United States Environmental Protection 1=1 m m Agency EPA/690/R-12/035F Final 11-29-2012 Provisional Peer-Reviewed Toxicity Values for 1,1,2-Trichloropropane (CASRN 598-77-6) Superfund Health Risk Technical Support Center National Center for Environmental Assessment Office of Research and Development U.S. Environmental Protection Agency Cincinnati, OH 45268 ------- AUTHORS, CONTRIBUTORS, AND REVIEWERS CHEMICAL MANAGER Carrie R. Fleming, PhD National Center for Environmental Assessment, Cincinnati, OH CONTRIBUTORS Custodio V. Muianga, PhD, MPH National Center for Environmental Assessment, Cincinnati, OH Jon Reid, PhD, DABT National Center for Environmental Assessment, Cincinnati, OH DRAFT DOCUMENT PREPARED BY ICF International 9300 Lee Highway Fairfax, VA 22031 PRIMARY INTERNAL REVIEWERS Zheng (Jenny) Li, PhD, DABT National Center for Environmental Assessment, Washington, DC Anuradha Mudipalli, MSc, PhD National Center for Environmental Assessment, Research Triangle Park, NC This document was externally peer reviewed under contract to Eastern Research Group, Inc. 110 Hartwell Avenue Lexington, MA 02421-3136 Questions regarding the contents of this document may be directed to the U.S. EPA Office of Research and Development's National Center for Environmental Assessment, Superfund Health Risk Technical Support Center (513-569-7300). li 1,1,2-Tri chl oroprop ane ------- TABLE OF CONTENTS COMMONLY USED ABBREVIATIONS iv BACKGROUND 1 DISCLAIMERS 1 QUESTIONS REGARDING PPRTVs 1 INTRODUCTION 2 REVIEW OF POTENTIALLY RELEVANT DATA (CANCER AND NONCANCER) 3 HUMAN STUDIES 6 Oral Exposures 6 Inhalation Exposures 6 ANIMAL STUDIES 6 Oral Exposures 6 Short-Term Studies 6 Subchronic Studies 6 Chronic Studies 7 Developmental Studies 7 Reproductive Studies 7 Other Studies 7 Inhalation Exposures 8 OTHER DATA (ACUTE STUDIES, OTHER EXAMINATIONS) 8 Tests Evaluating Carcinogenicity, Genotoxicity, and/or Mutagenicity 10 Acute Studies 10 Metabolism/Toxicokinetic Studies 11 MO A/Mechanistic Studies 11 Immunotoxicity 11 Neurotoxicity 11 Other 11 DERIVATION 01 PROVISIONAL VALUES 11 DERIVATION OF ORAL REFERENCE DOSES 13 Derivation of Subchronic Provisional RfD (Subchronic p-RfD) 13 Derivation of Chronic Provisional RfD (Chronic p-RfD) 15 DERIVATION OF INHALATION REFERENCE CONCENTRATIONS 15 Derivation of Subchronic Provisional RfC (Subchronic p-RfC) 15 Derivation of Chronic Provisional RfC (Chronic p-RfC) 15 CANCER WEIGHT-OF-EVIDENCE DESCRIPTOR 15 DERIVATION OF PROVISIONAL CANCER POTENCY VALUES 16 Derivation of Provisional Oral Slope Factor (p-OSF) 16 Derivation of Provisional Inhalation Unit Risk (p-IUR) 16 APPENDIX A. PROVISIONAL SCREENING VALUES 17 APPENDIX B. DATA TABLES 18 APPENDIX C. BMD OUTPUTS 19 APPENDIX D. REFERENCES 20 in 1,1,2-Tri chl oroprop ane ------- COMMONLY USED ABBREVIATIONS BMC benchmark concentration BMCL benchmark concentration lower bound 95% confidence interval BMD benchmark dose BMDL benchmark dose lower bound 95% confidence interval HEC human equivalent concentration HED human equivalent dose IUR inhalation unit risk LOAEL lowest-observed-adverse-effect level LOAELadj LOAEL adjusted to continuous exposure duration LOAELhec LOAEL adjusted for dosimetric differences across species to a human NOAEL no-ob served-adverse-effect level NOAELadj NOAEL adjusted to continuous exposure duration NOAELhec NOAEL adjusted for dosimetric differences across species to a human NOEL no-ob served-effect level OSF oral slope factor p-IUR provisional inhalation unit risk POD point of departure p-OSF provisional oral slope factor p-RfC provisional reference concentration (inhalation) p-RfD provisional reference dose (oral) RfC reference concentration (inhalation) RfD reference dose (oral) UF uncertainty factor UFa animal-to-human uncertainty factor UFC composite uncertainty factor UFd incomplete-to-complete database uncertainty factor UFh interhuman uncertainty factor UFl LOAEL-to-NOAEL uncertainty factor UFS subchronic-to-chronic uncertainty factor WOE weight of evidence iv 1,1,2-Tri chl oroprop ane ------- FINAL 11-29-2012 PROVISIONAL PEER-REVIEWED TOXICITY VALUES FOR 1,1,2-TRICHLOROPROPANE (CASRN 598-77-6) BACKGROUND A Provisional Peer-Reviewed Toxicity Value (PPRTV) is defined as a toxicity value derived for use in the Superfund Program. PPRTVs are derived after a review of the relevant scientific literature using established Agency guidance on human health toxicity value derivations. All PPRTV assessments receive internal review by a standing panel of National Center for Environment Assessment (NCEA) scientists and an independent external peer review by three scientific experts. The purpose of this document is to provide support for the hazard and dose-response assessment pertaining to chronic and subchronic exposures to substances of concern, to present the major conclusions reached in the hazard identification and derivation of the PPRTVs, and to characterize the overall confidence in these conclusions and toxicity values. It is not intended to be a comprehensive treatise on the chemical or toxicological nature of this substance. The PPRTV review process provides needed toxicity values in a quick turnaround timeframe while maintaining scientific quality. PPRTV assessments are updated approximately on a 5-year cycle for new data or methodologies that might impact the toxicity values or characterization of potential for adverse human health effects and are