Group D: not classifiable as to human carcinogenicity (U.S. EPA, 1986).

No occupational guidelines or recommendations were located for tribromophenols (ACGIH, 1991; NIOSH 1990; OSHA, 1989).

In conclusion, data were available for only 2,4,6-tribromophenol. In a 3-week repeated inhalation study in rats (IBT, 1977), a concentration of 100 mg/m' of 2,4,6-tribromophenol produced overt clinical signs of toxicity. An exposure level of 1000 mg/m' caused gross and histological alterations in the liver and kidneys, and possibly death in 2/10 rats. Respiratory effects were not evident at either exposure level. This study is considered inadequate for derivation of an RfC because of the short duration and because a NOAEL could not be established.

REFERENCES:

ACGIH (American Conference of Governmental Industrial Hygienists). 1991. Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices. ACGIH, Cincinnati, OH.

Deichamnn, W.B. and M.L. Keplinger. 1981. Phenols and phenolic compounds. In: Patty's Industrial Hygiene and Toxicology, Vol IIA, 3rd ed., G.D. Clayton and F.E. Clayton, Eds. John Wiley and Sons, New York. pp. 2567-2627.

Dow Chemical Company (1946). Preliminary tests on the toxicity of 2,4,6-tribromophenol. Fiche No. OTS0522208.


800068

IBT (Industrial Bio-Test Laboratories). 1976. Acute dust inhalation toxicity study in rats. Sponsored by Great Lakes Chemical Corporation. Fiche No. OTS0523305.

IBT (Industrial Bio-Test Laboratories). 1977. 21-Day subacute dust inhalation toxicity study with 2,4,6-tribromophenol in albino rats. Sponsored by Great Lakes Chemical Corporation. Fiche No. OTS0523305.

IRDC (International Research Development Corporation). 1974a. Acute inhalation toxicity in the albino rat. Sponsored by Great Lakes Chemical Corporation. Fiche No.' OTS0523297.

IRDC (International Research Development Corporation). 1974b. Acute oral toxicity (LDjo) study in albino rats. Sponsored by Great Lakes Chemical Corporation. Fiche No. OTS0523299.

IRDC (International Research Development Corporation). 1978. Pilot teratology study in rats. Sponsored by Great Lakes Chemical Corporation. Fiche No. OTS0523308.

NIOSH (National Institute for Occupational Safety and Health). 1990. NIOSH Pocket Guide to Chemical Hazards. U.S. Department of Health and Human Services. DHHS (NIOSH) Publication No. 90-117.

OSHA (Occupational Safety and Health Administration). 1989. 29CFR 1910. Air Contaminants; Final Rule. Federal Register. 54(12).

U.S. EPA. 1986. Guidelines for Carcinogen Risk Assessment. Federal Register. 51(185): 33992-34003.

Velsicol Chemical Corporation. 1977. Pharmacokinetic study of 2,4,6-tribromophenol in rats. Sponsored by Great Lakes Chemical Corporation. Fiche No. OTS0523314.


800069

1,3,5-TRIMETHYLBENZENE (CASRN 108-67-8)

INTRODUCTION

This chemical is not the subject of an ATSDR toxicological profile and is not listed on IRIS (U.S. EPA, 1993a) or the RfD/RfC and CRAVE Status Reports (U.S. EPA, 1993b,c). Trimethylbenzenes are listed in the HEAST (U.S. EPA, 1992) as having inadequate data for quantitative risk assessment. The U.S. EPA prepared a Health Effects Assessment document on trimethylbenzenes (U.S. EPA, 1987a) and a Drinking Water Health Advisory Document for 1,3,5-trimethylbenzene (U.S. EPA, 1987b). Literature searches of TOXLINE (1986-1991) and TSCATS were also conducted.

The U.S. EPA (1987a) determined that there was insufficient information for the derivation of a chronic oral RfD for 1,3,5-trimethylbenzene. No oral studies were cited in the HEA document (U.S. EPA, 1987a), but two acute oral studies of 1,3,5-trimethylbenzene (Pyykko, 1980; Ungvary et al., 1981) were cited in the HA document (U.S. EPA, 1987b). No developmental, or reproduction studies were discussed in the HEA or HA documents (U.S. EPA, 1987a,b).

