U.S. Environmental Protection Agency Hazard Characterization Document December, 2012 SCREENING-LEVEL HAZARD CHARACTERIZATION SPONSORED CHEMICAL Benzoyl Chloride (CASRN 98-88-4) SUPPORTING CHEMICALS Benzoic Acid (CASRN 65-85-0) Hydrochloric Acid (CASRN 7647-01-0) The High Production Volume (HPV) Challenge Program1 was conceived as 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 sponsored chemicals; sponsorship entailed the identification and initial assessment of the adequacy of existing toxicity data/information, conducting new testing if adequate data did 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 Set ) 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 by developing hazard characterizations (HCs). These HCs consist of an evaluation of the quality and completeness of the data set provided in the Challenge Program submissions. They are not intended to be definitive statements regarding the possibility of unreasonable risk of injury to health or the environment. The evaluation is performed according to established EPA guidance ' and is based primarily on hazard data provided by sponsors; however, 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. In order to determine whether any new hazard information was developed since the time of the HPV submission, a search of the following databases was made from one year prior to the date of the HPV Challenge submission to the present: (ChemID to locate available data sources including Medline/PubMed, Toxline, HSDB, IRIS, NTP, AT SDR, IARC, EXTOXNET, EPA SRS, etc.), STN/CAS online databases (Registry file for locators, ChemAbs for toxicology data, RTECS, 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. Risk Assessment Guidelines; http://cfpub.epa.gov/ncea/raf/rafguid.cfm. 4 European Chemicals Agency, http://echa.europa.eu. ------- U.S. Environmental Protection Agency Hazard Characterization Document December, 2012 Merck, etc.) and Science Direct and ECHA4. OPPT's focus on these specific sources is based on their being of high quality, highly relevant to hazard characterization, and publicly available. OPPT does not develop HCs for those HPV chemicals which have already been assessed internationally through the HPV program of the Organization for Economic Cooperation and Development (OECD) and for which Screening Initial Data Set (SIDS) Initial Assessment Reports (SIAR) and SIDS Initial Assessment Profiles (SIAP) are available. These documents are presented in an international forum that involves review and endorsement by governmental authorities around the world. OPPT is an active participant in these meetings and accepts these documents as reliable screening-level hazard assessments. These hazard characterizations are technical documents intended to inform 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. 2 ------- U.S. Environmental Protection Agency Hazard Characterization Document December, 2012 Sponsored Chemical CASRN 98-88-4 Supporting Chemicals CASRN 65-85-0 CASRN 7647-01-0 Chemical Abstract Index Sponsored Chemical Name Benzoyl chloride Supporting Chemicals Benzoic acid Hydrochloric acid Structural Formula Sponsored Chemical SMILES: Q=C(c(cccc 1 )c 1 )C1 Summary Benzoyl chloride is a colorless liquid with moderate vapor pressure that reacts immediately with water to produce hydrochloric acid and benzoic acid. It would be expected to have high mobility in soil and volatilization would be high based on its Henry's Law constant; however, the rapid rate of hydrolysis suggests that these and other environmental fate pathways are not applicable for this substance. The rate of atmospheric photooxidation is slow. Benzoyl chloride is expected to have low persistence (PI) and low bioaccumulation potential (Bl). Human Health Hazard Summary The acute oral and dermal toxicity of benzoyl chloride (CASRN 98-88-4) is low in rats and rabbits, respectively. The acute inhalation toxicity of benzoyl chloride (CASRN 98-88-4) in rats is high. A 28-day repeated-dose toxicity study showed microscopic lesions in the lung of rats administered 0.025 mg/L/day of the supporting chemical benzoic acid (CASRN 65-85-0) via aerosol. Three 90-day inhalation repeated-dose toxicity studies were submitted for the supporting chemical hydrochloric acid (CASRN 7647-01-0). In the study with mice, mortality was observed in males at 0.0149 mg/L/day (NOAEC not