United States Environmental Protection 1=1 m m Agency EPA/690/R-12/016F Final 11-20-2012 Provisional Peer-Reviewed Toxicity Values for Ethylene Cyanohydrin (CASRN 109-78-4) 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 Harlal Choudhury, DVM, PhD, DABT National Center for Environmental Assessment, Cincinnati, OH DRAFT DOCUMENT PREPARED BY ICF International 9300 Lee Highway Fairfax, VA 22031 PRIMARY INTERNAL REVIEWERS Ghazi Dannan, PhD National Center for Environmental Assessment, Washington, DC Q. Jay Zhao, PhD, MPH, DABT National Center for Environmental Assessment, Cincinnati, OH 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 Ethylene Cyanohydrin ------- 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 Exposure 6 Inhalation Exposure 9 OTHER DATA (SHORT-TERM TESTS, OTHER EXAMINATIONS) 9 Tests Evaluating Genotoxicity 14 Short-term Studies 14 Metabolism Studies 15 DERIVATION 01 PROVISIONAL VALUES 16 DERIVATION OF ORAL REFERENCE DOSE 17 Derivation of Subchronic Provisional RfD (Subchronic p-RfD) 17 Derivation of Chronic Provisional RfD (Chronic p-RfD) 18 DERIVATION OF INHALATION REFERENCE CONCENTRATIONS 20 CANCER WEIGHT-OF-EVIDENCE DESCRIPTOR 20 MODE-OF-ACTION (MOA) DISCUSSION 21 MUTAGENIC MO A 21 DERIVATION OF PROVISIONAL CANCER POTENCY VALUES 21 APPENDIX A. PROVISIONAL SCREENING VALUES 22 APPENDIX B. DATA TABLES 23 APPENDIX C. BMD MODELING OUTPUTS FOR ETHYLENE CYANOHYDRIN 25 APPENDIX D. REFERENCES 26 in Ethylene Cyanohydrin ------- 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 NOAELrec 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 Ethylene Cyanohydrin ------- FINAL 11-20-2012 PROVISIONAL PEER-REVIEWED TOXICITY VALUES FOR ETHYLENE CYANOHYDRIN (CASRN 109-78-4) 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 (http://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 (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 Ethylene Cyanohydrin ------- FINAL 11-20-2012 INTRODUCTION Ethylene cyanohydrin (CAS No. 109-78-4), also known as P-hydroxypropionitrile, is a white/straw-colored liquid that is used as a solvent for certain cellulose esters and inorganic salts, as an organic intermediate for acrylates, and in the synthesis of acrylonitrile. The chemical structure of ethylene cyanohydrin is shown in Figure 1, and selected physicochemical properties of ethylene cyanohydrin are provided in Table 1. OH—CH2—CH2—CN Figure 1. Ethylene Cyanohydrin Structure Table 1. Physicochemical Properties Table for Ethylene Cyanohydrin (CASRN 109-78-4)a Property (unit) Value Boiling point (°C) 221 Melting point (°C) -46 Density (g/cm3) 1.04 Vapor pressure (mm Hg at 25°C) 0.08 pH (unitless) NA Solubility in water (mg/L at 20°C) 1.00 x 106 Relative vapor density (air =1) 2.45 Molecular weight (g/mol) 71.08 aACGIH (2011), ChemlDPlus (2011). NA = not applicable. No Reference Dose (RfD), Reference Concentration (RfC), or cancer assessment for ethylene cyanohydrin is included in the U.S. EPA IRIS (U.S. EPA, 201 la) database, in the Drinking Water Standards and Health Advisories List (U.S. EPA, 2009), or in the HEAST (U.S. EPA, 201 lb). U.S. EPA (2005a) developed a PPRTV assessment for ethylene cyanohydrin, deriving a subchronic p-RfD of 1 x 10 1 mg/kg-day and a chronic p-RfD of 3 x 10 2 mg/kg-day. Subchronic and chronic p-RfC values were not determined. The Chemical Assessments and Related Activities (CARA) list does not include a Health and Environmental Effects Profile (HEEP) for ethylene cyanohydrin (U.S. EPA, 1994). The toxicity of ethylene cyanohydrin has not been reviewed by the ATSDR (2011) or the World Health Organization (WHO, 2011). CalEPA (2008, 2009a) has not derived toxicity values for exposure to ethylene cyanohydrin. No occupational exposure limits for ethylene cyanohydrin have been derived or recommended by the American Conference of Governmental Industrial Hygienists (ACGIH, 2011), the National Institute of Occupational Safety and Health (NIOSH, 2011), or the Occupational Safety and Health Administration (OSHA, 2010). 2 Ethylene Cyanohydrin ------- FINAL 11-20-2012 The HEAST (U.S. EPA, 201 lb) does not report a U.S. EPA (1986) cancer weight-of-evidence (WOE) classification or an oral slope factor (OSF) for ethylene cyanohydrin. The International Agency for Research on Cancer (IARC, 2011) has not reviewed the carcinogenic potential of ethylene cyanohydrin. Ethylene cyanohydrin is not included in the 12th Report on Carcinogens (NTP, 2011). CalEPA (2009b) has not derived a quantitative estimate of carcinogenic potential for ethylene cyanohydrin. Literature searches were conducted on sources published from 1900 through May 2012 for studies relevant to the derivation of provisional toxicity values for ethylene cyanohydrin (CASRN 109-78-4). 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); WHO; and Worldwide Science. The following databases outside of HERO were searched for health information: ACGIH, AT SDR, 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 ethylene cyanohydrin and includes all potentially relevant repeated short-term-, subchronic-, and chronic-duration studies. The phrase "statistical significance," used throughout the document, indicates ap-walue of <0.05. 3 Ethylene Cyanohydrin ------- FINAL 11-20-2012 Table 2. Summary of Potentially Relevant Data for Ethylene Cyanohydrin (CASRN 109-78-4) Category Number of Male/Female, Strain, Species, Study Type, Study Duration Dosimetry" Critical Effects NOAEL' BMDL/ BMCLa LOAEL' Reference (Comments) Notesb Human 1. Oral (mg/kg-d)a Subchronic ND Chronic ND Developmental ND Reproductive ND Carcinogenic ND 2. Inhalation (mg/m3)" Subchronic ND Chronic ND Developmental ND Reproductive ND Carcinogenic ND Animal 1. Oral (mg/kg-d)a Subchronic 10/10 S-D rat, drinking water, 90 d 0,10,30,90, or 270 (Adjusted) Questionable effects on brain and heart weights 270 NDr NDr Sauerhoff et al. (1976a) PS, PR S-D rat, dietary, 52-64 d 0 or 301 (M), 343 (F) (Adjusted) None 301/343 NDr NDr Bachhuber et al. (1955) PR Chronic Carcinogenic 43/0 Wistar rat, dietary, 78 wk 0, 7, 74, or 221 (Adjusted) Decreased body weight 74 NDr 221 Hirose et al. (1980a) PS, PR 50/0 ICR mouse, dietary, 78 wk 0, 18, 180, or 539 (Adjusted) Decreased body weight 180 NDr 539 Hirose et al. (1980b) PR 4 Ethylene Cyanohydrin ------- FINAL 11-20-2012 Table 2. Summary of Potentially Relevant Data for Ethylene Cyanohydrin (CASRN 109-78-4) Category Number of Male/Female, Strain, Species, Study Type, Study Duration Dosimetry3 Critical Effects NOAEL3 BMDL/ BMCL3 LOAEL3 Reference (Comments) Notesb Developmental ND Reproductive ND 2. Inhalation (mg/m3)" Subchronic ND Chronic ND Developmental ND Reproductive ND Carcinogenic ND ""Dosimetry: NOAEL, BMDL/BMCL, and LOAEL values are converted to an adjusted daily dose (ADD in mg/kg-d) for oral noncancer effects. All exposure values of long-term exposure (4 wk and longer) are converted from a discontinuous to a continuous (weekly) exposure. HED = avg. mg test article ^ avg. kg body weight ^ Number daily dosed. HEDn = (avg. mg test article ^ avg. kg body weight ^ Number daily dosed)14. bNotes: IRIS = utilized by IRIS, date of last update, PS = principal study, NPR = not peer reviewed, PR = peer reviewed, ND = no data, NDr = not determined, NR = not reported. 