revised as appropriate. It is important to utilize the PPRTV database flittp://hhpprtv.ornl.gov) to obtain the current information available. When a final Integrated Risk Information System (IRIS) assessment is made publicly available on the Internet (http://www.epa.gov/iris). the respective PPRTVs are removed from the database. DISCLAIMERS The PPRTV document provides toxicity values and information about the adverse effects of the chemical and the evidence on which the value is based, including the strengths and limitations of the data. All users are advised to review the information provided in this document to ensure that the PPRTV used is appropriate for the types of exposures and circumstances at the site in question and the risk management decision that would be supported by the risk assessment. Other U.S. Environmental Protection Agency (EPA) programs or external parties who may choose to use PPRTVs are advised that Superfund resources will not generally be used to respond to challenges, if any, of PPRTVs used in a context outside of the Superfund program. QUESTIONS REGARDING PPRTVs Questions regarding the contents and appropriate use of this PPRTV assessment should be directed to the EPA Office of Research and Development's National Center for Environmental Assessment, Superfund Health Risk Technical Support Center (513-569-7300). 1 1,1,2-Tri chl oroprop ane ------- FINAL 11-29-2012 INTRODUCTION 1,1,2-Trichloropropane, CAS No. 598-77-6, is a chlorinated hydrocarbon that is a liquid at room temperature. 1,1,2-Trichloropropane is one of the trichloropropane (TCP) isomers. TCPs are by-products of synthetic processes used to manufacturer propylene chlorohydrins and other propylene derivatives. The molecular formula is C3H5CI3, and the structure is shown in Figure 1. Table 1 provides a list of physicochemical properties. CI CI Figure 1. Chemical Structure of l,l?2-Trichloropropane Table 1. Physicochemical Properties of l,l?2-Trichloropropane (CASRN 598-77-6)a Property (unit) Value Boiling point (°C at 760 mmHg) 132 Melting point (°C) No data Density (g/mL at 25°C) 1.305 Vapor pressure (mmHg at 25°C) 3.1 pH (unitless) No data Solubility in water (mg/L at 25°C) 1900 Relative vapor density (air =1) No data Molecular weight (g/mol) 147.43 aChemID (2010). The United States Environmental Protection Agency (U.S. EPA) Integrated Risk Information System (IRIS) database (U.S. EPA, 1988a) provides an oral reference dose (RfD) of o 5x10 mg/kg-day based on an oral subchronic study (Villeneuve et al., 1985) in rats. IRIS does not report a chronic inhalation reference concentration (RfC) or cancer assessment (U.S. EPA, 1988a). No RfD, RfC, or cancer assessment for 1,1,2-trichloropropane is included on the Drinking Water Standards and Health Advisories List (U.S. EPA, 2009a). A subchronic o RfD value of 5 x 10 mg/kg-day is included in the Health Effects Assessment Summary Tables (HEAST) (U.S. EPA, 2011), which was derived from the IRIS RfD, but no RfC is derived. The Chemical Assessments and Related Activities (CARA) list includes a Health and Environmental 2 1,1,2-Tri chl oroprop ane ------- FINAL 11-29-2012 Effects Profile (HEEP) for trichloropropanes that, due to inadequate noncancer data, derives no toxicity value for 1,1,2-trichloropropane (U.S. EPA, 1994). The toxicity of 1,1,2-trichloropropane has not been reviewed by the Agency for Toxic Substances and Disease Registry (ATSDR, 2011) or the World Health Organization (WHO, 2011). The California Environmental Protection Agency (CalEPA, 2008, 2009) has not derived toxicity values for exposure to 1,1,2-trichloropropane. No occupational exposure limits for 1,1,2-trichloropropane have been recommended or derived by the American Conference of Governmental Industrial Hygienists (ACGIH, 2011), the National Institute of Occupational Safety and Health (NIOSH, 2010), or the Occupational Safety and Health Administration (OSHA, 2006). The HEAST (U.S. EPA, 2011) does not report any cancer toxicity values or an oral slope factor (OSF) for 1,1,2-trichloropropane. The International Agency for Research on Cancer (IARC, 2011) has not reviewed the carcinogenic potential of 1,1,2-trichloropropane. 1,1,2-Trichloropropane is not included in the 12th Report on Carcinogens (NTP, 2011). CalEPA (2008) has not derived a quantitative estimate of carcinogenic potential for 1,1,2-trichloropropane. Literature searches were conducted on sources published from 1900 through August 3, 2011 for studies relevant to the derivation of provisional toxicity values for 1,1,2-trichloropropane, CAS No. 598-77-6. Searches were conducted using U.S. EPA's Health and Environmental Research Online (HERO) database of scientific literature. HERO searches the following databases: AGRICOLA; American Chemical Society; BioOne; Cochrane Library; DOE: Energy Information Administration, Information Bridge, and Energy Citations Database; EBSCO: Academic Search Complete; GeoRef Preview; GPO: Government Printing Office; Informaworld; IngentaConnect; J-STAGE: Japan Science & Technology; JSTOR: Mathematics & Statistics and Life Sciences; NSCEP/NEPIS (EPA publications available through the National Service Center for Environmental Publications [NSCEP] and National Environmental Publications Internet Site [NEPIS] database); PubMed: MEDLINE and CANCERLIT databases; SAGE; Science Direct; Scirus; Scitopia; SpringerLink; TOXNET (Toxicology Data