established) and moribundity in females at 0.07496 mg/L/day. The NOAEC for systemic toxicity in female mice was 0.0298 mg/L/day. In another study, mortality was observed in female rats at 0.0746 mg/L/day. The NOAEC for systemic toxicity in female rats was 0.0298. In the same study histopathological inflammatory changes of the nasal cavity was observed at > 0.0149 and 0.0298 in female and male rats respectively. The NOAEC for local toxicity in female rats is not established and the NOAEC in male rats is 0.0149 mg/L/day. In another study with rats rhinitis was observed in both sexes at all concentrations. The LOAEC for local toxicity is 0.0149 mg/L/day; the NOAEC for local toxicity is not established. In the 90-day inhalation repeated-dose toxicity studies previously mentioned with supporting chemical hydrochloric acid (CASRN 7647-01-0), no treatment- related effects on reproductive tissues and organs in mice and rats were observed during Chemical Abstract Service Registry Number (CASRN) 3 ------- U.S. Environmental Protection Agency Hazard Characterization Document December, 2012 histopathological examinations. No treatment-related effects were observed in dams, growth and development of offsprings, in a four-generation developmental toxicity study with supporting chemical benzoic acid (CASRN 65-85-0) administered via the diet. The NOAEL for maternal and developmental toxicity is 750 mg/kg-bw/day. The Benzoyl chloride (CASRN 98-88-4) induced gene mutations in bacteria in vitro; but did not induce chromosomal aberrations in mice in vivo. Benzoyl chloride (CASRN 98-88-4) is corrosive to the rabbit eye and irritating and corrosive to the rabbit skin. Benzoyl chloride has the potential to induce tumors in female mice. No data gaps were identified under the HPV Challenge Program. Environmental Hazard Summary For benzoyl chloride, the 96-hour LC50 for fish is 34.1 mg/L. Based on the supporting chemical, benzoic acid, the 48-h EC50 for aquatic invertebrates is > 100 mg/L. The72-h EC50 of benzoyl chloride for aquatic plants is 96 and 45 mg/L for growth rate and biomass, respectively. No data gaps were identified under the HPV Challenge Program. 4 ------- U.S. Environmental Protection Agency Hazard Characterization Document December, 2012 The sponsor, American Chemistry Council (ACC) Benzoates Panel, submitted a Test Plan and Robust Summaries to EPA for benzoyl chloride (CASRN 99-88-4; 9th CI name: benzoyl chloride) on December 24, 2003. EPA posted the submission on the ChemRTK HPV Challenge website on February 18, 2004 (http://www.epa.gov/oppt/chemrtk/pubs/summaries/benzchlr/cl4969tc.htm). EPA comments on the original submission were posted to the website on June 22, 2004. Public comments were also received and posted to the website. The sponsor submitted updated/revised documents on August 15, 2005, which were posted to the ChemRTK website on September 16, 2005. Justification for Supporting Chemicals Benzoyl chloride undergoes rapid hydrolysis to benzoic acid (CASRN 65-85-0) and hydrochloric acid (CASRN 7647-01-0). EPA comments state that "given the rapid hydrolysis of benzoyl chloride at low pH, the submitter should consider using data on the hydrolysis products, benzoic acid and hydrogen chloride, to address the repeated-dose, reproductive and developmental toxicity endpoints instead of the proposed OECD TG 422" and that data on benzoic acid can be used to address the algal toxicity endpoint. As recommended by the EPA, the sponsor provided data for benzoic acid and hydrochloric acid to satisfy both aquatic and human health toxicity endpoints. Upon further review, hydrochloric acid is not considered an adequate supporting chemical for benzoyl chloride to satisfy aquatic toxicity endpoints. Aquatic toxicity test guidelines require neutralization of the test media before test initiation and since tests with hydrochloric acid are not neutralized the resulting toxicity is overly conservative due to deviations in pH. Additional information on hydrogen chloride can be found at the following website: http://www.chem.unep.ch/irptc/sids/oecdsids/7647010 1. Chemical Identity 1.1 Identification and Purity Benzoyl chloride also known as benzenecarbonyl chloride is an organochlorine compound with the formula C6H5COCI. It is a colorless very pungent liquid mainly used for the production of peroxides but is generally useful in other area such as in the production of dyes, perfumes, pharmaceuticals, and resins. It reacts with water to produce hydrochloric acid and benzoic acid. 1.2 Physical-Chemical Properties The physical-chemical properties of benzoyl chloride are summarized in Table 1, while the environmental fate properties are provided in Table 2. Physical-Chemical Properties Characterization Benzoyl chloride is a colorless liquid with moderate vapor pressure. It reacts rapidly with water and therefore, the water solubility of this substance cannot be measured or estimated. 