5 Ethylene Cyanohydrin ------- FINAL 11-20-2012 HUMAN STUDIES Oral Exposures No oral studies on the subchronic, chronic, developmental, or reproductive toxicity or on the carcinogenicity of ethylene cyanohydrin in humans were identified. Inhalation Exposures No inhalation studies on the acute, sub chronic-duration, chronic-duration, developmental, or reproductive toxicity or on the carcinogenicity of ethylene cyanohydrin in humans were identified. ANIMAL STUDIES Oral Exposure The effects of oral exposure of animals to ethylene cyanohydrin were evaluated in two sub chronic-duration studies (i.e., Sauerhoff et al., 1976a; Bachhuber et al., 1955) and one combined chronic-duration toxicity and carcinogenicity study (i.e., Hirose et al., 1980a,b). Subchronic Studies Sauerhoff et al., 1976a The study by Sauerhoff et al. (1976a) is selected as the principal study for derivation of the subchronic p-RfD value. In this peer-reviewed study, ethylene cyanohydrin (>99% purity) was administered in the drinking water to 10 S-D rats/sex/dose of 0, 10, 30, 90, or 270 mg/kg-day for 90 days. Weekly adjustments were made to the dose formulations based on water consumption and body weight. The rats were obtained from Spartan Research Animals Inc. (Haslett, MI) and were housed individually in wire-bottomed cages with water and commercial laboratory animal chow available ad libitum. No further details of animal husbandry were provided. The study authors stated that the stability and concentration of ethylene cyanohydrin were confirmed in the drinking water. The rats were weighed and food consumption determined weekly. All rats were observed frequently for clinical signs of toxicity (schedule not reported). On Day 85, hematologic evaluations (i.e., packed cell volume, erythrocyte count, leukocyte count, hemoglobin [Hb], percentage neutrophils, and percentage lymphocytes) and urinalyses (i.e., specific gravity, pH, sugar, protein, ketones, occult blood, and bilirubin) were conducted on five rats/sex from the control and 270-mg/kg-day groups. At necropsy on Days 91 and 92, blood samples were collected from five rats/sex/dose for the determination of the serum levels of urea nitrogen, alkaline phosphatase activity, and glutamic pyruvic transaminase activity. A gross pathologic examination was conducted on all rats, and the weights of brain, heart, liver, kidney, and testes were determined. Samples of the following tissues were obtained and fixed in 10% buffered formalin: heart, liver, kidney, gonads, uterus, thyroid, trachea, parathyroid, lung, adrenal gland, spleen, pancreas, stomach, small intestine, large intestine, urinary bladder, accessory sex glands, skeletal muscle, peripheral nerve, spinal cord, brain, eye, pituitary gland, thymus, and aorta. Following routine processing and staining with hematoxylin and eosin, all of the aforementioned tissues from the control and 270-mg/kg-day groups were examined microscopically (five rats/sex). Analysis of variance and Dunnett's test (p < 0.05) were used to determine whether ethylene cyanohydrin induced significant alterations in body weights, food consumption, water consumption, hematological values, clinical chemical parameters, organ weights, and organ-to-body-weight ratios. The statistical analyses are considered adequate; parametric testing is only appropriate when the assumptions of normality of distribution and homogeneity of variances are met. This study was 6 Ethylene Cyanohydrin ------- FINAL 11-20-2012 conducted prior to the adoption of Good Laboratory Practice (GLP) standards as described in 40 CFR Part 160. No treatment-related effects were noted on mortality, clinical signs, body weights, food or water consumption, clinical chemistry, hematology, or gross or microscopic pathology (Sauerhoff et al., 1976a). The study authors concluded that the NOAEL was 270 mg/kg-day, the highest dose tested. A LOAEL was not identified. A PPRTV document for ethylene cyanohydrin was previously published by U.S. EPA (2005a). The 2005 document used the study by Sauerhoff et al. (1976a) to derive a subchronic p-RfD of 1 x 10 1 mg/kg-day, based on a NOAEL of 30 mg/kg-day. It was stated that the decreases in absolute brain and heart weights represented a treatment-related and toxicologically significant effect due to the mechanism of toxicity for the cyanohydrin compounds as a class. U.S. EPA (2005a) further stated that the heart and brain are especially sensitive to alterations in cellular energy status, and would be expected to be sensitive to compounds that interfere with energy metabolism. In this regard, Sauerhoff et al. (1976a) stated the following: "No significant differences occurred between the mean organ weights or organ to body weight ratios of male rats receiving (ethylene cyanohydrin) and controls. Brain and heart weights offemales receiving 270 and 90 mg/kg-day were slightly but significantly (p<0.05) lower than controls. The weight differences of these tissues were not accompanied by pathologic alteration. " The effects on brain and heart weights in the females were statistically significant at 270 and 90 mg/kg-day. It was not indicated whether the decreases in absolute brain and heart weights were dose-related. Furthermore, the decreases in absolute weights were not accompanied by corresponding organ-to-body-weight differences; the magnitudes of the "slightly but significantly lower" organ weights were not provided; the organ-weight decreases were not associated