Network): ANEUPL, CCRIS, ChemlDplus, CIS, CRISP, DART, EMIC, EPIDEM, ETICBACK, FEDRIP, GENE-TOX, HAPAB, HEEP, HMTC, HSDB, IRIS, ITER, LactMed, Multi-Database Search, NIOSH, NTIS, PESTAB, PPBIB, RISKLINE, TRI, and TSCATS; Virtual Health Library; Web of Science (searches Current Content database among others); World Health Organization; and Worldwide Science. The following databases outside of HERO were searched for relevant health information: ACGIH, ATSDR, CalEPA, U.S. EPA IRIS, U.S. EPA HEAST, U.S. EPA HEEP, U.S. EPA OW, U.S. EPA TSCATS/TSCATS2, NIOSH, NTP, OSHA, and RTECS. REVIEW OF POTENTIALLY RELEVANT DATA (CANCER AND NONCANCER) Table 2 provides an overview of the relevant database for 1,1,2-trichloropropane and includes all potentially relevant repeated short-term-, subchronic-, and chronic-duration studies. Principal studies are identified. The phrase, "statistical significance" used throughout the document, indicates ap-walue of <0.05. 3 1,1,2-Tri chl oroprop ane ------- FINAL 11-29-2012 Table 2. Summary of Potentially Relevant Data for 1,1,2-Trichloropropane (CASRN 598-77-6) Category Number Of Male/Female, Strain, Species, Study Type, Study Duration Dosimetry3 Critical Effects NO A EL' BMDL/ BMCLa LOAEL' Reference (Comments) Notesb Human 1. Oral (mg/kg-d) Subchronic No data Chronic No data Developmental No data Reproductive No data Carcinogenicity No data 2. Inhalation (mg/m3) Subchronic No data Chronic No data Developmental No data Reproductive No data Carcinogenicity No data Animal 1. Oral (mg/kg-d)a Subchronic 10/10, Sprague-Dawley rat, drinking water, 7 d/wk, 90 d Males: 0,0.14, 1.4,14, and 139 (Adjusted) Females: 0, 0.15,1.5,15, and 152 (Adjusted) Males: mild lesions in liver, kidney, and thyroid at 139 mg/kg-d Females: mild lesions in liver, kidney, and thyroid at 152 mg/kg-d 14 NDr 139 Villeneuve et al. (1985) IRIS, PS, PR Chronic No data Developmental No data 4 1,1,2-Tri chl oroprop ane ------- FINAL 11-29-2012 Table 2. Summary of Potentially Relevant Data for 1,1,2-Trichloropropane (CASRN 598-77-6) Category Number Of Male/Female, Strain, Species, Study Type, Study Duration Dosimetry3 Critical Effects NOAEL3 BMDL/ BMCL3 LOAEL3 Reference (Comments) Notesb Reproductive No data Carcinogenicity No data 2. Inhalation (mg/m3) Subchronic No data Chronic No data Developmental No data Reproductive No data Carcinogenicity No data ""Dosimetry: NOAEL and LOAEL values from long-term exposure (4 weeks and longer) are converted from a discontinuous to a continuous (weekly) exposure, e.g., NOAELadj = NOAEL x Drinking Water per Day x (1 -f- Body Weight) x (Days Dosed ^ Total Days) unless otherwise indicated. bIRIS = Utilized by IRIS, date of last update; NA = not applicable; PS = principal study, PR = Peer Reviewed. NDr = Not determinable. 5 1,1,2-Tri chl oroprop ane ------- FINAL 11-29-2012 HUMAN STUDIES Oral Exposures The effects of oral exposure of humans to 1,1,2-trichloropropane have not been evaluated in sub chronic-duration, chronic-duration, developmental, reproductive, or carcinogenicity studies. Inhalation Exposures The effects of inhalation exposure of humans to 1,1,2-trichloropropane have not been evaluated in subchronic-duration, chronic-duration, developmental, reproductive, or carcinogenicity studies. ANIMAL STUDIES Oral Exposures The effects of oral exposure of animals to 1,1,2-trichloropropane have been evaluated in one subchronic study (Villeneuve et al., 1985). No short-term, chronic, developmental, reproductive, or other studies were identified. Short-Term Studies No short-term studies were identified. Subchronic Studies The study by Villeneuve et al. (1985) is selected as the principal study for the derivation of the subchronic p-RfD. In a peer-reviewed study, Villeneuve et al. (1985) administered 1-, 10-, 100-, or 1000-mg/L 1,1,2-trichloropropane (Columbia Organic Chemicals, Columbia, SC; purity >99%; solubilized in 0.5% Emulphor) in drinking water to young adult Sprague-Dawley rats (10/sex/treatment) for 90 days. Additionally, two control groups were used, one using tap water alone, while the other control group was given tap water with 0.5% Emulphor. Because body weights and water intake were not reported for 1,1,2-trichloropropane-dosed animals, adjusted daily doses are calculated as 0, 0.14, 1.4, 14, and 139 mg/kg-day for males and 0, 0.15, 1.5, 15, and 152 mg/kg-day for females using default values for body weight (0.267 and 0.204 kg for males and females, respectively) and drinking water consumption rate (0.037 and 0.031 L/day for males and females, respectively) (U.S. EPA, 1988b). Animals weighed between 60-70 g at study initiation. Food and water were provided ad libitum. Animals were examined for clinical signs of toxicity daily. Body-weight changes and water intake were also monitored throughout the study. GLP compliance was not reported by the study authors. At the end of treatment, animals were sacrificed, and the brain, liver, kidney, heart, and spleen were weighed and histologically examined (Villeneuve et al., 1985). Hematological analysis (hemoglobin, packed cell volume, mean corpuscular hemoglobin, mean corpuscular volume, mean corpuscular hemoglobin concentration, total erythrocytes, and total and differential counts of leukocytes) was conducted following sacrifice. Serum biochemical analysis conducted following sacrifice included measurement of sodium, potassium, inorganic phosphorus, total