SCREENING-LEVEL HAZARD CHARACTERIZATION OF HIGH PRODUCTION VOLUME CHEMICALS SPONSORED CHEMICAL 2-H-Benzimidazole-2-thione, l,3-dihydro-4 (or 5)-methyl-, Zinc Salt (2:1) (CAS No. 61617-00-3) [9th CI Name: 2H-Benzimidazole-2-thione, l,3-dihydro-4 (or 5)-methyl-, zinc salt (2:1)] March 2008 INTERIM Prepared by High Production Volume Chemicals Branch Risk Assessment Division Office of Pollution Prevention and Toxics Environmental Protection Agency 1200 Pennsylvania Avenue, NW Washington, DC 20460-0001 ------- SCREENING-LEVEL HAZARD CHARACTERIZATION OF HIGH PRODUCTION VOLUME CHEMICALS The High Production Volume (HPV) Challenge Program1 is a voluntary initiative aimed at developing and making publicly available screening-level health and environmental effects information on chemicals manufactured in or imported into the United States in quantities greater than one million pounds per year. In the Challenge Program, producers and importers of HPV chemicals voluntarily sponsor chemicals; sponsorship entails the identification and initial assessment of the adequacy of existing toxicity data/information, conducting new testing if adequate data do not exist, and making both new and existing data and information available to the public. Each complete data submission contains data on 18 internationally agreed to "SIDS" (Screening Information Data Set1'2) endpoints that are screening-level indicators of potential hazards (toxicity) for humans or the environment. The Environmental Protection Agency's Office of Pollution Prevention and Toxics (OPPT) is evaluating the data submitted in the HPV Challenge Program on approximately 1400 sponsored chemicals. OPPT is using a hazard- based screening process to prioritize review of the submissions. The hazard-based screening process consists of two tiers described below briefly and in more detail on the Hazard Characterization website3. Tier 1 is a computerized sorting process whereby key elements of a submitted data set are compared to established criteria to "bin" chemicals/categories for OPPT review. This is an automated process performed on the data as submitted by the sponsor. It does not include evaluation of the quality or completeness of the data. In Tier 2, a screening-level hazard characterization is developed by EPA that consists of an objective evaluation of the quality and completeness of the data set provided in the Challenge Program submissions. The evaluation is performed according to established EPA guidance2'4 and is based primarily on hazard data provided by sponsors. EPA may also include additional or updated hazard information of which EPA, sponsors or other parties have become aware. The hazard characterization may also identify data gaps that will become the basis for a subsequent data needs assessment where deemed necessary. Under the HPV Challenge Program, chemicals that have similar chemical structures, properties and biological activities may be grouped together and their data shared across the resulting category. This approach often significantly reduces the need for conducting tests for all endpoints for all category members. As part of Tier 2, evaluation of chemical category rationale and composition and data extrapolation(s) among category members is performed in accord with established EPA2 and OECD5 guidance. The screening-level hazard characterizations that emerge from Tier 2 are important contributors to OPPT's existing chemicals review process. These hazard characterizations are technical documents intended to support subsequent decisions and actions by OPPT. Accordingly, the documents are not written with the goal of informing the general public. However, they do provide a vehicle for public access to a concise assessment of the raw technical data on HPV chemicals and provide information previously not readily available to the public. The public, including sponsors, may offer comments on the