Pyylcko (1980) administered 10 mmol/kg/day (1202 mg/kg/day) 1,3,5-trimethylbenzene in corn oil to 8-10 rats for 3 days. No effects on survival or behavior were noted in the treated or control groups. 1,3,5-Trimethylbenzene treatment resulted in a significant reduction in body weight, as compared to controls. Weight loss, however, resulting from fasting periods during the experiment, was noted in both the treated and control groups. Treatment with 1,3,5-trimethylbenzene also resulted in significant increases in liver weight and in the cytochrome bj content of the liver and kidney. Increases in the activity of various microsomal enzymes in the liver, kidneys and lungs were also reported in the treated animals. The LOAEL of 1202 mg/kg/day was used as the basis of a provisional 1-day HA of 12 mg/L for a 10-kg child. An identical 1-day HA was derived from an acute inhalation study in rats (NOAEL of 1500 mg/m' for 6 hours) (Wiglusz et al., 1975a,b).

Ungvary et al. (1981) administered 13.7 mmol/kg/day (1647 mg/kg/day) 1,3,5-trimethylbenzene orally to rats for 4 days. An increase in hepatic cytochrome P450 and cytochrome bj were reported in the treated animals. Other endpoints of toxicity were not evaluated.

Information regarding the absorption of inhaled 1,3,5-trimethylbenzene were not located. As reported in the HEA (U.S. EPA, 1987a), 93.7% of a single oral dose of 1,3,5-


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trimethylbenzene was excreted as metabolites in the urine of male Wistar rats over a period of 3 days. In New Zealand White rabbits, 78.7% of a single oral dose of 1,3,5-trimethylbenzene was excreted in the urine over a period of 10 days (Laham and Potvin, 1989). In both studies, it is possible that more of the given dose was absorbed from the gastrointestinal tract in that only urinary excretion was monitored.

Data regarding the toxicity of trimethylbenzene are limited to one occupational study (Battig et al., 1958) and several subchronic inhalation studies in rats (Battig et al., 1958; Bernshtein, 1972; Wiglusz et al., 1975a,b). Of all of these studies, only Wiglusz et al. (1975a) was available for review; details of the others were obtained from secondary sources. Based on the available data, U.S. EPA (1987b) determined that the data were inadequate for derivation of a subchronic or chronic inhalation RfC. A provisional chronic inhalation RfC, with very low confidence, can be derived based on the occupational study by Battig et al. (1958). ACGIH (1986) recommended a TLV-TWA of 25 ppm based on this occupational study.

U.S. EPA (1987a,b,c) reported the results of the occupational study of Battig et al. (1958). In this study, an increase in toxic symptoms were found in 27 workers exposed for several years to "Fleet-X-DV-99", as compared to 10 unexposed controls (Battig et al., 1958). Clinical findings in the workers included central nervous system effects (vertigo, headaches, drowsiness), chronic, asthma-like bronchitis (classification criteria not reported), hyperchromic anemia (<4.5 million erythrocytes/mm*) and disturbances in blood clotting. Fleet-X-DV-99 is a solvent containing 97.5% aromatic hydrocarbons (>30% 1,3,5-trimethylbenzene and >50% 1,2,4-trimethylbenzene) and 2.5% of paraffinic and naphthenic hydrocarbons. Rough quantitation of the exposure levels reported concentrations of hydrocarbon vapor ranging from 10-60 ppm.