protein, calcium, cholesterol, glutamic oxaloacetic transaminase, total bilirubin, alkaline phosphatase, glucose, uric acid, lactate dehydrogenase, and serum sorbitol dehydrogenase activity. Hepatic mixed function oxidase activities (aniline hydroxylase, aminopyrine demethylase, and ethoxyresorufin deethylase) were measured as indicators of liver function. The study authors performed statistical analysis using one-way analysis of variance 6 1,1,2-Tri chl oroprop ane ------- FINAL 11-29-2012 followed by Duncan's Multiple Range Test to determine significant differences (p < 0.05) between treated and control groups. One female from the 15-mg/kg-day dose group and one male from the 139-mg/kg-day group died during the study, but the cause of death was not determined (Villeneuve et al., 1985). However, the study authors did not consider these deaths treatment-related. There were no statistically significant differences in body-weight gain, water intake, or absolute organ weights in any of the treatment or control groups (quantitative data not provided). Relative liver weight was statistically significantly increased in males treated with 139 mg/kg-day (reportedly, 4% of body weight compared to 3.7% in both the vehicle and water controls; values for the other dose groups are not provided). In high-dose females (152 mg/kg-day), serum cholesterol levels were statistically significantly increased compared to both vehicle (135%) and water controls (139%) (96 nmol HCHO/mg protein/hour compared to 71 in the vehicle and 69 in the water controls; values for the other dose groups were not provided). The study authors reported no other dose- related effects on clinical, organ weight, biochemical, hematological, or hepatic mixed function oxidase activities (quantitative data not provided). Villeneuve et al. (1985) described histological effects in the liver, kidneys, and thyroid of treated animals. High-dose males (139 mg/kg-day) and females (152 mg/kg-day) exhibited changes in the liver described as "mild but significant" by the study authors. These changes included anisokaryosis, accentuated zonation, and occasional fatty vacuolation (quantitative data not provided). Mild changes in kidney histopathology were also noted at the high dose in both sexes of rats and included eosinophilic inclusions, pyknosis, nuclear displacement, fine glomerular adhesions, interstitial reactions, and histologic proteinuria (quantitative data not provided). Mild thyroid changes in the high-dose groups of both sexes included angular collapse of some follicles, reduction in colloid density, and increased epithelial height (quantitative data not provided). The study authors reported that these effects were more prevalent and more severe in treated males as compared to treated females (quantitative data not provided). No other histological effects were described by the study authors. Based on histological lesions reported in the liver, kidneys, and thyroid of high-dose males and females, with the males acknowledged by the study authors as the more sensitive sex, a LOAEL of 139 mg/kg-day is identified, with a corresponding NOAEL of 14 mg/kg-day. Chronic Studies No chronic studies were identified. Developmental Studies No developmental toxicity studies were identified in the literature. Reproductive Studies No reproductive toxicity studies were identified. Other Studies No other toxicity studies on 1,1,2-trichloropropane were identified. 7 1,1,2-Tri chl oroprop ane ------- FINAL 11-29-2012 Inhalation Exposures No inhalation exposure studies were identified. OTHER DATA (ACUTE STUDIES, OTHER EXAMINATIONS) No studies were identified that examined the genotoxic potential of 1,1,2-trichloropropane in vitro or in vivo. One acute dermal toxicity study, two acute inhalation toxicity studies, and one acute oral toxicity study that examined the effects of 1,1,2-trichloropropane were identified (Hazleton Labs, 1992; Smyth et al., 1954). These studies are summarized in Table 3 and discussed further below. 8 1,1,2-Tri chl oroprop ane ------- FINAL 11-29-2012 Table 3. Other 1,1,2-Trichloropropane (CASRN 598-77-6) Studies Test Materials and Methods Results Conclusions References Carcinogenicity (exposures other than oral or inhalation) No data Acute studies 5 male Carworth-Wistar rats/dose, gavage exposure followed by 14-d observation period LD50 calculated using the method of Thompson (1947) using the tables of Weil (1952) LD50 1.23 g/kg (0.94-1.62)3 Death following exposure (mechanism unreported) Smyth etal. (1954) Acute studies Sprague-Dawley Rat (6 males/6 females), acute inhalation, 6 hr exposure; 3500 ppm (21,000 mg/m3) 100% mortality during the 6-hr exposure apparently caused by central nervous system depression; ataxia and incoordination; congested lungs, liver, and kidneys; poorly differentiated kidneys and purple lungs observed in males; pale kidneys observed in 1/6 females Death, possibly from central nervous system depression, following exposure Hazleton Labs (1992; unpublished) Acute studies 6 male albino rats, 4 hr inhalation exposure followed by a 14 d observation period; 2000 ppm (12,000 mg/m3) 3/6 rats died within the 14 d following a 4 hr inhalation exposure to 12,000 mg/m3 Death following exposure (mechanism unreported) Smyth etal. (1954) Acute studies 4 male New Zealand giant albino rabbits, dermal exposure to clipped skin occluded with plastic film for 24 hr; 14-d observation period LD50 calculated using the method of Thompson (1947) using the tables of Weil (1952) Dermal LD50 14.1 mL/kg (8.8-22.9)a Death following exposure (mechanism unreported) Smyth etal. (1954) Metabolism/ toxicokinetic No data Mode of action/ mechanistic No data Immunotoxicity No data Neurotoxicity No data "Values represent calculated means with parentheses noting the limits of ±1.96 standard deviations. 