hazard characterization documents. The screening-level hazard characterizations, as the name indicates, do not evaluate the potential risks of a chemical or a chemical category, but will serve as a starting point for such reviews. In 2007, EPA received data on uses of and exposures to high-volume TSCA existing chemicals, submitted in accordance with the requirements of the Inventory Update Reporting (IUR) rule. For the chemicals in the HPV Challenge Program, EPA will review the IUR data to evaluate exposure potential. The resulting exposure information will then be combined with the screening-level hazard characterizations to develop screening-level risk characterizations4'6. The screening-level risk characterizations will inform EPA on the need for further work on individual chemicals or categories. Efforts are currently underway to consider how best to utilize these screening-level risk characterizations as part of a risk- based decision-making process on HPV chemicals which applies the results of the successful U.S. High Production Volume Challenge Program and the IUR to support judgments concerning the need, if any, for further action. 1 U.S. EPA. High Production Volume (HPV) Challenge Program; http://www.epa.gov/chemrtk/index.htm. 2 U.S. EPA. HPV Challenge Program - Information Sources; http://www.epa.gov/chemrtk/pubs/general/guidocs.htm. 3 U.S. EPA. HPV Chemicals Hazard Characterization website (http://www.epa.gov/hpvis/abouthc.html). 4 U.S. EPA. Risk Assessment Guidelines; http://cfpub.epa.gov/ncea/raf/rafguid.cfm. 5 OECD. Guidance on the Development and Use of Chemical Categories; http://www.oecd.org/dataoecd/60/47/1947509.pdf. 6 U.S. EPA. Risk Characterization Program; http://www.epa.gov/osa/spc/2riskchr.htm. 2 ------- SCREENING-LEVEL HAZARD CHARACTERIZATION 2-H-Benzimidazole-2-thione, l,3-dihydro-4 (or 5)-methyl-, zinc salt (2:1) (CAS No. 61617-00-3) Introduction The sponsor, R.T. Vanderbilt Company, submitted a Test Plan and Robust Summaries to EPA for 2-H-benzimidazole-2-thione, l,3-dihydro-4 (or 5)-methyl-, zinc salt (2:1) (CAS No. 61617-00-3; 9th CI name: 2H-benzimidazole-2-thione, l,3-dihydro-4 [or 5]-methyl-, zinc salt [2:1]) on January 2, 2003. EPA posted the submission on the ChemRTK HPV Challenge website on January 31, 2003 (http://www.epa.gov/chemrtk/pubs/summaries/zincmerc/cl4230tc.htm). EPA comments on the original submission were posted to the website on June 17, 2003. Public comments were also received and posted to the website. The sponsor submitted updated/revised documents on November 3, 2006, which were posted to the ChemRTK website on January 30, 2008. This screening-level hazard characterization is based primarily on the review of the test plan and robust summaries of studies submitted by the sponsor(s) under the HPV Challenge Program. In preparing the hazard characterization, EPA considered its own comments and public comments on the original submission as well as the sponsor's responses to comments and revisions made to the submission. A summary table of SIDS endpoint data with the structure(s) of the sponsored chemical(s) is included in the Appendix. The screening-level hazard characterization for environmental and human health effects is based largely on SIDS endpoints and is described according to established EPA or OECD effect level definitions and hazard assessment practices. Sum m ;m-Conclusion The lou k of 2-1 l-hcii/iniidaAilc-2-ihioiie. I. ^-dihulro-. 4 (or 5)-nielh\ I-. /inc sail (2 11 indicates llial lis potential lo hioacciininlale is e\pec led lo he low 2-11-I >cii/iniidaAilc-2-ihioiie. I. '-dihulro-. 