with adverse gross or microscopic pathology; and no other additional evidence of toxicity was observed in these animals systemically or in specific organs. The decreases in absolute weights were observed only in females; however, in a concurrent metabolism study (Sauerhoff et al., 1976b), no sex-related differences were observed in the pharmacokinetics (plasma concentrations) of the compound following oral administration, and only 0.44% of the administered radioactive dose was isolated in the expired air as [14C]-HCN. The study authors also reported rapid elimination of the compound in the urine (ti/2 = 6.13 hours). Additionally, there was no evidence of toxicity in the rat following treatment for 52-64 days at a dietary dose of approximately 340 mg/kg-day (Bachhuber et al., 1955), and there was only evidence for slight toxicity in studies of longer duration at equivalent or higher doses. In the chronic-duration studies, discussed below, there was evidence of only minimal toxicity (i.e., decreased terminal body weights) in rats and mice dosed orally at up to 221 and 539 mg/kg-day, respectively, for up to 78 weeks (Hirose et al., 1980a,b). In addition, the oral LD50 is 3200 mg/kg for the rat and 1800 mg/kg for the mouse (HSDB, 2003). Taken together, these data suggest that cyanide toxicity is a minor concern for ethylene cyanohydrin. Therefore, the NOAEL is considered to be 270 mg/kg-day, the highest dose tested, for derivation of the subchronic p-RfD value. 7 Ethylene Cyanohydrin ------- FINAL 11-20-2012 Bachhuber et al., 1955 In a peer-reviewed study by Bachhuber et al. (1955), 5-6 S-D rats (number/sex not specified) were fed diets containing either 0 or 0.35% (equivalent to 301/343 mg/kg-day in males/females) ethylene cyanohydrin for 52-64 days. Body-weight gains, skeletal alterations, clinical signs, and gross abnormalities were recorded (a detailed list of the parameters evaluated was not provided). No adverse effects were reported. The NOAEL was 0.35% (equivalent to 301 mg/kg-day in males and 343 mg/kg-day in females); a LOAEL was not identified. This study is considered unsuitable for use as a principal study due to the fact that the only data presented are a single entry of weight gain/day. Chronic-duration Studies Hirose etal., 1980a The study by Hirose et al. (1980a) is selected as the principal study for derivation of the chronic p-RfD value. In this peer-reviewed study, ethylene cyanohydrin (purity not reported) was administered in commercial Oriental M diet to 43 male Wistar rats/dose of 0 (n = 31), 100, 1000, or 3000 ppm (equivalent to 0, 7, 74, or 221 mg/kg-day based on U.S. EPA [1988] species default values) for 78 weeks. The rats were obtained from Nihon Rat Co. (Saitama, Japan) and were housed six/cage in a room at 24 ± 2°C with alternate 12-hour periods of light. Diet and water were available ad libitum. The study was terminated after 78 weeks. Necropsies were performed at termination and for animals that died while on the study. The liver, kidneys, and spleen were weighed. Organs and tissues (detailed list not provided) were fixed, routinely prepared, and examined microscopically. For hematological and blood biochemical analyses, blood was collected from all rats before sacrifice, and the white blood cells (WBCs), red blood cells (RBCs), Hb, hematocrit (Ht), serum total protein (TP), alkaline phosphatase (SAP), glucose, blood urea nitrogen (BUN), serum glutamic-oxaloacetic transaminase (SGOT), and serum glutamic-pyruvic transaminase (SGPT) were measured. Statistical analyses were not reported. This study was conducted prior to the adoption of GLP standards as described in 40 CFRPart 160. Final body weight was decreased by 10% at 100 and 1000 ppm and by 13% at 3000 ppm compared to the controls (Hirose et al., 1980a; see Table B.l). The effect on body weight at 1000 ppm was similar to that at 100 ppm, and no other evidence of toxicity was noted in these dose groups. Therefore, the effects observed at 100 and 1000 ppm are considered incidental. At 3000 ppm, the study authors reported that, RBCs, Hb, and Ht were decreased by 14—16% compared to the controls, possibly indicative of mild anemia, and that WBCs were decreased by 24% (see Table B.2). Due to the slight magnitude of change from the controls, these effects are considered to be treatment-related, but not adverse. Although statistical significance and standard deviations were not reported, the possibility of a dose-related trend could not be dismissed, and the 13% decrease in body weight at the high dose is considered adverse. No increased incidence of tumors was reported at any dose. Although not stated by the study authors, a LOAEL of 221 mg/kg-day based on a biologically significant decrease in body weight (>10%>) is identified, with a corresponding NOAEL of 74 mg/kg-day. The 2005 PPRTV assessment for ethylene cyanohydrin (U.S. EPA, 2005a) cited Hirose et al. (1980a) and stated the following regarding decreased terminal body weights. " ...data showing growth throughout the study were not presented, statistical analysis was not performed, and group means were reported without any measure of within group 8 Ethylene Cyanohydrin ------- FINAL 11-20-2012 variability (standard deviation), making it difficult to evaluate the data and precluding independent statistical analysis." However, after reevaluation of the rat study by Hirose et al. (1980a), the critical effect is decreased body weight (>10%) at 221 mg/kg-day based on a WOE approach. In addition to the decreased body weights, findings suggestive of a treatment-related, nonadverse anemia were noted in the 221 mg/kg-day rats. Decreased terminal body weights (decreased 10% at 539 mg/kg-day) were also present in the concurrently performed mouse study (Hirose et al., 1980b; see below) and were observed in a dose-dependent manner. Because decreases in body weight were noted in two species, the 13% decrease in body weights in the rat is considered biologically significant effect. Hirose et al., 1980b In a concurrently performed, peer-reviewed study by Hirose et al. (1980b), ethylene cyanohydrin (purity not reported) was administered in commercial Oriental M diet to 50 male ICR mice/dose of 0 (n = 30), 100, 1000, or 3000 ppm (determined by the reviewers to be equivalent to 0, 18, 180, or 539 mg/kg-day based on U.S. EPA [1988] species default