9 1,1,2-Tri chl oroprop ane ------- FINAL 11-29-2012 Tests Evaluating Carcinogenicity, Genotoxicity, and/or Mutagenicity The carcinogenicity, genotoxicity, and mutagenicity potential of 1,1,2-trichloropropane have not been evaluated. Acute Studies One acute oral toxicity study in rats (Smyth et al., 1954), two acute inhalation toxicity studies in rats (Hazleton Labs 1992; Smyth et al., 1954), and one acute dermal toxicity study in rabbits (Smyth et al., 1954) were identified. Smyth et al. (1954) performed one oral acute study in which five male Carworth-Wistar rats/dose (weighing 90-120 g) were administered a single dose of 1,1,2-trichloropropane and observed for mortality for up to 14 days. The study authors tested a range of doses spaced in a logarithmic series, although the exact doses used were not reported. An oral LD50 of 1.23 g/kg was calculated using the method of Thompson (1947) and the tables of Weil (1952). The study authors reported no other effects. Hazleton Labs (1992) conducted an unpublished, acute inhalation toxicity study in which 6 male and 6 female Sprague-Dawley rats (average weights: 295 and 204 g, respectively) were exposed to 3500-ppm 1,1,2-trichloropropane for 6 hours. This exposure is converted to 21,000 mg/m3 by multiplying 3500 ppm by the molecular weight of 1,2,2-trichloropropane (147.43 g/mol) and dividing the value by the standard molar volume of an ideal gas (24.45). No air controls were reported. Ataxia and effects on coordination were observed within 45 minutes after beginning exposure to 1,1,2-trichloropropane. After 2 hours of exposure all animals were prostrate, and after 3 hours of exposure some animals stopped breathing. All animals died prior to termination of the 6-hour exposure period. The study authors stated that the apparent cause of mortality was central nervous system depression. Autopsy revealed that the lungs, liver, and kidneys of all animals were congested. In males, kidneys were poorly differentiated, and lungs had a purple appearance. Pale kidneys were observed in one female. Authors observed similar effects in animals exposed to four other chlorinated hydrocarbons (3500 ppm of 1,2,2-trichloropropane, 1,1,2-trichloropropene-l, 1,1,1-trichloropropane, and ethyltrichloroethylene) and no effects from another chlorinated hydrocarbon (3500 ppm of 2,2-dichloropropane). Of the chemicals tested, the effects of 1,1,2-trichloropropane were noted to be most severe (quantitative data not provided). Smyth et al. (1954) exposed 6 male albino rats to inhaled concentrations of 2000-ppm 1,1,2-trichloropropane for 4 hours. This exposure is converted to 12,000 mg/m3 by multiplying 2000 ppm by the molecular weight of 1,1,2-trichloropropane (147.43 g/mol) and dividing the value by the standard molar volume of an ideal gas (24.45). Animals were observed for mortality for 14 days following the exposure period, during which 3 of the 6 rats had died. No other details were provided in the study report. Smyth et al. (1954) also assessed dermal penetration in 4 male New Zealand giant albino rabbits weighing 2.5-3.5 kg using the one-day cuff method. Fur was clipped closely to the skin and the test site was occluded with plastic film for the 24-hour exposure period. Effects were assessed up to 14 days after exposure. An acute dermal LD50 value was calculated using a similar method to that reported for oral exposure in rats (Smyth et al., 1954). The study authors 10 1,1,2-Tri chl oroprop ane ------- FINAL 11-29-2012 calculated a dermal LD50 of 14.1 mL/kg for rabbits, indicating dermal penetration. No other effects were described. Metabolism/Toxicokinetic Studies No metabolism or toxicokinetic studies were identified. MOA/Mechanistic Studies No MOA or mechanistic studies were identified. Immunotoxicity No immunotoxicity studies were identified. Neurotoxicity No neurotoxicity studies were identified. Other In parallel to the Villeneuve et al. (1985) investigation of the subchronic oral administration of 1,1,2-trichloropropane in rats, a similar investigation using the same methods was conducted using 1,2,3-trichloropropane. 1,2,3-Trichloropropane led to effects to the liver, kidney, and thyroid (Villeneuve et al., 1985). The histological effects observed after 1,2,3-trichloropropane exposure were similar to those in the 1,1,2-trichloropropane study. Lesions observed in the livers, kidneys, and thyroid of rats exposed to 1000-mg/L 1.1.2-trichloropropane were also observed in rats exposed to 1000-mg/L 1,2,3-trichloropropane, though effects were generally more prevalent and more severe in rats exposed to 1.2.3-trichloropropane. In addition to the lesions reported with 1,1,2-trichloropropane exposure, female rats exposed to 1000-mg/L 1,2,3-trichloropropane demonstrated biliary hyperplasia. Additional differences indicated that the response to 1,2,3-trichloropropane may be more severe than to 1,1,2-trichloropropane. Both chemicals led to increased relative liver weights in males; however, the effect was also observed in females treated with 1,2,3-trichloropropane. Additionally, relative kidney and brain weights were elevated in 1,2,3-trichloropropane-exposed rats, but were unaffected by 1,1,2-trichloropropane exposure. 