U.S. EPA (1987a,b,c) reported the results of several subchronic inhalation studies in rats. Battig et al. (1958) exposed rats to 1700 ppm (n=8) Fleet-X-DV-99 solvent for 4 months or 500 ppm (number not specified) for 70 days (5 days/week, 8 hours/day). Four of the 8 rats exposed to 1700 ppm died within 2 weeks of exposure, while none of the animals in the 500 ppm died. Histological changes in the kidneys, liver, spleen and lung were reported in the rats exposed to 1700 ppm. Alterations in differential WBC counts (increase in the percentage of segmented neutrophilic granulocytes and a decrease in the percentage of lymphocytes) were reported at ^500 ppm. Similar alterations in differential WBC counts as well as a significant elevation of SGOT levels were found in rats (n-6) exposed to 3.0 mg/L (610 ppm) 1,2,5-trimethylbenzene 6 hours/day, 6 days/week for 5 weeks (Wiglusz et al., 1975a,b). No exposure-related effects on


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hemoglobin levels and erythrocyte or leukocyte counts, or on the activity of SGPT, glutamate dehydrogenase or ornithine carbamyl transferase were found in the Wiglusz et al. (1975a,b) studies. Bernshtein (1972) exposed rats to 1 mg/L (200 ppm) of a mixture of trimethylbenzenes 4 hours/day for 6 months. An inhibition of phagocytic activity of the leukocytes was reported. This study was summarized by Sandmeyer (1981) and further experimental details were not provided.

A provisional chronic inhalation RfC of 2 x 10"̂ mg/m' for an isomeric mixture of trimethylbenzene can be derived based on the effects reported in exposed workers (Battig et al., 1958). The LOAEL of 10 ppm (49 mg/m', assuming the solvent content to be exclusively trimethylbenzenes) is adjusted for occupational exposure (10 m'/20 m' x 5 days/7 days) resulting in a LOAELHEC of 17.5 mg/m'. Application of an uncertainty factor of 1000 (10 for the use of a LOAEL, 10 to extrapolate from subchronic to chronic exposure and 10 to protect sensitive individuals), yields a provisional chronic inhalation RfC of 2 x 10'̂ mg/m' for trimethylbenzene.

We have derived a provisional oral RfD of 6 x 10"* mg/kg/day for 1,2,4-trimethylbenzene by extrapolating from the inhalation RfC for the mixture of 1,2,4- and 1,3,5-trimethylbenzene. A similar approach is used to derive a provisional oral RfD for 1,3,5-trimethyIbenzene.

An equivalent oral dose of 4.3 mg/kg/day for 1,3,5-trimethylbenzene can similarly be derived from the inhalation LOAEL in Battig et al. (1958) by using absorption factors of 0.80 for inhalation exposure and 0.937 for oral exposure. Because information was not available regarding the absorption of inhaled 1,3,5-trimethylbenzene, the value of 0.80 for 1,2,4-trimethylbenzene absorption was used. For oral absorption, two values were available for 1,3,5-trimethylbenzene: The value of 0.937 for rats (U.S. EPA, 1987a) was used instead of the value of 0.787 for rabbits (Laham and Potvin, 1989) because use of the rat data resulted in a more conservative oral dose (4.3 mg/kg/day using the rat data and 5.1 mg/kg/day using the rabbit data). The equivalent oral dose is calculated as follows:

LOAELAD, = 49 mg/m' X (10m'/20m') X (5day/7day)

= 17.5 mg/m'

Inhaled dose = 17.5 mg/m' X 20 m'/day X l/70kg

= 5.0 mg/kg/day


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Oral dose = 5.0 mg/kg/day X (o.80/0.937)

= 4.3 mg/kg/day

Application of an uncertainty factor of 10,000 (10 for use of a LOAEL, 10 to extrapolate less than lifetime exposure, 10 for an inadequate database, and 10 to protect sensitive individuals) to the ec[uivalent oral LOAEL yields a provisional oral RfD of 4 x 10"* mg/kg/day. As with the provisional oral RfD for 1,2,4-trimethylbenzene, confidence in the provisional oral RfD for 1,3,5-trimethylbenzene is low.

CARCINOGENICITY

No information on the carcinogenicity of 1,3,5-trimethylbenzene was located in the HEA (U.S. EPA, 1987a), the HA (U.S. EPA, 1987b) or on the updated literature searches. Also, lARC has not reviewed the carcinogenicity data on 1,3,5-trimethylbenzene .