5 ------- U.S. Environmental Protection Agency Hazard Characterization Document December, 2012 Table 1. Physical-Chemical Properties of Benzoyl Chloride1 Property Benzoyl chloride CASRN 98-88-4 Molecular Weight 140.47 Physical State Transparent, colorless liquid Melting Point -1°C (measured); -0.6°C (measured) Boiling Point 197.2°C (measured); 198.3°C (measured); Vapor Pressure 0.38-1.0 mm Hg at 20°C (measured); 1.0 mm Hg at 32°C (measured); 2.8 mm Hg at 50°C (measured) Dissociation Constant (pKa) Not applicable Henry's Law Constant Not applicable due to hydrolysis Water Solubility Not applicable due to hydrolysis Log K0w Not applicable due to hydrolysis 'American Chemistry Council Benzoates Panel. 2005. Revised Test Plan and Robust Summary for Benzoyl Chloride. Available online at http://www.epa.gov/chemrtk/pubs/summaries/benzchlr/cl4969tc.htm as of March 7, 2012. 2. General Information on Exposure 2.1 Production Volume and Use Pattern Benzoyl chloride had an aggregated production and/or import volume in the United States between 10 to 50 million pounds during calendar year 2005. Non-confidential information in the IUR indicated that the industrial processing and uses of the chemical include other basic organic chemical manufacturing as intermediates. Commercial and consumer uses for the chemical were claimed confidential. 2.2 Environmental Exposure and Fate Benzoyl chloride is expected to have high mobility in soil, and volatilization is expected to be high; however, the rapid rate of hydrolysis indicates that volatilization, mobility in soil, and biodegradation will not be important environmental fate processes. The hydrolysis half-life of benzoyl chloride was reported as 16 seconds at 2°C. Benzoyl chloride was reported to achieve 92% of its theoretical biological oxygen demand (BOD) after 20 days using the closed bottle (OECD 301D) test; however, due to the rapid rate of hydrolysis these results likely pertain to the hydrolysis product (benzoic acid), not the parent substance. The rate of atmospheric photooxidation is slow. Benzoyl chloride is expected to have low persistence (PI) and low bioaccumulation potential (Bl). 6 ------- U.S. Environmental Protection Agency Hazard Characterization Document December, 2012 Table 2. Environmental Fate Characteristics of Benzoyl Chloride1 Property Benzoyl chloride CASRN 98-88-4 Photodegradation Half-life 6.0 days (estimated)2 Hydrolysis Half-life 16 seconds5 Biodegradation Not applicable due to hydrolysis Bioaccumulation Factor Not applicable due to hydrolysis Log Koc Not applicable due to hydrolysis Fugacity (Level III Model)2'3 Air (%) Water (%) Soil (%) Sediment (%) 100 <0.1 <0.1 <0.1 Persistence4 PI (low) Bioaccumulation4 Bl (low) 'American Chemistry Council Benzoates Panel. 2005. Revised Test Plan and Robust Summary for Benzoyl Chloride. Available online at http://www.epa. go v/chemrtk/pubs/ summaries/benzchlr/c 14969tc .htm as of March 7,2012. 2U.S. EPA. 2012. Estimation Programs Interface Suite™ for Microsoft® Windows, v4.10. U.S. Environmental Protection Agency, Washington, DC, USA. Available online at http://www.epa.gov/opptintr/exposure/pubs/episuitedl.htm as of March 7, 2012. 3Half-lives of 0.004 hours were used for the water, soil, and sediment compartments while a half-life of 144 hours was used for the atmosphere compartment. 4Federal Register. 1999. Category for Persistent, Bioaccumulative, and Toxic New Chemical Substances. Federal Register 64, Number 213 (November 4, 1999) pp. 60194-60204. 