values) for 78 weeks. Mice were housed 10/cage in a room at 24 ± 2°C with alternate 12-hour periods of light. Diet and water were available ad libitum. After 78 weeks of treatment, animals were maintained on the control diet for 7 weeks and then terminated. The same parameters were examined in the mouse as in the previously described rat study (Hirose et al., 1980a). Although statistical significance and standard deviations were not reported, final body weights were decreased by 10% at 539 mg/kg-day, and a dose-related effect was observed (Hirose et al., 1980b; see Table B. 1). No other toxicological effect was reported, and no increased incidence of tumors was reported at any dose. Although not stated by the study authors, the LOAEL is 539 mg/kg-day, based on a decrease in body weight that was also observed in Hirose et al. (1980a), with a corresponding NOAEL of 180 mg/kg-day. Developmental Studies No developmental toxicity studies on ethylene cyanohydrin were identified. Reproduction Studies No reproductive toxicity studies on ethylene cyanohydrin were identified. Carcinogenic Studies Carcinogenic potential was evaluated in the combined chronic-duration toxicity and carcinogenicity studies by Hirose et al. (1980a,b) as previously described. No increased incidence of tumors was reported in any tissue at any dose. Inhalation Exposure No inhalation studies on the subchronic, chronic, developmental, or reproductive toxicity or on the carcinogenicity of ethylene cyanohydrin in animals were identified. OTHER DATA (SHORT-TERM TESTS, OTHER EXAMINATIONS) Other studies that are not appropriate for selection of a POD for ethylene cyanohydrin and the determination of p-RfD, p-RfC, p-OSF, or p-IUR values can, however, provide 9 Ethylene Cyanohydrin ------- FINAL 11-20-2012 supportive data that supplement a WOE approach to risk assessment. These studies may include genotoxicity (see Table 3a) and short-term, metabolic, and toxicokinetic studies (see Table 3b). 10 Ethylene Cyanohydrin ------- FINAL 11-20-2012 Table 3A. Summary of Ethylene Cyanohydrin Genotoxicity Studies Endpoint Test System Dose Concentration" Resultsb Comments References Without Activation With Activation Genotoxicity studies in prokaryotic organisms Reverse mutation Ethylene cyanohydrin was evaluated in the Ames assay with preincubation. The chemical was tested in the presence and absence of Arochlor 1254-induced male S-D rat and male Syrian hamster liver homogenate S9. Salmonella typhimurium TA98, TA100, TA1535, and TA97 and/or TA1537 were used. 10 mg/plate Ethylene cyanohydrin is not mutagenic in Salmonella typhimurium TA98, TA100, TA1535, and TA97 and/or TA1537. Zeiger et al. (1992) Mutation Ethylene cyanohydrin was evaluated in a fluctuation test. Klebsiella pneumoniae was tested with the chemical, and mutagenicity was determined on the basis of the proportion of streptomycin-resistant or dependent mutants. 0.015 M ND Ethylene cyanohydrin is not mutagenic in Klebsiella pneumoniae under the study's test conditions. Voogd and Vet (1969) SOS repair induction ND Genotoxicity studies in nonmammalian eukaryotic organisms Mutation ND Recombination induction ND Chromosomal aberration ND Chromosomal malsegregation ND Mitotic arrest ND Genotoxicity studies in mammalian cells—in vitro Forward mutation ND Chromosomal aberrations ND Sister chromatid exchange (SCE) ND DNA damage ND 11 Ethylene Cyanohydrin ------- FINAL 11-20-2012 Table 3A. Summary of Ethylene Cyanohydrin Genotoxicity Studies Endpoint Test System Dose Concentration" Resultsb Comments References Without With Activation Activation Genotoxicity studies in mammals—in vivo Chromosomal aberrations ND Sister chromatid exchange (SCE) ND DNA damage ND DNA adducts ND Mouse biochemical or visible specific locus test ND Dominant lethal ND Genotoxicity studies in subcellular systems DNA binding ND aLowest effective dose for positive results, highest dose tested for negative results. b+ = positive, ± = equivocal or weakly positive, - = negative, T = cytotoxicity, ND = no data. 12 Ethylene Cyanohydrin ------- FINAL 11-20-2012 Table 3B. Other Studies Test Materials and Methods Results Conclusions References Carcinogenicity other than oral/inhalation ND Other toxicity studies (exposures other than oral or inhalation) ND Short-term studies Albino guinea pigs were treated with cheese cloth patches containing either 0, 0.1, 0.2, or 0.5 mL ethylene cyanohydrin for 24 hr and observed for signs of toxicity until recovery was complete. Two Wistar albino rats and albino guinea pigs (number not stated) received whole body exposure to ethylene cyanohydrin by passing a known volume of air thru sintered glass immersed in the liquid for 1 hr followed by observation (duration not stated) for signs of toxicity. No estimate of concentration was provided. Dermal toxicity: There was an appearance of pain upon administration and little if any evidence of irritation at the site. There was no quantitative evidence of systemic toxicity via the dermal route. Inhalation: No signs of toxicity observed, either intermediate or delayed, in rats and guinea pigs. Results were not quantified. Low toxicity to rats or guinea pigs by skin penetration or inhalation. Sunderman and Kincaid (1953a) Sunderman and Kincaid (1953b) Metabolism/ toxicokinetics S-D rats (3/sex) were used in excretion studies for the separate collection of urine, feces, and expired air. Additional groups of three rats of each sex were used to characterize the concentration of 14C-activity in plasma as a function of time. Rats were dosed with approximately 3.0 mL/kg of isotopically-diluted 14C-ethylene cyanohydrin in water via gavage at a dose of 20 mg/kg and 19 |iCi/kg specific activity. Samples of blood were collected at various intervals up to 116 hr postdose. After animal termination, the carcasses were skinned, and muscle, fat, kidney, skin, spleen, liver, and carcass were collected and prepared for radioanalysis by liquid scintillation counting. Metabolites were isolated and identified in urine samples and hydrolyzed urine samples (acid and heat treated) using thin layer chromatography. 