WEIGHT OF EVIDENCE CLASSIFICATION

Because no carcinogenicity data were located, U.S. EPA (1987a) placed 1,3,5-trimethylbenzene into weight-of-evidence classification group D.

DERIVATION OF ORAL SLOPE FACTOR

According to EPA (1986) guidelines, classification of a chemical in weight-of-evidence Group D precludes quantitative risk assessment.

REFERENCES:

ACGIH (American Conference of Governmental Industrial Hygienists). 1986. Documentation of the Threshold Limit Values and Biological Exposure Indices. Fifth Edition. ACGIH, Cincinnati, OH. p. 608.

Battig, K., E. Grandjean, L. Rossi and J. Rickenbacher. 1958. Toxikologische Untersuchungen uber Trimethylbenzol. Arch. Gewerbepath. U. Gewerbehyg. 16:555 (Cited in U.S. EPA, 1987a,b,c).


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Bernshtein, L.M. 1972. No title provided. Vopr. Gig. TR. Profzabol. Mater. Nauch. Konf. Vol. 53 (Cited in Sandmeyer, 1981).

Laham, S, and M. Potvin. 1989. Identification and determination of mesitylene acidic metabolites in rabbit urine. Toxicol. Environ. Chem. 24:57-69.

Mobil Research and Development Corporation. 1982. Bioavailability, bioaccumulation and elimination of 1,2,4-trimethylbenzene in the rat. OTS0206420.

Pyy]cko, K. 1980. Effects of methylbenzenes on microsomal enzymes in rat liver, kidney and lung. Biochem. Biophys. Acta. 633:1-9. (Cited in U.S. EPA, 1987b).

Sandmeyer, E.E. 1981. Aliphatic hydrocarbons. In: Patty's Industrial Hygiene and toxicology. Vol. 3, G.D. Clayton and F.E. Clayton, Ed. John Wiley and Sons, Inc., New York. p. 3300-3302.

Ungvary, G., S. Szeberenyl and E. Tatrai. 1981. The effect of benzene and its methyl derivatives on the MFO system. Ind. Environ. Xenobiotics, Proc. Int. Conf. p. 285-292. (CA 97:1941636) (Cited in U.S. EPA, 1987b).

U.S. EPA. 1986. Guidelines for Carcinogen Risk Assessment. Federal Register. 51(185): 33992-34003.

U.S. EPA. 1987a. Health Effects Assessment for Trimethylbenzenes. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Solid Waste and Emergency Response, Washington, D.C. ECAO-CIN-H095.

U.S. EPA. 1987b. Drinking Water Health Advisory for 1,3,5-Trimethylbenzene. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Drinking Water, Washington, D.C. ECA0-CIN-W030.

U.S. EPA. 1987c. Drinking Water Health Advisory for 1,2,4-TrimethyIbenzene. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Drinking Water, Washington, D.C. ECA0-CIN-W029.



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U.S. EPA. 1993a. Integrated Risk Information System (IRIS). Online. Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH.

U.S. EPA. 1993b. Monthly Status Report of RfD/RfC Work Group (as of 05/01/93). Office of Research and Development. Environmental Criteria and Assessment Office, Cincinnati, OH.

U.S. EPA. 1993c. Monthly Status Report of CRAVE Work Group (as of 05/01/93). Office of Research and Development. Environmental Criteria and Assessment Office, Cincinnati, OH.

Wiglusz, R., M. Kienitz, G. Delag, E. Galuszko and P. Mikulski. 1975a. Peripheral blood of mesitylene vapor treated rats. Bull. Inst. Marit. Trop. Med. Gdynia. 26(3-4): 315-322. (Cited in U.S. EPA, 1987b).

Wiglusz, R., G. Delag and P. Mikulski. 1975b. Serum enzymes activity of mesitylene vapor treated rats. Bull. Inst. Marit. Trop. Med. Gdynia. 26(3-4): 303-313. (CA 85:41718p). (Cited in U.S. EPA, 1987b).