5Benzoyl Chloride hydrolyzes rapidly to produce hydrochloric acid and benzoic acid. Conclusion: Benzoyl chloride is a colorless liquid with moderate to high vapor pressure that reacts immediately with water to produce hydrochloric acid and benzoic acid. It would be expected to have high mobility in soil and volatilization would be high based on its Henry's Law constant; however, the rapid rate of hydrolysis suggests that these and other environmental fate pathways are not applicable for this substance. The rate of atmospheric photooxidation is slow. Benzoyl chloride is expected to have low persistence (PI) and low bioaccumulation potential (Bl). 7 ------- U.S. Environmental Protection Agency Hazard Characterization Document December, 2012 3. Human Health Hazard A summary of the human health toxicity data submitted for SIDS endpoint is provided in Table 3. The table is also noted were read across (RA) from supporting chemicals are utilized for the sponsored chemical. Acute Oral Toxicity Benzoyl chloride (CASRN 98-88-4) (1) Male Wistar rats (10/dose) were administered undiluted benzoyl chloride (>99.5% purity) via gavage at 1.0, 1.5, 2.0, 2.5, 3.1 or 5.0 mL/kg (~ 1210, 1820, 2420, 3030, 3750 or 6040 mg/kg) and observed for 14 days following dosing. Mortality was observed at 1820(2), 2420(5), 3030(6), 3750(9) and 6040(10) mg/kg. LD50 = 2528 mg/kg (2) Spartan rats (5/sex/dose, except for highest dose where only males were exposed) were orally administered 10 mL/kg of benzoyl chloride (purity not indicated) in corn oil at 500, 1250, 1984, 3150, 5000 or 7940 mg/kg and observed for 14 days following dosing. Mortality was observed in males at 3150(1), 5000(5), and 7940(5) mg/kg; mortality in females was observed at 1984(3), 3150(5), and 5000(5) mg/kg. LD50 (males) = 3619 mg/kg LD50 (females) = 1900 mg/kg LD50 (combined) = 2618 mg/kg (3) Rats (number, sex and strain unspecified) were orally administered benzoyl chloride in two separate studies. Further details or reliability scores were not provided in the robust summary for this study. LD50 = 2460 mg/kg LD50 = 1900 mg/kg Acute Dermal Toxicity Benzoyl chloride (CASRN 98-88-4) (1) New Zealand White rabbits (2/sex) were administered benzoyl chloride (purity not indicated) via the dermal route at 2000 mg/kg to unabraded or abraded skin under occluded conditions for 24 hours and observed for 14 days. No mortality was observed. LD50 > 2000 mg/kg (2) Rabbits (number, sex and strain unspecified) were administered benzoyl chloride (purity not indicated) via the dermal route. Further details or reliability scores were not provided in the robust summary. LD50 = 790 mg/kg 8 ------- U.S. Environmental Protection Agency Hazard Characterization Document December, 2012 Acute Inhalation Toxicity Benzoyl chloride (CASRN 98-88-4) (1) Male Wistar rats (10/concentration) were exposed to benzoyl chloride (> 99.5% purity) via nose-only inhalation at 0.190, 0.504, 0.708, 1.453 and 1.980 mg/L for 4 hours and observed for 21 days. Mortality occurred at 1.453(5) mg/L (within 1-19 days) and at 1.980(6) mg/L (within 4-48 hours). 4-h LC50 ~ 1.45 mg/L (2) Female Wistar rats (10/concentration) were exposed to benzoyl chloride (> 99.5% purity) via nose-only inhalation at 0.190, 0.504, 0.708, 1.453 and 1.980 mg/L for 4 hours and observed for 21 days. Mortality occurred at 1.453(1) mg/L (within 10 days) and at 1.980(3) mg/L (within 4 - 24 hours). 4-h LC50 ~ 1.98 mg/L (3) Wistar rats (10/sex/concentration) were exposed to benzoyl chloride (purity not indicated) via nose-only inhalation at 2.343 mg/L for 1 hour and observed for 21 days. Two females died 8 - 11 days after exposure. 1-h LC50 > 2.34 mg/L 4-h LC50 (estimated) ~ 9.37 mg/L (4) Spartan rats (5/sex/concentration) were exposed via inhalation to an aerosol of benzoyl chloride (purity not indicated) at 2.0 and 200 mg/L for 4 hours and observed for 14 days. Mortality occurred on observation day six at 2.0(1) mg/L and all animals died within 4 hours of exposure at 200 (5) mg/L. 4-h LC50 > 2 and < 200 mg/L (5) Rats (number, sex and strain unspecified) were exposed to benzoyl chloride (purity not indicated) via inhalation for 2 hours. Further details and reliability scores were not provided in the robust summary. 