14C-activity was found in urine (53.2% dose), including urinary SCN, feces (7.39%), and expired air as HCN (0.44%) and carbon dioxide (25.6%). Absorption was a first-order process with a rate constant of 1.0 hr 1 corresponding to a half-life of 0.69 hr. The half-life values for the a and (3 phase of plasma clearance are 4.41 and 53.3 hr, respectively. Two components in urine were found to contain 14C activity in addition to urinary thiocyanate. The pharmacokinetics of absorption and excretion were determined, and urinary metabolites were characterized. Sauerhoff et al. (1976b) Mode of action/ mechanistic ND Immunotoxicity ND Neurotoxicity ND ND = no data. 13 Ethylene Cyanohydrin ------- FINAL 11-20-2012 Tests Evaluating Genotoxicity Two mutagenicity studies are presented below indicating that ethylene cyanohydrin has limited mutagenic potential (Zeiger et al., 1992; Voogd and Vet, 1969). Zeiger et al. (1992) evaluated the potential of ethylene cyanohydrin and other test compounds to cause mutagenesis in the Ames assay with preincubation. The chemicals were tested in the presence and absence of Arochlor 1254-induced male S-D rat and male Syrian hamster liver homogenate S9. All chemicals were initially evaluated in a toxicity assay to determine the appropriate dose range for the mutagenicity assay. Chemicals were tested to a toxic dose (as indicated by decreased his+ colonies and/or bacterial lawn), a dose immediately below the toxic dose, to the limit of solubility, or to a maximum of 10 mg/plate. Concurrent solvent and positive controls were run with each trial. A chemical was designated nonmutagenic only after it had been tested in Salmonella typhimurium TA98, TA100, TA1535, and TA97 and/or TA1537, without activation and with 10% and 30% rat and hamster S9. Ethylene cyanohydrin was determined to be nonmutagenic at concentrations up to 10 mg/plate. Voogd and Vet (1969) evaluated the potential of ethylene cyanohydrin and other test compounds to cause mutagenesis in the fluctuation test, using a mutant of Klebsiella pneumoniae that requires uracil and proline for growth. Nutrient broth containing the test substance at 0.015 M was seeded with 100 bacteria/mL and subdivided in 105 portions of 3 mL each. After overnight incubation at 37°C, the total number of streptomycin-resistant and streptomycin-dependent bacteria was determined in 100 subsamples by a pour-plate technique using nutrient agar supplemented with 100 |ig/mL of dihydrostreptomycin. After 3 days incubation at 37°C, the colonies in the dihydrostreptomycin-containing agar were counted. The number of bacteria present in the five remaining subsamples was determined using nutrient-agar without dihydrostreptomycin. The mutation rate was calculated based on the number of subsamples without streptomycin-resistant or dependent mutants using a Poisson distribution. If mutants were present in all subsamples, the mutation rate was estimated by the number of mutants in the median portion. Ethylene cyanohydrin was determined to be nonmutagenic at 0.015 M. The negative control produced the appropriate response, and other evaluated test compounds were found to be mutagenic in this study. Short-term Studies Sunderman and Kincaid (1953a,b) conducted short-term studies of dermal and inhalation toxicity of ethylene cyanohydrin. In the dermal study, albino guinea pigs were treated with cheese cloth patches containing either 0, 0.1, 0.2, or 0.5 mL ethylene cyanohydrin (purity = 92.5%>) taped to shaved skin for 24 hours and observed (duration not stated) for signs of toxicity until recovery was complete. There appeared to be some pain in the exposed animals immediately after treatment but no other signs of toxicity. There was "little if any skin irritation" after 24 hours of exposure. The study authors provided no indication of what observations were conducted but concluded that ethylene cyanohydrin has a low toxicity via the dermal route of exposure. 14 Ethylene Cyanohydrin ------- FINAL 11-20-2012 In the same study, two Wistar albino rats and albino guinea pigs (number not stated) received 1 hour of whole-body exposure to ethylene cyanohydrin by passing a known volume of air through sintered glass immersed in the liquid for 1 hour followed by observation (duration not stated) for signs of toxicity. No estimate of the exposure concentration was provided. No immediate or delayed signs were observed in either rats or guinea pigs, but the study authors provided no indication of the nature or extent of the observations. The study authors concluded that ethylene cyanohydrin exhibited no toxicity in small experimental animals via the inhalation route and low toxicity via dermal route of exposure. Metabolism Studies In a study conducted by Sauerhoff et al. (1976b) performed concurrently with the sub chronic-duration toxicity study previously described (Sauerhoff et al., 1976a), three S-D rats/sex were housed individually in modified glass Roth-type metabolism cages designed for the separate collection of urine, feces, and expired air for excretion studies. Additional groups of three rats/sex were used to characterize the concentration of 14C-activity in plasma as a function of time. These rats were housed individually in stainless steel metabolism cages. Approximately 3.0 mL/kg of isotopically-diluted 14C-ethylene cyanohydrin ([14C]-CN) in water were administered by gavage to provide a dose of 20 mg/kg of the test compound at a specific activity of 19 |iCi/kg. Urine, feces, and expired air (carbon dioxide and hydrogen cyanide [HCN] trapping solutions) were collected up to 120 hours postdose and prepared for radioanalysis. Samples of blood were collected from a freshly cut section of tail at 1, 2, 4, 8, 12, 20, 28, 36, 44, 52, 60, 68, 76, 80, 92, 104, and 116 hours postdose. Plasma samples were prepared and radioassayed. All rats were euthanized by decapitation at 120 hours post dosing with cyanohydrin. The carcasses were skinned, and muscle, fat, kidney, skin, spleen, liver, and carcass were collected and prepared for radioanalysis. Liquid scintillation counting was used to determine the concentration of radioactivity in prepared samples. Metabolites were isolated and characterized in urine samples and hydrolyzed urine samples (acid and heat treated) using thin layer chromatography. The overall recovery of the ethylene cyanohydrin administered dose from urine, feces, expired air, tissues, carcass, and cage washings of all rats was 95.6 ± 5.8% (mean ± SD; Sauerhoff et al., 1976b). 