For internal use o n l y . DRAFT - Do n o t c i t e o r q u o t e .

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BENZOTHIAZOLE, 2(3H)-BENZOTHIAZOLONE, 2-ANILINOBENZOTHIAZOLE

PROVISIONAL ORAL RfDs AND SLOPE FACTORS

Few data were located regarding the health effects of these chemicals. Oral LD50 values for benzothiazole were 375-493 mg/kg in male rats (Lorke, 1983; Mayhew and Muni, 1987). Benzthiazole was not mutagenic in Salmonella typhimurium (Sano and Korte, 1986) and 2(3H)-benzothiazolone (2-hydroxybenzothiazole) was not active in assays for mutagenicity in bacteria or unscheduled DNA synthesis in primary cultures of adult rats hepatocytes (Probst and Hill, 1980). Although it is not possible to derive RfDs or slope factors for these chemicals directly, it was considered that these values might be obtained by analogy to 2-mercaptobenzothiazole (MBT). However, pharmacokinetic data on MBT (Colucci and Buyske, 1965; El Dareer et al., 1989; Larsen et al., 1988; Nagamatsu et al., 1979) do not suggest that transformation to any of these chemicals would occur, and no obvious pathways for transformation of these compounds to MBT were identified. In addition, there is some evidence that the sulfur-containing mercapto group is involved in MBT carcinogenicity (NTP, 1988) and other aspects of MBT toxicity (Feinman, 1987). Therefore, RfD and slope factor values were not derived for these chemicals.

REFERENCES;

Colucci, D.F. and D.A. Buyske. 1965. The Biotransformation of a Sulfonamide to a Mercaptan and to Mercapturic Acid and Glucuronide Conjugates. Biochem. Pharmacol. 14: 457-466.

El Dareer, S.M., J.R. Kalin, K.F. Tillery, D.L. Hill, J.W. Barnett, Jr. 1989. Disposition of 2 Mercaptobenzothiazole and 2 Mercaptobenzothiazole Disulfide in Rats Dosed Intravenously, Orally and Topically and in Guinea-Pigs Dosed Topically. J. Toxicol. Environ. Health. 27(1): 65-84.

Feinman, S.E. 1987. Sensitivity to Rubber Chemicals. NIOSH. #00179484.

Larsen, G.L., J.E. Bakke, V.J. Fell and J.K Huwe. 1988. In Vitro Metabolism of the methylthio group of 2-methylthiobenzothiazole by Rat Liver. Xenobiotica. 18(3): 313-322.

Lorke, D. 1983. A New Approach to Practical Acute Toxicity Testing. Arch. Toxicol. 54(4): 275-288.


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Mayhew, D.A., and I.A. Muni. 1987. Dermal, Eye and Oral Toxicological Evaluations. Phase II. Acute Oral LD Determinations of Benzothiazole, Dithiane, and Oxathiane. Govt. Reports Announcements & Index (GRA&I). Issue 2.

Nagamatsu, K., Y. Kido, G. Urakubo, Y. Aida, Y. Ikeda, Y. Suzuki. 1979. Absorption, Distribution, Excretion and Metabolism of 2-Mercaptobenzothiazole in Guinea Pig. Eisei Kagaku. 25: 59-65. (Cited in NTP, 1988.)

NTP (National Toxicology Program) Technical Report. 1988. Toxicology and Carcinogenesis Studies of 2-Mercaptobenzothiazole. (CAS No. 149-30-4) in F344/N Rats and B6C3F1 Mice. Natl Toxicol. Program Tech. Rep. Ser., 332:

Probst, G.S. and L.E. Hill. 1980. Chemically-Induced Dna Repair Synthesis in Primary Rat Hepatocytes: A Correclation with Bacterial Mutagenicity. Ann. N.Y. Acad. Sci. 349:405-406.

Sano, S.K. and D.W. Korte, Jr. 1986. Mutagenic Potential of Benzothiazole. Govt. Reports Announcements & Index (GRA&I). Issue 12.


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