2-h LC50 = 1.87 mg/L Repeated-Dose Toxicity Benzoic acid (CASRN 65-85-0, supporting chemical) Sprague-Dawley rats (10/sex/concentration) were exposed to technical-grade benzoic acid as a dust aerosol at 0, 25, 250 or 1200 mg/m3 (~ 0, 0.025, 0.25, 1.2 mg/L) for 6 hours/day, 5 days/week for 28 days. Average particle size was 4.7 [j,m. Microscopic lesions in the lungs with an increase in inflammatory cell infiltrate and interstitial fibrosis was observed in all test animals. Animals exposed to > 0.25 mg/L exhibited upper respiratory tract irritation and decreased absolute and relative kidney weights. LOAEC (systemic toxicity) = 0.025 mg/L/day (based on microscopic lesions in the lungs) NOAEC (systemic toxicity) = Not Established 9 ------- U.S. Environmental Protection Agency Hazard Characterization Document December, 2012 Hydrochloric acid (CASRN 7647-01-0, supporting chemical) (1) B6C3F1 mice (10/sex/concentration) were exposed to hydrochloric acid (99.99% purity) at nominal concentrations of 0, 10, 20 or 50 ppm (~ 0 [air], 0.0149, 0.0298 and 0.0746 mg/L) for 6 hours/day, 5 days/week for 90 days. Time-weighted average concentrations were 0, 9.8, 19.1 and 46.7 ppm (~ 0, 0.0146, 0.0285 and 0.0696 mg/L). Animals were observed for an additional day following completion of exposure. Mortality was observed in male rats at 0.0149 mg/L (1/10) and 0.0746 mg/L treatment groups (1/10); and a single female was killed in extremis following treatment at 0.0746 mg/L. Statistically significant (p < 0.05) reductions in body weight and food consumption (> 10% decrease, compared with controls) were observed in males and females at 0.0746 mg/L. At 0.0746 mg/L, inflammation of the lips (cheilitis) with accumulation of iron-storing protein macrophages, white blood cell globules in the epithelium of the nasal passage and decreased liver weight was observed but not statistically significant. White blood cell globules in the nasal passage epithelium were also observed at 0.0149 and 0.0298 mg/L. http://www.chem.unep.ch/irptc/sids/oecdsids/7647010 LOAEC (systemic toxicity) = 0.0149 mg/L/day (based on mortality in males) NOAEC (systemic toxicity) = Not Established LOAEC (systemic toxicity) = 0.0746 mg/L/day (based on moribund female) NOAEC (systemic toxicity) = 0.0298 mg/L/day (2) Crl:CD(SD)Br rats (10/sex/concentration) were exposed to hydrochloric acid (99.99% purity) at nominal concentrations of 0, 10, 20 or 50 ppm (~ 0 [air], 0.0149, 0.0298 and 0.0746 mg/L) for 6 hours/day, 5 days/week for 90 days. Time-weighted average concentrations were 0, 9.8, 19.0 and 46.7 ppm (~ 0, 0.0146, 0.0283 and 0.0696 mg/L). Animals were observed for an additional day following completion of exposure. Mortality was observed in a single female at 0.0746 mg/L. A slight reduction in food consumption was observed in one female at 0.0149 mg/L and one male at 0.0746 mg/L. Minimal to mild rhinitis in the anterior portion of the nasal cavity was observed at the following incidences in treatment groups as follows: males (0/10, 3/10 and 5/10) and females (1/10, 1/10 and 4/10) respectively. No treatment-related effects were observed on urinalysis, hematology and serum chemistry. http ://www. chem .unep. ch/irptc/sids/oecdsids/7647010 LOAEC (systemic toxicity) = 0.0746 mg/L/day (based on mortality in females) highest dose tested NOAEC (systemic toxicity) = 0.0298mg/L/day LOAEC (local toxicity) = 0.0149 mg/L/day (histopathological inflammatory changes in the nasal cavity in females) LOAEC (local toxicity) = 0.0298 mg/L/day (histopathological inflammatory changes in the nasal cavity in males) NOAEC (local toxicity) = 0.0149 mg/L/day (3) Fischer 344 rats (10/sex/concentration) were exposed to hydrochloric acid (99.99% purity) at nominal concentrations of 0, 10, 20 or 50 ppm (~ 0 [air], 0.0149, 0.0298 and 0.0746 mg/L) for 6 hours/day, 5 days/week for 90 days. Time-weighted average concentrations were 0, 9.8, 19.1 and 46.8 ppm (~ 0, 0.0146, 0.0285 and 0.0698 mg/L). Animals were observed for an additional day following completion of exposure. No mortality was observed. Decreases in food consumption at 0.0298 and 0.0746 mg/L, and body weight (0.0746 mg/L) were observed in males. Minimal to mild rhinitis in the anterior portion of the nasal cavity was observed in all 10 ------- U.S. Environmental Protection Agency Hazard Characterization Document December, 2012 treated animals at the following incidences: males (3/10, 7/10 and 9/10) and females (3/10, 5/10 and 6/10), respectively, http://www.chem.unep.ch/irptc/sids/oecdsids/7647010 LOAEC (local toxicity) = 0.0149 mg/L/day (based on rhinitis in both sexes) NOAEC (local toxicity) = Not Established Reproductive Toxicity Hydrochloric acid (CASRN 7647-01-0, supporting chemical) In the 90-day repeated-dose inhalation toxicity studies with B6C3F1 mice, Crl:CD(SD)Br