14C-Activity was found in urine (53.2% dose), including urinary thiocyanate (SCN), feces (7.39% dose), and expired air as HCN (0.44% dose) and carbon dioxide (25.6% dose). The plasma concentration of the 14C-activity over time was not sex-dependent. Absorption was a first-order process with a rate constant of 1.0 hour-1 corresponding to a half-life of 0.69 hour. Peak plasma levels of 47 |ig parent equivalents/g plasma were observed 4 hours postdose. The clearance of 14C-activity from plasma was biphasic with half-life values for the a and P phases of plasma clearance of 4.41 and 53.3 hours, respectively. Tissue distribution was not reported. Two unidentified components in urine were found to contain 14C-activity along with the thiocyanate. The major unknown component in urine was hydrolyzable to a compound that exhibited the same retention factor (R,j as the parent. One minor component was found in unhydrolyzed urine that exhibited the same Rf as the parent. The study authors concluded that the low toxicity of ethylene cyanohydrin was due to the rapid elimination in the urine and low rate of conversion to cyanide. 15 Ethylene Cyanohydrin ------- FINAL 11-20-2012 DERIVATION OF PROVISIONAL VALUES Table 4 presents a summary of noncancer reference values. Table 5 presents a summary of cancer values. No cancer values could be derived. Table 4. Summary of Noncancer Reference Values for Ethylene Cyanohydrin (CASRN 109-78-4) Toxicity Type (Units)3 Species/ Sex Critical Effect Reference Value POD Method POD UFC Principal Study Subchronic p-RfD (mg/kg-d) Rat/M/F Questionable effects on brain and heart weights 3 x 10_1 NOAEL 270 1000 Sauerhoff et al. (1976a) Chronic RfD (mg/kg-d) Rat/M Biologically significant decrease in body weight 7 x 10~2 NOAEL 74 1000 Hirose et al. (1980a) Subchronic p-RfC (mg/m3) ND Chronic p-RfC (mg/m3) ND ND = no data. Table 5. Summary of Cancer Values for Ethylene Cyanohydrin (CASRN 109-78-4) Toxicity Type Species/Sex Tumor Type Cancer Value Principal Study p-OSF ND p-IUR ND ND = no data 16 Ethylene Cyanohydrin ------- FINAL 11-20-2012 DERIVATION OF ORAL REFERENCE DOSE Derivation of Subchronic Provisional RfD (Subchronic p-RfD) Two subchronic-duration oral studies were located: Sauerhoff et al. (1976a) and Bachhuber et al. (1955). The highest doses tested were similar in these studies; however, the parameters examined and reported were very limited in the study by Bachhuber et al. (1955). The point of departure (POD) is the NOAEL identified at the highest dose tested (Sauerhoff et al., 1976a). Therefore, the study by Sauerhoff et al. (1976a) serves as the principal study for derivation of the subchronic p-RfD. It should be emphasized that the subchronic p-RfD is based on a free standing NOAEL with questionable effects on brain and heart weights. Sauerhoff et al. (1976a) was conducted prior to the adoption of GLP standards. However, this peer-reviewed study generally meets the standards of study design and performance with regard to numbers of animals, examination of potential toxicity endpoints, and presentation of information. Adjusted for daily exposure: The following dosimetric adjustments were made for each dose in the principal study for dietary treatment. NOAELadj = NOAEL x [conversion to daily dose] = 270 mg/kg-day x (days of week dosed ^ 7 days in week) = 270 mg/kg-day x (7 7) = 270 mg/kg-day Subchronic p-RfD = NOAELadj ^ UFC = 270 mg/kg-day ^ 1000 = 3 x 10-1 mg/kg-day Table 6 summarizes the uncertainty factors (UFs) for the subchronic p-RfD for ethylene cyanohydrin, and the confidence descriptors for the subchronic p-RfD are provided in Table 7. Table 6. UFs for Subchronic p-RfD of Ethylene Cyanohydrin 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 selected because there are no acceptable two-generation reproductive or developmental toxicity studies. 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 in 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 subchronic-duration study was utilized as the critical study. UFC 1000 17 Ethylene Cyanohydrin ------- FINAL 11-20-2012 Table 7. Confidence Descriptor for Subchronic p-RfD for Ethylene Cyanohydrin Confidence Categories Designation3 Discussion Confidence in Study M The study was given a medium confidence level because the peer-reviewed study examined a wide range of doses on growth, food consumption, and hematological effects in male and female rats, but only limited data were available for independent verification of conclusions. Confidence in Database L The database was given a low confidence level because only two subchronic-duration studies were located; no reproductive or developmental studies were located. Confidence in Subchronic p-RfDb L The overall confidence in the subchronic p-RfD is low due to a lack of confidence in the database and the questionable effects on brain and heart weights that were observed. aL = low, M = medium, H = high. bThe overall confidence cannot be greater than the lowest entry in table. Derivation of Chronic Provisional RfD (Chronic p-RfD) One combined chronic-duration toxicity-carcinogenicity report was located that addressed chronic-duration toxicity of ethylene cyanohydrin and is identified as the principal study for derivation of a chronic p-RfD (Hirose et al., 1980a,b). This single report details studies conducted in both the male rat and the male mouse. The critical effect for both species was decreased body weight at the high dose of 221 mg/kg-day for the rat and 539 mg/kg-day for the mouse. The body-weight decrease in mice was about 10% (36.9 g control vs. 36.8 g high-dose group) and is supported by decreased body weight in rats (562 g control vs. 486 g high-dose group). The rats showed decreased terminal body-weight in the two lower dosage groups (504 and 507 g); however, in the absence of standard deviation data, the magnitude of body-weight decrease in these two groups raises concern for the biological relevance in these two groups. Although the importance of this effect in the rat was dismissed in a previously published PPRTV document (U.S. EPA, 2005a) because statistical analyses and standard deviations were not reported, upon further consideration, the 13% decrease in body weights in rats exposed to the high dose is considered a potentially biologically significant effect as it was corroborated in another species. Furthermore, rats showed decreased hematological parameters in exposed groups; and in the absence of standard deviation values, the decreased Hb values in the high-dose groups (14-16%) versus control) are considered potentially biologically relevant. The NOAEL (74 mg/kg-day) identified in male rats based on decreased body weights and supported by decreased hematological parameters (reduced Hb values) is selected as the POD. Hirose et al. (1980) was conducted prior to the adoption of GLP standards. This peer-reviewed study generally meets the standards of study design and performance with regard to numbers of animals, examination of potential toxicity endpoints, and presentation of information. However, test chemical purity was not reported. 