1,2,3-trichloropropane decreased body-weight gains and daily water intake; these changes may be responsible for the changes in relative—but not absolute—organ weights. Serum cholesterol levels (females only), hepatic aminopyrine demethylase activity (males and females), and aniline hydroxylase activity (males only) were increased compared to both vehicle and water controls in animals treated with 1000-mg/L 1,2,3-trichloropropane. Although they share a NOAEL (100 mg/L) and LOAEL (1000 mg/L) in this study, 1,2,3-trichloropropane is reported to be more toxic than 1,1,2-trichloropropane on the basis of more numerous and severe effects at the LOAEL. DERIVATION OF PROVISIONAL VALUES Tables 4 and 5 present a summary of noncancer and cancer reference values, respectively. 11 1,1,2-Tri chl oroprop ane ------- FINAL 11-29-2012 Table 4. Summary of Noncancer Reference Values for 1,1,2-Trichloropropane (CASRN 598-77-6) Toxicity Type (units) Species/Sex Critical Effect p-Reference Value POD Method POD UFC Principal Study Subchronic p-RfD (mg/kg-d) Rat/M Mild lesions in liver, kidney, and thyroid 1 x 1(T2 NOAEL 14a 1000 Villeneuve et al. (1985) RfD (mg/kg-d) IRIS (U.S. EPA, 1988a) Rat/M+F Mild lesions in liver, kidney, and thyroid 5 x i(T3 NOAEL 15a 3000b Villeneuve et al. (1985) Subchronic p-RfC (mg/m3) NDr NDr NDr NDr NDr NDr NDr Chronic p-RfC (mg/m3) NDr NDr NDr NDr NDr NDr NDr aVilleneuve et al. (1985) reported within the study that intake at the NOAEL dose of 100 mg/L was 15-20 mg/kg-d. U.S. EPA (1988a) used the lower value, 15 mg/kg-d, to derive a chronic RfD. The same effect was used to derive a subchronic p-RfD; however, the dose is slightly altered in following current guidance for dosimetric adjustments (U.S. EPA, 1988a). bU.S. EPA (1988b) applied an uncertainty factor of 3000 based on a UFA of 10, a UFS of 10, a UFH of 10, and a UFD of 3 (note: a UFD of 10 is applied to the subchronic p-RfD derived in this PPRTV document following current practice to account for lack of data on reproductive and developmental effects). NDr = Not determined. Table 5. Summary of Cancer Values for 1,1,2-Trichloropropane (CASRN 598-77-6) Toxicity Type Species/Sex Tumor Type Cancer Value Principal Study p-OSF NDr NDr NDr NDr p-IUR NDr NDr NDr NDr NDr = Not determined. 12 1,1,2-Tri chl oroprop ane ------- FINAL 11-29-2012 DERIVATION OF ORAL REFERENCE DOSES Derivation of Subchronic Provisional RfD (Subchronic p-RfD) The Villeneuve et al. (1985) study is selected as the critical study for the derivation of a subchronic p-RfD. This study is a published, peer-reviewed study and meets the standards of study design and performance with numbers of animals, examination of potential toxicity endpoints, and presentation of information. Furthermore, this is the only study of subchronic duration located in the literature. The critical endpoints are an increased incidence of mild lesions in the liver, kidneys, and thyroid observed in male and female rats exposed to 1.1.2-trichloropropane in drinking water for 90 days, with males reported as the most sensitive sex. The same study was used by IRIS (U.S. EPA, 1988a) to derive a chronic RfD. The critical endpoint is supported by similar effects described by Villeneuve et al. (1985) following oral exposure to the related chemical, 1,2,3-trichloropropane. Further details of the study on 1.2.3-trichloropropane are provided in the "Other Data" section of this document. Details of the 1,1,2-trichloropropane study are provided in the "Review of Potentially Relevant Data" section of this document. The point of departure (POD) from this study is a NOAEL (14 mg/kg-day for mild liver, kidney, and thyroid lesions in male rats). Benchmark dose (BMD) analysis cannot be performed on these data because quantitative data for the critical effects are not provided in the study report. The following dosimetric adjustments were made for each dose in the principal study for the water treatment. NOAELadj = NOAEL x Water Consumption per Day x (1 Body Weight) x (Days Dosed + Total Days) = 100 mg/L x 0.037 L/day x (1 - 0.267 kg) x (90 days dosed ^ 90 total days) = 100 mg/L x 0.037 L/day x 3.75 kg-1 x 1 = 14 mg/kg-day The subchronic p-RfD based on a NOAEL of 14 mg/kg-day for mild liver, kidney, and thyroid lesions in the male rat (Villeneuve et al., 1985) is derived as follows: Subchronic p-RfD = NOAEL -h UFc = 14 mg/kg-day 1000 = 1 x 10~2 mg/kg-day Table 6 summarizes the uncertainty factors for the subchronic p-RfD of 1,1,2-trichloropropane. 