rats and Fischer 344 rats exposed to vapors of hydrochloric acid described previously, reproductive tissues from animals in all dose groups were evaluated histopathologically after being weighed and examined macroscopically. No treatment-related effects on the histopathology of reproductive tissues or organs were found. No weight-related changes or lesions were reported. http ://www. chem .unep. ch/irptc/sids/oecdsids/7647010 Developmental Toxicity Benzoic acid (CASRN 65-85-0, supporting chemical) In a four-generation study, rats of an unspecified strain (20/sex/dose) were exposed to diets containing 0.5 or 1% benzoic acid (~ 375 and 750 mg/kg-bw/day). The exposure periods were: generation 1 and 2-lifelong, generation 3-16 weeks and generation 4-until breeding. In all four generations, no treatment-related effects on body weight, body weight gain, food efficiency and organ weight was observed. No treatment-related effects on fertility and lactation were observed. The animals of the third generation were sacrificed and examined histopathologically after lactation of pups (-16 weeks). No treatment-related histopathological findings were specified. However, information in the original report was inadequate to determine the organs and tissues examined. Robust summary informations assumes that as a minimum the brains, heart, liver, kidney, testis and were examined (sic)." No treatment-related effects on the dams, growth and development of the offsprings were observed. NOAEL (maternal toxicity) ~ 750 mg/kg-bw/day (highest dose tested) NOAEL (developmental toxicity) -750 mg/kg-bw/day (highest dose tested) Genetic Toxicity — Gene Mutation In vitro Benzoyl chloride (CASRN 98-88-4) (1) Salmonella typhimurium strains TA98, TA100, TA1535 and TA1537 were exposed to benzoyl chloride (purity not indicated) in acetone at concentrations of 0, 15, 30, 60, 120, 240 or 480 |ig/tube; 0, 75, 150, 300, 600 or 1200 |ig/tube; 225, 450, 900, 1800 or 3600 |ig/tube and 0, 225, 450, 900, 1800 or 3600 |ig/tube in the presence and absence of metabolic activation. The responses of the controls were not specified. The test substance precipitated at 450|ig/tube and was cytotoxic starting at 1200 |ig/tube. No evidence of mutagenicity was observed in any of the strains. 11 ------- U.S. Environmental Protection Agency Hazard Characterization Document December, 2012 Benzoyl chloride was not mutagenic in this assay. (2) S. typhimurium strains TA98, TA100, TA1535, TA1537 and TA1538 and Saccharomyces cerevisiae D4 were exposed to benzoyl chloride (purity not indicated) in DMSO at concentrations ranging from 0.0001 to 1 |iL/plate in the presence and absence of metabolic activation. Benzoyl chloride was cytotoxic at 1 |iL/plate. Positive control substances were tested concurrently, but responses were not provided. No evidence of mutagenicity was observed in any of the strains. Benzoyl chloride was not mutagenic in this assay. (3) S. typhimurium strains TA98 and TA100 were exposed to benzoyl chloride (purity not indicated) at concentrations of 0.1, 1 and 10 |imole/plate in the absence of metabolic activation. There was a positive mutagenic response for TA98. No further details or reliability score was provided in the robust summary. Benzoyl chloride was mutagenic in this assay. (4) Escherichia coli strains H/r30R and Hs30R were exposed to benzoyl chloride (purity not indicated). Further details were not provided. A reliability scored was not provided in the robust summary. Benzoyl chloride was not mutagenic in this assay. (5) S. typhimurium strains G46, TA98, TA100, TA1535, TA1537, C3076 and D3052 and is. coli strains WP2 and WP2 uvrA- were exposed to benzoyl chloride (purity not provided) in the presence and absence of metabolic activation. The gradient plate technique was used, which results in a range of concentrations over which chemically-induced mutant colonies are present. Benzoyl chloride was not mutagenic in any strains of S. typhimurium or E. coli in the presence and absence of metabolic activation. A reliability score was not provided in the robust summary. Benzoyl chloride was not mutagenic in this assay. (6) E. coli strains WP2 B/r try and WP2 try her and Bacillus subtillis H17(Rec+), M45 (Rec-) were exposed to benzoyl chloride (purity not indicated) in the presence and absence of metabolic activation. Further details were not provided. A reliability score was not provided in the robust summary. Benzoyl chloride was not mutagenic in this assay. (7) S. typhimurium strains TA98, TA100 and TA104 and is. coli strains WP2uvrA/pKM101 were exposed to benzoyl chloride (purity not indicated) at concentrations up to 1000 |ig/plate in the presence and absence of metabolic activation. Benzoyl chloride was mutagenic in E. coli strains WP2uvrA/pKM101 and unspecified strains of S. typhimurium. A reliability score was not provided in the robust summary. Benzoyl chloride was mutagenic in this assay. 