4 (or 5 )-niclh\ I-. /inc sail (2 h is not readiK biodegradable, indicating llial il lias ilic poiciiiial lo peiMsi in llie en\ iroiinieni The e\ alnalion of a\ ailahle lo\icil> dala lor fish. aquatic 11 in eriehrales and aquatic plants indicates llial I lie potential acnie lia/ard of 2-1 l-heii/iniida/ole-2-iliioiie. I. ^-dihulro-4 (or 5i-nielli> I-. /me sail (2 11 to aqnalic organisms is moderate \cnie oral, inhalation and dermal lo\icil> of 2-1 l-heii/iniida/ole-2-ihioiie. I. ^-dihulro-4 (or 5i-nielh\ I-. /inc salt (2 11 to rals is low. 2-1 l-l!eii/iniida/ole-2-ilnoiie. I. '-dih\dro-4 (or 5i-nielh\ I-. /inc sail (2 11 is noi irritating to rahhil skin nre\es In a dielars combined repealed-dose reprodiicli\e de\ elopnienial lo\icil> screening lest, smns of parental lo\icil> included decreased food consumption and hods weight, clinical cheniism alterations, decreased spleen and ih\ inns w eights and hisiopalhological changes (lis perirophs i in the I in cr and th\ roid Maternal mortality iiidicali\e of difficulties at pariiiriiion was ohser\ed al the mid- and high-doses \i the high-dose, decreases in ilic iiiimher of maliiig pairs and ilic iinmher of pregnancies, an increase in prc-coiial mucin al and an apparent lack of esirons c> clicils were ohser\ ed. \l the niid-and low-doses, an increase in gestation length was ohsen ed 2-11- I!eii/iniida/ole-2-ilnoiie. I. '-dih\dro-4 (or 5i-nielh\ I-. /inc sail (2 11 did noi induce gene mutation in hacleria and did noi induce chromosomal aherrations m mammalian cells in viim I lie potential health lia/ard of 2-1 l-heii/innda/iile-2-ihioiie. I. '-dih\dro-4 inr 5i-nielh\ I-. /inc sail (2 11 is high hased on reprodncliN e de\ elopnienial lo\icil> \o dala gaps were identified under ilic I ll'N ( hallenge I'rograni 3 ------- 1. Physical-Chemical Properties and Environmental Fate A summary of physical-chemical and environmental fate data submitted is provided in the Appendix. For the purpose of the screening-level hazard characterization, the review and summary of these data were limited to the octanol-water partition coefficient and biodegradation endpoints as indicators of bioaccumulation and persistence, respectively. Octanol-Water Partition Coefficient LogKow: 3.07 (measured) Biodegradation In a ready biodegradation test using non-adapted sludge as the inoculum, 27% of 2-H-benzimidazole-2-thione, 1,3-dihydro-, 4 (or 5)-methyl-, zinc salt (2:1) had degraded after 28 days. 2-H-benzimidazole-2-thione, 1,3-dihydro-, 4 (or 5)-methyl-, zinc salt (2:1) is not readily biodegradable. Conclusion: The log Kow of 2-H-benzimidazole-2-thione, 1,3-dihydro-, 4 (or 5)-methyl-, zinc salt (2:1) indicates that its potential to bioaccumulate is expected to be low. 2-H-Benzimidazole-2-thione, 1,3-dihydro-, 4 (or 5)-methyl-, zinc salt (2:1) is not readily biodegradable, indicating that it has the potential to persist in the environment. 2. Environmental Effects - Aquatic Toxicity Acute Toxicity to Fish Rainbow trout (Oncorhynchus mykiss) were exposed 2-H-benzimidazole-2-thione, l,3-dihydro-4 (or 5)-methyl-, zinc salt (2:1) at nominal concentrations of 0.67, 1.2, 2.1, 3.8, 6.7 or 12 mg/L under static renewal conditions for 96 hours. Measured concentrations ranged from 87 to 120% of nominal concentrations. 96-h LCS0 = 5.6 mg/L Acute Toxicity to Aquatic Invertebrates Water fleas (Daphnia magna) were exposed to 2-H-benzimidazole-2-thione, l,3-dihydro-4 (or 5)-methyl-, zinc salt (2:1) at nominal concentrations of 0.08, 0.14, 0.25, 0.45, 0.8, 1.4, 2.5, 4.5 or 8 mg/L under static conditions for 48 hours. Mean measured concentrations were in excess of 120% of the nominal concentrations. Although specific measurements at each concentration were not provided, the LC50 value provided is based on measured concentrations. 48-h LCS0 = 1.4 mg/L Toxicity to Aquatic Plants Green algae (Scenedesmus subspicatus) were exposed to 2-H-benzimidazole-2-thione, l,3-dihydro-4 (or 5)-methyl-, zinc salt (2:1) at nominal concentrations of 0.69, 1.38, 2.75, 5.5 or 11 mg/L under static conditions for 72 hours. Measured concentrations ranged from 85 to 96% of nominal concentrations. 