13 1,1,2-Tri chl oroprop ane ------- FINAL 11-29-2012 Table 6. Uncertainty Factors for Subchronic p-RfD of l,l?2-Trichloropropane (CASRN 598-77-6) UF Value Justification UFa 10 A UFa of 10 is applied for interspecies extrapolation to account for potential toxicokinetic and toxicodynamic differences between rats and humans. UFd 10 A UFd of 10 is applied because there are no acceptable two-generation reproduction studies or developmental studies by this route of exposure. UFh 10 A UFh of 10 is applied for intraspecies differences to account for potentially susceptible individuals in the absence of information on the variability of response to humans. UFl 1 A UFl of 1 is applied for using a POD based on a NOAEL. UFS 1 A UFs of 1 is applied because a sub chronic-duration study was utilized as the critical study. UFC 1000 Product of UFa, UFd, UFh, UFl, and UFS. The confidence of the subchronic p-RfD for 1,1,2-trichloropropane is low as explained in Table 7 below. Table 7. Confidence Descriptors for Subchronic p-RfD for 1,1,2-Trichloropropane (CASRN 598-77-6) Confidence Categories Designation" Rationale Confidence in study M The confidence in the study is medium. Villeneuve et al. (1985) examined most—but not all—of the appropriate subchronic endpoints. The study was peer reviewed. The study included multiple effect levels, and both a NOAEL and LOAEL were identified. The study by Villeneuve et al. (1985) was also used to derive a chronic RfD by IRIS (U.S. EPA, 1988a). Confidence in database L The confidence in the database is low because the database for subchronic oral exposure includes only the single study by Villeneuve et al. (1985). The database does not include any acceptable reproduction or development studies. Confidence in subchronic p-RfD L The overall confidence in the subchronic p-RfD is low. The overall confidence cannot be greater than lowest entry in table. aL = Low, M = Medium, H = High. 14 1,1,2-Tri chl oroprop ane ------- FINAL 11-29-2012 Derivation of Chronic Provisional RfD (Chronic p-RfD) A chronic RfD of 5 x 10 3 mg/kg-day is available on IRIS (U.S. EPA, 1988a), based on increased incidence of mild lesions in the liver, kidney, and thyroid reported in rats exposed to 1000 mg/L 1,1,2-trichloropropane (adjusted to 150 mg/kg-day) via drinking water for 90 days, with a NOAEL of 100 mg/L (adjusted to 15 mg/kg-day) (Villeneuve et al., 1985). The principal study used by IRIS is also utilized in this document for a subchronic p-RfD. The IRIS database should be checked to determine if any changes have been made. DERIVATION OF INHALATION REFERENCE CONCENTRATIONS Derivation of Subchronic Provisional RfC (Subchronic p-RfC) No inhalation exposure studies on 1,1,2-trichloropropane were identified. Derivation of Chronic Provisional RfC (Chronic p-RfC) No inhalation exposure studies on 1,1,2-trichloropropane were identified. CANCER WEIGHT-OF-EVIDENCE DESCRIPTOR Table 8 identifies the cancer weight-of-evidence (WOE) descriptor for 1,1,2-trichloropropane. Table 8. Cancer WOE Descriptor for 1,1,2-Trichloropropane (CASRN 598-77-6) Possible WOE Descriptor Designation Route of Entry (oral, inhalation, or both) Comments "Carcinogenic to Humans " NA NA No human cancer studies are available. "Likely to Be Carcinogenic to Humans " NA NA No animal cancer data are available. "Suggestive Evidence of Carcinogenic Potential" NA NA No evidence assessing carcinogenicity is available. "Inadequate Information to Assess Carcinogenic Potential" Selected Both No evidence assessing carcinogenicity via the oral or inhalation route is available in the literature. "Not Likely to Be Carcinogenic to Humans " NA NA No strong evidence of noncarcinogenicity in humans is available. NA = not applicable. 15 1,1,2-Tri chl oroprop ane ------- FINAL 11-29-2012 While there is no evidence assessing the carcinogenicity of 1,1,2-trichloropropane via either the oral or the inhalation route of exposure, the related compound, 1,2,3-trichloropropane, is a likely human carcinogen via the oral route of exposure (U.S. EPA, 2009b) based on evidence of genotoxicity and occurrence of tumors at multiple sites in both rats and mice. Additionally, halogenated propanes have been generally found to be positive in assays testing for mutagenicity (Lag et al., 1994; Ratpan and Plaumann, 1988). This indicates a need for future studies addressing the carcinogenic potential of 1,1,2-trichloropropane. DERIVATION OF PROVISIONAL CANCER POTENCY VALUES Derivation of Provisional Oral Slope Factor (p-OSF) No oral carcinogenicity studies on 1,1,2-trichloropropane were identified. Derivation of Provisional Inhalation Unit Risk (p-IUR) No inhalation carcinogenicity studies on 1,1,2-trichloropropane were identified. 16 1,1,2-Tri chl oroprop ane ------- FINAL 11-29-2012 APPENDIX A. PROVISIONAL SCREENING VALUES No screening values are presented. 17 1,1,2-Tri chl oroprop ane ------- FINAL 11-29-2012 APPENDIX B. DATA TABLES No data tables are presented. 18 1,1,2-Tri chl oroprop ane ------- FINAL 11-29-2012 APPENDIX C. BMD OUTPUTS No BMD outputs are presented. 19 1,1,2-Tri chl oroprop ane ------- FINAL 11-29-2012 APPENDIX D. REFERENCES ACGIH (American Conference of Governmental Industrial Hygienists). (2011) Threshold limit values for chemical substances and physical agents and biological exposure indices. Cincinnati, OH. As cited in HSDB (Hazardous Substances Data Bank). Available online at http://toxnet.nlm.nih.eov/cei-bin/sis/htmleen7HSDB. Accessed on 8/17/2011. 625688 ATSDR (Agency for Toxic Substances and Disease Registry). (2011) Toxicological profile information sheet. U.S. Department of Health and Human Services, Public Health Service, Atlanta, GA. Available online at http://www.atsdr.cdc.eov/toxprofiles/index.asp. Accessed on 8/17/2011. 595415 CalEPA (California Environmental Protection Agency). (2008) All OEHHA acute, 8-hour and chronic reference exposure levels (chRELs) as on December 18, 2008. Office of Environmental Health Hazard Assessment, Sacramento, CA. Available online at http://www.oehha.ca.eov/air/allrels.html. Accessed on 8/17/2011. 