12 ------- U.S. Environmental Protection Agency Hazard Characterization Document December, 2012 Genetic Toxicity - Chromosomal Aberrations In vivo Benzoyl chloride (CASRN 98-88-4) In a micronucleus assay, male and female mice (number and species not specified) were administered benzoyl chloride (99.97% purity) in corn oil via oral gavage at 0 or 1750 mg/kg- bw/day. No further details were provided. There were no indications of clastogenic effects on the chromosomes of the bone marrow erythroblasts. Benzoyl chloride was not clastogenic in this test. Additional Information Carcinogenicity Benzoyl chloride (CASRN 98-88-4) 1) Female Specific-Pathogen-Free (SPF) ICR mice (10/dose) were exposed via the dermal route at 5 |iL (diluted 1:1 with benzene) or 10 |iL benzoyl chloride (purity not provided) 3 times/week for 4 weeks and 2 times/week for 39 weeks (total exposure period was 43 weeks) and examined at necropsy for skin papillomas, skin carcinomas or lung tumors. The 5 and 10 |iL treatment groups, 2/10 and 3/10 mice had skin papillomas, skin carcinomas or lung tumors. No details were provided on the control group that was included. Benzoyl chloride has the potential to induce tumors in female mice in this study. 2) Female mice Specific-Pathogen-Free (SPF) ICR mice (10/dose) were administered 10 |iL (neat) or 5 |iL benzoyl chloride to the skin dorsal of 3-week old weanling mice with a micropipette 3 times/week for 4 weeks, then 2 times/week for 9.8 months, after which they were necropsied and examined for skin or lung tumors. A vehicle control group (of 30 female mice) was treated similarly with benzene. Another group of 20 female (7-week old) mice was exposed dermally to 2.3 |iL benzoyl chloride 2 times/week for 50 weeks (11.7 months), followed by an observation period that ended at 18.7 months with necropsy of surviving mice. Organs and tissues were prepared for histological examination, but the tissues examined were not specified. There were 2/20 skin-tumors and 5/20 lung-tumors in the 7-week old treated mice. Among the treated 3-week old mice, a skin tumor was observed in one rat in the 5|iL dose groups and incidence of lung tumors was 0/10 and 3/10 for the 5|iL and 10 |iL doses, respectively. The tumor incidence in the control group was 0/30 skin tumors and 2/30 lung tumors. Benzoyl chloride has the potential to induce lung tumors in female mice in this study. 13 ------- U.S. Environmental Protection Agency Hazard Characterization Document December, 2012 Eye Irritation Benzoyl chloride (CASRN 98-88-4) (1) Undiluted benzoyl chloride (0.1 mL, purity not indicated) was instilled into the conjunctival sac of the right eye of five rabbits (sex and strain unspecified) for 5 minutes with the left eye serving as the untreated controls. Eyes were rinsed after exposure. Irritation was scored up to 21 days using fluorescein. Benzoyl chloride was considered corrosive. No irritation score was stated. Benzoyl chloride was corrosive to rabbit eyes in this study. (2) Undiluted benzoyl chloride (0.1 mL, purity not indicated) was instilled into the conjunctival sac of the right eye of three or five (not clear in the robust summary) rabbits (sex and strain unspecified) and observed for up to 21 days. No irritation score was stated. Benzoyl chloride was corrosive to rabbit eyes in this study. (3) Undiluted benzoyl chloride (100 |iL, purity not indicated) was instilled into the conjunctival sac of one eye of two rabbits (sex and strain unspecified) and observed for up to 7 days. Severe redness and moderate to severe chemosis were observed in the conjunctiva up to the end of the observation period. Slight to moderate swollen and hyperemic irises and slight diffuse cornea opacity were also observed. No irritation score was stated. Benzoyl chloride was corrosive to