72-h EC50 (biomass) = 6.6 mg/L 72-h EC50 (growth) = 10 mg/L Conclusion: The evaluation of available toxicity data for fish, aquatic invertebrates and aquatic plants indicates that the potential acute hazard of 2-H-benzimidazole-2-thione, l,3-dihydro-4 (or 5)-methyl-, zinc salt (2:1) to aquatic organisms is moderate. 4 ------- 3. Human Health Effects Acute Oral Toxicity Sherman-Wistar rats (5 males/dose) were administered 2-H-benzimidazole-2-thione, 1,3-dihydro-, 4 (or 5)-methyl-, zinc salt (2:1) in corn oil via gavage at 0, 0.5, 1.0, 2.0, 4.0 or 8.0 mL/kg-bw and observed for up to 14 days. Mortality occurred at the highest dose. At 4.0 mL/kg-bw, all animals were severely depressed within 12 hours of dosing. No abnormalities were noted in any test animals at necropsy. LDS0 ~ 800 mg/kg-bw Acute Inhalation Toxicity Sprague-Dawley rats (5/dose, sex ratio not provided) were exposed nose-only to 2-H-benzimidazole-2-thione, 1,3-dihydro-, 4 (or 5)-methyl-, zinc salt (2:1) at measured aerosol concentrations of 0 or 2.12 mg/L for 4 hours. Exposure did not result in any deaths. LC50 > 2.12 mg/L Acute Dermal Toxicity Sprague-Dawley rats (5/sex/dose) were administered 2-H-benzimidazole-2-thione, 1,3-dihydro-, 4 (or 5)-methyl-, zinc salt (2:1) via the dermal route at 2000 mg/kg-bw to clipped, intact skin for 24 hours under semi-occluded conditions. There were no deaths, signs of systemic toxicity or signs of dermal irritation and all animals showed expected body weight gains. No abnormalities were noted at necropsy. LDS0 > 2000 mg/kg-bw Repeated-Dose Toxicity In a combined repeated-dose/reproductive/developmental toxicity screening test, Sprague-Dawley rats (10/sex/dose) were administered 2-H-benzimidazole-2-thione, l,3-dihydro-4 (or 5)-methyl-, zinc salt (2:1) in the diet at 1000, 2750 or 7500 ppm (~ 50, 138 or 375 mg/kg-bw/day) for 14 days throughout mating and gestation and up to day 5 of lactation (up to 47 days total). Doses were reduced to 900, 2500 or 6750 ppm on day 29 (~ 45, 125 or 338 mg/kg- bw/day) and the high-dose group was further reduced to 5500 ppm (~ 275 mg/kg-bw/day) on day 33. One high- dose female and eight mid-dose females were sacrificed in extremis during late gestation. The majority of these mortalities were due to a possible impairment of the process of parturition. Dose dependent reductions in food consumption and body weight gain were observed at all doses. Clinical chemistry alterations, including increases in cholesterol, plasma creatinine, phosphorous and chloride levels, were observed at all doses. Decreased liver weights were observed at the mid- and high-dose levels and decreased spleen and thymus weights were observed at all doses. Histopathological changes including hypertrophy of the liver and thyroid were observed at all doses. LOAEL ~ 45 - 50 mg/kg-bw/day (based on decreased food consumption and body weight, clinical chemistry alterations, decreased spleen and thymus weights and histopathological changes [hypertrophy] in the liver and thyroid) Reproductive/Developmental Toxicity In the combined repeated-dose/reproductive/developmental toxicity screening test described previously, there was a marked reduction in the number of mating pairs (4/10) and only 2/10 achieved pregnancy at the high-dose. One pregnant female was sacrificed due to possible dystocia. Females with no evidence of mating showed a lack of estrous cyclicity. An increase in pre-coital interval was also observed. Eight females at the mid-dose were sacrificed in extremis during late gestation and the appearance of offspring in six of these animals was indicative of difficulties at parturition. Of the females at the mid-dose that started delivery, there was an apparent increase in gestation length. At the low dose, all females produced a live litter, but there was a slight increase in gestation length. There were no clinical findings associated with live offspring during the study. LOAEL (systemic toxicity) ~ 45 - 50 mg/kg-bw/day (based on decreased food