595416 CalEPA (California Environmental Protection Agency). (2009) OEHHA toxicity criteria database. Office of Environmental Health Hazard Assessment, Sacramento, CA. Available online at http://www.oehha.ca.eov/riskAChemicalDB/index.asp. Accessed on 8/17/2011. 595417 ChemlDplus. (2010) 1,1,2-Trichloropropane. National Library of Medicine, Bethesda, MD. Available online at http://chem.sis.nlm.nih.eov/chemidplus/. Accessed on 8/17/2011. 629639 Hazleton Labs. (1992) Initial submission: Acute inhalation exposure - rats (final report) on eight chemicals with cover letter dated 022192 (Report No. 88920001101). Vienna, VA: Hazleton Labs. 670850 IARC (International Agency for Research on Cancer). (2011) Monographs on the evaluation of carcinogenic risks to humans. Lyon, France: IARC. Available online at http://monoeraphs.iarc.fr/ENG/Monoeraphs/PDFs/index.php. Accessed on 8/17/2011. 597416 Lag, M; Omichinski, JG; Dybing, E; et al. (1994) Mutagenic activity of halogenated propanes and propenes: effect of bromine and chlorine positioning. Chem Biol Interact 93:73-84. 759898 NIOSH (National Institute for Occupational Safety and Health). (2011) NIOSH pocket guide to chemical hazards. Index of chemical abstracts service registry numbers (CAS No.). Center for Disease Control and Prevention, U.S. Department of Health, Education and Welfare, Atlanta, GA. Available online at http://www.cdc.eov/niosh/npe/npedcas.html. Accessed on 8/17/2011. 625692 NTP (National Toxicology Program). (2011) 12th Report on Carcinogens. U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, Research Triangle Park, NC. Available online at http://ntp.niehs.nih.eov/ntp/roc/twelfth/rocl2.pdf. Accessed on 8/17/2011. 093207 20 1,1,2-Tri chl oroprop ane ------- FINAL 11-29-2012 OSHA (Occupational Safety and Health Administration). (2006) Air contaminants: occupational safety and health standards for shipyard employment, subpart Z, toxic and hazardous substances. U.S. Department of Labor, Washington, DC; OSHA Standard 1915.1000. Available online at http://www.osha.gov/pls/oshaweb/owadisp.show document?p table STANDARDS&p id=10286. Accessed on 8/17/2011. 625691 Ratpan, F; Plaumann, H. (1988) Mutagenicity of halogenated propanes and their methylated derivatives. Environ Mutagen 12(2):253-259. 759899 Smyth, HF Jr; Carpenter, CP; Weil, CS; et al. (1954) Range-finding toxicity data: list V. AMA Arch IndHyg Occup Med 10:61-68. 064773 Thompson, WR. (1947) Use of moving averages and interpolation to estimate median effective dose. I. Fundamental formulas, estimation of error, and relation to other methods. Microbiol Mol Biol Rev 11(2): 115-145. As cited in Smyth et al. (1954). Available online at http://mmbr.asm.Org/cgi/reprint/l 1/2/115. 066696 U.S. EPA (Environmental Protection Agency). (1988a) Integrated Risk Information System (IRIS) Summary of 1,1,2-Trichloropropane. Office of Research and Development, National Center for Environmental Assessment, Washington, DC. Available online at http://www.epa.gov/iris/subst/0372.htm. Accessed on 8/17/2011. 003752 U.S. EPA (Environmental Protection Agency). (1988b) Recommendations for and documentation of biological values for use in risk assessment. Environmental Criteria and Assessment Office, Cincinnati, OH; EPA/600/6-87/008. Available online at http://cfpub.epa.gov/ncea/cfm/recordisplav.cfm?deid=34855#Download. Accessed on 8/17/2011. 064560 U.S. EPA (Environmental Protection Agency). (1994) Chemical assessments and related activities (CARA). Office of Health and Environmental Assessment, Washington, DC; EPA/600/R-94/904. Available online at http://nepis.epa.gov/Exe/ZyPURL.cgi?Dockev=6000lG8L.txt. Accessed on 8/17/2011. 596444 U.S. EPA (Environmental Protection Agency). (2009a) 2009 Edition of the drinking water standards and health advisories. Office of Water, Washington, DC; EPA/822/R-09/011. Available online at http://deq.state.wv.us/wqd/groundwater/downloads/dwstandards2009 %5B l%5D.pdf. Accessed on 8/17/2011. 644141 U.S. EPA (Environmental Protection Agency). (2009b) Toxicological review of 1,2,3-trichloropropane in support of summary information on the Integrated Risk Information System (IRIS). Office of Research and Development, National Center for Environmental Assessment, Washington, DC. Available online at http://www.epa.gov/iris/toxreviews/0200tr.pdf. Accessed on 8/17/2011. 003752 U.S. EPA (Environmental Protection Agency). (2011) Health effects assessment summary tables (HEAST). Prepared by the Office of Research and Development, National Center for Environmental Assessment, Cincinnati OH for the Office of Emergency and Remedial Response, Washington, DC. Available online at http://epa-heast.ornl.gov/. Accessed on 8/17/2011. 595422 21 1,1,2-Tri chl oroprop ane ------- FINAL 11-29-2012 Villeneuve, DC; Chu, I; Secours, VE; et al. (1985) Results of a 90-day toxicity study on 1,2,3- and 1,1,2-Trichloropropane administered via the drinking water. Sci Total Environ 47:421-426. 670854 Weil, CS. (1952) Tables for convenient calculation of median-effective dose (LD50 or ED50) and instructions in their use. Biometrics 8:249-263. As cited in Smyth et al. (1954). Available online at http://www.garfield.library.upenn.edu/classicsl979/A1979HJ87400001.pdf. 066697 WHO (World Health Organization). (2011) Online catalogs for the Environmental Health Criteria series. Available online at http://www.who.int/topics/environmental health/en/. Accessed on 8/17/2011. 595424 22 1,1,2-Tri chl oroprop ane ------- |