18 Ethylene Cyanohydrin ------- FINAL 11-20-2012 Adjusted for daily exposure: The following dosimetric adjustments were made for each dose in the principal study for dietary treatment. NOAELadj = NOAEL x [conversion to daily dose] = 74 mg/kg-day x (days of week dosed ^ 7 days in week) = 74 mg/kg-day x 7 ^ 7 = 74 mg/kg-day Chronic p-RfD = NOAELadj ^ UFC = 74 mg/kg-day ^ 1000 = 7 x 10~2 mg/kg-day Table 8 summarizes the UFs for the chronic p-RfD for ethylene cyanohydrin, and the confidence descriptors for the chronic p-RfD are provided in Table 9. Table 8. UFs for Chronic p-RfD of Ethylene Cyanohydrin 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 selected because there are no acceptable two-generation reproduction studies or developmental studies. 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 in 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 chronic-duration study was utilized as the critical study. UFC 1000 19 Ethylene Cyanohydrin ------- FINAL 11-20-2012 Table 9. Confidence Descriptor for Chronic p-RfD for Ethylene Cyanohydrin Confidence Categories Designation3 Discussion Confidence in Study M The study was given a medium confidence level because the peer-reviewed study examined a variety of hematological effects and organ weight changes, but only limited data were available for independent verification of conclusions. Confidence in Database L The database was given a low confidence level because only two subchronic-duration studies were located; no reproductive or developmental studies were located. Confidence in Subchronic p-RfDb L The overall confidence in the subchronic p-RfD is low due to a lack of confidence in the database and the level of response in the endpoint that was selected for the POD. aL = low, M = medium, H = high. bThe overall confidence cannot be greater than the lowest entry in table. DERIVATION OF INHALATION REFERENCE CONCENTRATIONS No published studies investigating the effects of subchronic- or chronic-duration inhalation toxicity of ethylene cyanohydrin in humans or animals were identified that were acceptable for use for dose response assessment. CANCER WEIGHT-OF-EVIDENCE DESCRIPTOR IRIS (U.S. EPA, 201 la) does not provide a cancer WOE descriptor for the oral or inhalation routes. A combined chronic-duration toxicity-carcinogenicity report detailing studies performed both in the rat and the mouse was located that addressed the carcinogenic potential of ethylene cyanohydrin (Hirose et al., 1980a,b). There was no evidence of carcinogenicity. The cancer WOE descriptor (see Table 10) is considered to be "Inadequate Information to Assess Carcinogenic Potential." 20 Ethylene Cyanohydrin ------- FINAL 11-20-2012 Table 10. Cancer WOE Descriptor for Ethylene Cyanohydrin (CASRN 109-78-4) Possible WOE Descriptor Designation Route of Entry (oral, inhalation, or both) Comments "Carcinogenic to Humans " NS NA There are no human data available. "Likely to be Carcinogenic to Humans " NS NA There is not enough evidence to support this statement. "Suggestive Evidence of Carcinogenic Potential" NS NA There is not enough evidence to support this statement. "Inadequate Information to Assess Carcinogenic Potential" Selected Both One study was conducted in rats and mice for 78 wk at doses resulting in decreased body weights without any increase in the incidence of neoplastic lesions (Hirose et al., 1980a,b). The duration of this study is shorter than the preferred lifetime exposure, which may have prevented identifying carcinogenicity later in life. There are no studies describing carcinogenicity following an inhalation exposure. "Not Likely to be Carcinogenic to Humans " NS NA There is not enough evidence to support this statement. NS = not selected; NA = not applicable. MODE-OF-ACTION (MOA) DISCUSSION The Guidelines for Carcinogen Risk Assessment (U.S. EPA, 2005b) define MOA "... as a sequence of key events and processes starting with interaction of an agent with a cell, proceeding through operational and anatomical changes, and resulting in cancer formation" (p. 1-10). Examples of possible modes of carcinogenic action for any given chemical include "... mutagenicity, mitogenesis, programmed cell death, cytotoxicity with reparative cell proliferation, and immune suppression" (p. 1-10). No carcinogenicity studies in human or animals demonstrating carcinogenic potential of cyanohydrin were located (see the "Cancer Weight-of- Evidence Descriptor" above). MUTAGENIC MOA Ethylene cyanohydrin was not mutagenic in Salmonella typhimurium TA97, TA98, TA100, TA1535, or TA1537 (with or without activation) or Klebsiella pneumoniae (without activation). There is no evidence of carcinogenic potential in humans or animals. DERIVATION OF PROVISIONAL CANCER POTENCY VALUES The lack of data on the carcinogenicity of ethylene cyanohydrin precludes the derivation of quantitative estimates for either oral (p-OSF) or inhalation (p-IUR) exposure. 21 Ethylene Cyanohydrin ------- FINAL 11-20-2012 APPENDIX A. PROVISIONAL SCREENING VALUES There are no provisional screening values for ethylene cyanohydrin. 22 Ethylene Cyanohydrin ------- FINAL 11-20-2012 APPENDIX B. DATA TABLES Table B.l. Body Weights (g) in Male Rodents Treated with Ethylene Cyanohydrin in the Diet for 78 Weeks3 Body weights Dose ppm (HEDadj mg/kg-day) Rat 0(0) 100 (7) 1000 (74) 3000 (221) Initial 148.0 148.6 148.7 150.4 Final 562.0 504.0 (|10) 507.5 (|10) 486.3 (413) Body weights Mouse 0(0) 100(18) 1000 (180) 3000 (539) Initial 36.9 37.1 36.6 36.8 Final 46.7 46.2(41%) 43.2(47%) 42.0(410) aData were obtained from Table 1 on page 3 of the study by Hirose et al. (1980). Percent difference from controls is included in parentheses and was calculated by the reviewers. 