consumption and body weight, clinical chemistry alterations, decreased spleen and thymus weights and histopathological changes to the liver and thyroid) LOAEL (reproductive/developmental toxicity) ~ 45 - 50 mg/kg-bw/day (based on increased gestation length) 5 ------- Genetic Toxicity - Gene Mutation In vitro Salmonella typhimurium strains TA1535, TA1537, TA102, TA98 and TA100 were exposed to 2-H-benzimidazole- 2-thione, 1,3-dihydro-, 4 (or 5)-methyl-, zinc salt (2:1) at concentrations of 0, 50, 150, 500, 1500 or 5000 |.ig/platc in the presence and absence of metabolic activation. The cytotoxic concentration was 5000 |.ig/platc with and without metabolic activation. Positive controls were tested concurrently, but data were not provided. A slight decrease in the frequency of revertant colonies was observed at the highest concentration. 2-H-Benzimidazole-2-thione, l,3-dihydro-4 (or 5)-methyl-, zinc salt (2:1) was not mutagenic in this assay. Genetic Toxicity - Chromosomal Aberrations In vitro Human lymphocytes were exposed to 2-H-benzimidazole-2-thione, 1,3-dihydro-, 4 (or 5)-methyl-, zinc salt (2:1) at concentrations of 0, 31.25, 62.5, 125, 250, 375 or 500 |_ig/mL in the presence and absence of metabolic activation and examined for chromosomal aberrations. Lymphocytes were exposed for 4 hours in the presence of metabolic activation, followed by a 20-hour expression period. In the absence of metabolic activation, cells were exposed for 4 hours followed by a 20-hour expression period in one trial and a 24-hour expression period in a second trial. Positive and negative controls were tested concurrently and responded appropriately. 2-H-Benzimidazole-2-thione, l,3-dihydro-4 (or 5)-methyl-, zinc salt (2:1) did not induce chromosomal aberrations in this assay. Additional Information Skin Irritation New Zealand White rabbits (6, sex not specified) were administered the 2-H-benzimidazole-2-thione, 1,3-dihydro-, 4 (or 5)-methyl-, zinc salt (2:1) via the dermal route at 0.5 g to four sites (two abraded, two unabraded). The test sites were occluded for 24 hours. After exposure, treated areas were examined for up to 48 hours. Irritation scores were zero at all observation points. 2-H-benzimidazole-2-thione, 1,3-dihydro-, 4 (or 5)-methyl-, zinc salt (2:1) was not irritating to rabbit skin in this study. Eye Irritation New Zealand White rabbits (6, sex not specified) had 0.1 g of 2-H-Benzimidazole-2-thione, l,3-dihydro-4 (or 5)- methyl-, zinc salt (2:1) instilled into the right eye; the left eye served as a control. Eyes were not washed. After instillation, eyes were examined for up to 7 days. The average Draize score was 0.3 on a scale of 0 - 110. 2-H-benzimidazole-2-thione, 1,3-dihydro-, 4 (or 5)-methyl-, zinc salt (2:1) was not irritating to the rabbit eye in this study. Conclusion: Acute oral, inhalation and dermal toxicity of 2-H-benzimidazole-2-thione, l,3-dihydro-4 (or 5)-methyl-, zinc salt (2:1) to rats is low. 2-H-Benzimidazole-2-thione, l,3-dihydro-4 (or 5)-methyl-, zinc salt (2:1) is not irritating to rabbit skin or eyes. In a dietary combined repeated-dose/reproductive/developmental toxicity screening test, signs of parental toxicity included decreased food consumption and body weight, clinical chemistry alterations, decreased spleen and thymus weights and histopathological changes (hypertrophy) in the liver and thyroid. Maternal mortality indicative of difficulties at parturition was observed at the mid- and high-doses. At the high-dose, decreases in the number of mating pairs and the number of pregnancies, an increase in pre-coital interval and an apparent lack of estrous cyclicity were observed. At the mid- and low-doses, an increase in gestation length was observed. 2-H-Benzimidazole-2-thione, l,3-dihydro-4 (or 5)-methyl-, zinc salt (2:1) did not induce gene mutation in bacteria and did not induce chromosomal aberrations in mammalian cells in vitro. The potential health hazard of 2-H-benzimidazole-2-thione, l,3-dihydro-4 (or 5)-methyl-, zinc salt (2:1) is high based on reproductive/developmental toxicity. 