23 Ethylene Cyanohydrin ------- FINAL 11-20-2012 Table B.2. Mean Hematological and Blood Biochemical Values of Male Rats Treated with Ethylene Cyanohydrin for 78 Weeks3 Group Dose (ppm) No. of Rats RBC (x 104/mm3) WBC (x 102/mm3) Hb (mg/dL) Ht (%) SGOP (K units) SGPT (K units) SAP (KA units) Glucose (mg/dL) TP (g/dL) BUN (mg/dL) 1 3000 19 624 78 11.8 41.0 130 30 14.5 68 6.9 20 2 1000 24 713 86 13.8 43.6 128 30 14.3 73 6.5 13 3 100 20 701 98 13.8 45.5 130 22 14.8 75 6.9 18 4 0 13 727 103 14.0 49.0 127 23 11.7 74 6.4 19 aHirose et al. (1980a). 24 Ethylene Cyanohydrin ------- FINAL 11-20-2012 APPENDIX C. BMD MODELING OUTPUTS FOR ETHYLENE CYANOHYDRIN No data supported BMD modeling. 25 Ethylene Cyanohydrin ------- FINAL 11-20-2012 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). Last review date: September 17, 2007. Available online at http://toxnet.nlm.nih.eov/cgi-bin/sis/htmlgen7HSDB. Accessed on January 7, 2011. 783980. ATSDR (Agency for Toxic Substances and Disease Registry). (2011) Toxicological profile information sheet. U.S. Department of Health and Human Services, Public Health Service. Available online at http://www.atsdr.cdc.gov/toxprofiles/index.asp. Accessed on January 7, 2011. 684152. Bachhuber, TE; Lalich, JJ; Angevine, DM; et al. (1955) Lathyrus factor activity of beta-aminopropionitrile and related compounds. Proc Soc Exp Biol Med 89(2):294-297. 673229. CalEPA (California Environmental Protection Agency). (2008) All OEHHA acute, 8-hour and chronic reference exposure levels (chRELs) as of December 18, 2008. Office of Environmental Health Hazard Assessment, Sacramento, CA. Available online at http://www.oehha.ca.gov/air/allrels.html. Accessed on January 7, 2011. 595416. CalEPA (California Environmental Protection Agency). (2009a) OEHHA toxicity criteria database. Office of Environmental Health Hazard Assessment, Sacramento, CA. Available online at http://www.oehha.ca.gov/tcdb/. Accessed on January 7, 2011. 595417. CalEPA (California Environmental Protection Agency). (2009b) Hot spots unit risk and cancer potency values. Appendix A. Office of Environmental Health Hazard Assessment, Sacramento, CA. Available online at http://www.oehha.ca.gov/air/hot spots/pdf/CPFs042909.pdf. Accessed on January 7, 2011. 684164. ChemlDplus Advanced. (2011) United States Library of Medicine, Specialized Information Services, Washington, DC. Available online at http://chem.sis.nlm.nih.gov/chemidplus/. Accessed on January 7, 2011. 629639. Hirose, M; Fukushima, S; Shibata, M; et al. (1980a,b) Chronic effects of oral ethylene cyanohydrin on male rats and mice. NagoyaMedJ25(1—2): 1—5. 673233. HSDB (Hazardous Substances Data Bank). (2003) Ethylene cyanohydrin. TOXNET Toxicology data network. National Library of Medicine, Washington, DC. Available online at http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen7HSDB. Accessed on January 7, 2011. 1324484. IARC (International Agency for Research on Cancer). (2011) IARC Monographs on the evaluation of carcinogenic risks to humans. Available online at http://monographs.iarc.fr/ENG/Monographs/PDFs/index.php. Accessed on January 7, 2011. 783869. 26 Ethylene Cyanohydrin ------- FINAL 11-20-2012 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.gov/niosh/npg/npgdcas.html. Accessed on January 7, 2011. 625692. NTP (National Toxicology Program). (2011) Report on carcinogens, 12th edition. 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.gov/ntp/roc/twelfth/rocl2.pdf. Accessed on January 7, 2011. 737606. OSHA (Occupational Safety and Health Administration). (2010) 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 January 7, 2011. 625691. Sauerhoff, MW; Braun, WH; Ramsey, JC. (1976a,b) Toxicological evaluation and pharmacokinetic profile of beta-hydroxypropionitrile in rats. J Toxicol Environ Health 2(l):31-44. 673227. Sunderman, FW; Kincaid, JF. (1953a,b) Toxicity studies of acetone cyanohydrin and ethylene cyanohydrin. Arch IndHyg Occ Med 8(4):371-376. 670415. U.S. EPA (Environmental Protection Agency). (1986) Guidelines for carcinogen risk assessment. Risk Assessment Forum, Washington, DC; EPA/630/R-00/004. September 1986. Available online at http://epa.gov/raf/publications/pdfs/CA%20GUIDELINES 1986.PDF. 199530. U.S. EPA (Environmental Protection Agency). (1988) 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. 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 nepis.epa.gov/Exe/ZvPURL.cgi?Dockev=60001G8L.txt 596444. U.S. EPA (Environmental Protection Agency). (2005a) Provisional peer reviewed toxicity values for ethylene cyanohydrins (CASRN 109-78-4). Superfund Health Risk Technical Support Center, Cincinnati, OH. 1260325 U.S. EPA (Environmental Protection Agency). (2005b) Guidelines for carcinogen risk assessment. Risk Assessment Forum, Washington, DC; EPA/630/P-03/001F. Fed Reg 70(66): 17765-17817. Available online at http://www.epa.gov/raf/publications/pdfs/CANCER G I N FS FINAL 3-25-05.PDF. 086237. 27 Ethylene Cyanohydrin ------- FINAL 11-20-2012 U.S. EPA (Environmental Protection Agency). (2009) 2009 Edition of the drinking water standards and health advisories. Office of Water, Washington, DC; EPA/822/R-09/011. Available online at http://water.epa.gov/action/advisories/drinkine/upload/dwstandards2009.pdf. Accessed on January 7, 2011. 644141. U.S. EPA (Environmental Protection Agency). (201 la) Integrated risk information system (IRIS). Office of Research and Development, National Center for Environmental Assessment, Washington, DC. Available online at http J/www, epa. gov/iris/. Accessed on January 7, 201 1. 192196. U.S. EPA (Environmental Protection Agency). (201 lb) 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.onil.gov/. Accessed on January 7, 2011. 595422. Voogd, CE; Vet, P. (1969) Mutagenic action of ethylene halogenhydrins. CellMol Life Sci 25:85-86. Available online at http://dx.doi.org/10.1007/BF019Q3914. 673231. WHO (World Health Organization). (2011) Online catalogs for the Environmental Health Criteria Series. Available online at http://www.who.int/ipcs/publications/ehc/en/. Accessed on January 7, 2011. 783977. Zeiger, E; Anderson, B; Haworth, S; et al. (1992) Salmonella mutagenicity tests: V. Results from the testing of 311 chemicals. EnvironMolMutagen 19:2-141. Available online at http://dx.doi.org/10.1002/em.2850190603. 095748. 28 Ethylene Cyanohydrin ------- |