4. Hazard Characterization 6 ------- The log Kow of 2-H-benzimidazole-2-thione, 1,3-dihydro-, 4 (or 5)-methyl-, zinc salt (2:1) indicates that its potential to bioaccumulate is expected to be low. 2-H-Benzimidazole-2-thione, 1,3-dihydro-, 4 (or 5)-methyl-, zinc salt (2:1) is not readily biodegradable, indicating that it has the potential to persist in the environment. The evaluation of available toxicity data for fish, aquatic invertebrates and aquatic plants indicates that the potential hazard of 2-H-benzimidazole-2-thione, l,3-dihydro-4 (or 5)-methyl-, zinc salt (2:1) to aquatic organisms is moderate. Acute oral, inhalation and dermal toxicity of 2-H-benzimidazole-2-thione, l,3-dihydro-4 (or 5)-methyl-, zinc salt (2:1) to rats is low. 2-H-Benzimidazole-2-thione, l,3-dihydro-4 (or 5)-methyl-, zinc salt (2:1) is not irritating to rabbit skin or eyes. In a dietary combined repeated-dose/reproductive/developmental toxicity screening test, signs of parental toxicity included decreased food consumption and body weight, clinical chemistry alterations, decreased spleen and thymus weights and histopathological changes (hypertrophy) in the liver and thyroid. Maternal mortality indicative of difficulties at parturition was observed at the mid- and high-doses. At the high-dose, decreases in the number of mating pairs and the number of pregnancies, an increase in pre-coital interval and an apparent lack of estrous cyclicity were observed. At the mid- and low-doses, an increase in gestation length was observed. 2-H- Benzimidazole-2-thione, l,3-dihydro-4 (or 5)-methyl-, zinc salt (2:1) did not induce gene mutation in bacteria and did not induce chromosomal aberrations in mammalian cells in vitro. The potential health hazard of 2-H-benzimidazole-2-thione, l,3-dihydro-4 (or 5)-methyl-, zinc salt (2:1) is high based on reproductive/developmental toxicity. 5. Data Gaps No data gaps were identified under the HPV Challenge Program. 7 ------- APPENDIX Summary Tabic of the Screening Information Data Set as Submitted underthe U.S. HPV Challenge Program Endpoints SPONSORED CHEMICAL 2-H-Ben/Jmida/x)le-2-thione, 1,3-dihvdro-, 4 (or 5)-mcthvl-, zinc salt (2:1) (61617-00-3) Structure Summary of Physical-Chemical Properties and Environmental Fate Data Melting Point (°C) >700 Boiling Point (°C) 605 (estimated) Vapor Pressure (hPa at 25°C) 6.19 x 10"14 (estimated) Log K„w 3.07 Water Solubility (mg/L at 25°C) 32 at 20°C Indirect (OH) Photodegradation Half-life (t1/2) 1.205 h (estimated) Stability in Water (Hydrolysis) (ti/2) Stable. Lacks hydrolysable functional groups. Fugacity (Level III Model) Air (%) Water (%) Soil (%) Sediment (%) 0.002 17.5 82.1 0.41 Biodegradation at 28 days (%) 27 Not readily biodegradable Summary of Environmental Effects - Aquatic Toxicity Data Fish 96-h LCS0 (mg/L) 5.6 Aquatic Invertebrates 48-h ECS0 (mg/L) 1.4 Aquatic Plants 72-h ECS0 (mg/L) (growth) (biomass) 10 6.6 8 ------- Summary Tabic of the Screening Information Data Set as Submitted under the U.S. HPV Challenge Program Endpoints SPONSORED CHEMICAL 2-H-Ben/imi(la/()le-2-thione. 1,3-dihvdro-, 4 (or 5)-mcthvl-, zinc salt (2:1) (61617-00-3) Summary of Human Health Data Acute Oral Toxicity LDS0 (mg/kg-bw) -800 Acute Inhalation Toxicity LCS0 (mg/L) >2.13 Acute Dermal Toxicity LDS0 (mg/kg-bw) >2000 Repeated-Dose Toxicity NOAEL/LOAEL Oral (mg/kg-bw/day) NOAEL = Not established LOAEL -45-50 Reproductive/Developmental Toxicity NOAEL/LOAEL Oral (mg/kg-bw/day) Systemic and Reproductive/Developmental Toxicity NOAEL = Not established LOAEL - 45 - 50 Genetic Toxicity - Gene Mutation In vitro Negative Genetic Toxicity - Chromosomal Aberrations In vitro Negative Additional Information - Skin Irritation Eye Irritation Not irritating Not irritating 9 ------- |