rabbit eyes in this study. Skin Irritation Benzoyl chloride (CASRN 98-88-4) (1) Undiluted benzoyl chloride (0.5 mL, purity not indicated) was applied to the clipped, abraded skin of New Zealand White rabbits (3/sex) under semi-occluded conditions for 4 hours and assessed immediately and at 24 and 72 hours after exposure. The primary irritation index was 3.8. Benzoyl chloride was irritating to rabbit skin in this study. (2) Undiluted benzoyl chloride (0.5 mL, 99.5% purity) was applied to the ears of two rabbits (sex and strain unspecified) under occluded conditions for 24 hours. Rabbits were observed for 7 days after exposure. Severe erythema and edema were observed throughout the observation period. Necrosis was apparent at the end of the observation period. Benzoyl chloride was corrosive to rabbit skin in this study. Conclusion: The acute oral and dermal toxicity of benzoyl chloride (CASRN 98-88-4) is low in rats and rabbits, respectively. The acute inhalation toxicity of benzoyl chloride (CASRN 98-88- 4) in rats is high. A 28-day repeated-dose toxicity study showed microscopic lesions in the lung of rats administered 0.025 mg/L/day of the supporting chemical benzoic acid (CASRN 65-85-0) via aerosol. Three 90-day inhalation repeated-dose toxicity studies were submitted for the supporting chemical hydrochloric acid (CASRN 7647-01-0). In the study with mice, mortality was observed in males at 0.0149 (NOAEC not established) and moribundity in females at 14 ------- U.S. Environmental Protection Agency Hazard Characterization Document December, 2012 0.07496 mg/L/day. The NOAEC for systemic toxicity in female mice was 0.0298 mg/L/day. In another study, mortality was observed in female rats at 0.0746 mg/L/day. The NOAEC for systemic toxicity in female rats was 0.0298. In the same study histopathological inflammatory changes of the nasal cavity was observed at > 0.0149 and 0.0298 in female and male rats respectively. The NOAEC for local toxicity in female rats is not established and the NOAEC in male rats is 0.0149 mg/L/day. In another study with rats rhinitis was observed in both sexes at all concentrations. The LOAEC for local toxicity is 0.0149 mg/L/day; the NOAEC for local toxicity is not established. In the 90-day inhalation repeated-dose toxicity studies previously mentioned with supporting chemical hydrochloric acid (CASRN 7647-01-0), no treatment- related effects on reproductive tissues and organs in mice and rats were observed during histopathological examinations. No treatment-related effects were observed in dams, growth and development of offsprings, in a four-generation developmental toxicity study with supporting chemical benzoic acid (CASRN 65-85-0) administered via the diet. The NOAEL for maternal and developmental toxicity is 750 mg/kg-bw/day. The Benzoyl chloride (CASRN 98-88-4) induced gene mutations in bacteria in vitro; but did not induce chromosomal aberrations in mice in vivo. Benzoyl chloride (CASRN 98-88-4) is corrosive to the rabbit eye and irritating and corrosive to the rabbit skin. Benzoyl chloride has the potential to induce tumors in female mice. 15 ------- U.S. Environmental Protection Agency Hazard Characterization Document December, 2012 Tabic 3. Summarv Tabic of the Screening Information Data Set as Submitted under the U.S. HPV Challenge Program - Human Health Data Endpoints SPONSORED CHEMICAL Benzoyl Chloride (CASRN 98-88-4) SUPPORTING CHEMICAL Hydrochloric Acid (CASRN 7647-01-0) SUPPORTING CHEMICAL Benzoic Acid (CASRN 65-85-0) Acute Oral Toxicity LDS0 (mg/kg) = 2528 (rat) Acute Dermal Toxicity LDS0 (mg/kg) > 2000 (rabbit) Acute Inhalation Toxicity LCS0 (mg/L) -1.45 (rat) Repeated-Dose Toxicity NOAEC/LOAEC 90-Day Inhalation (mg/L) LOAEC = 0.0149 NOAEC m;ik. = Not Established LOAEC female = 0.0746 NOAEC io,iii,io = Not Established (mice) LOAEC ie„,aie = 0.0746 (hdt) NOAEC female = 0.0298 (rat) LOAEC females a,„l,„al,s > 0.0149 a lid 0.0298 (local toxicity, rat) LOAEC = 0.0149 NOAEC = Established (local loxicilv. rat) (RA) LOAEC maie = 0.0149 NOAEC maie = Not Established LOAEC fenlale = 0.0746 NOAEC female = Not Established (mice) LOAEC female = 0.0746 (hdt) NOAEC female = 0.0298 (rat) LOAEC females and males — 0.0149 and 0.0298 (local toxicity, rat) LOAEC = 0.0149 NOAEC = Established (local toxicity, rat) LOAEC = 0.025 NOAEC = Not Established (rat) Reproductive Toxicity NOAEC/LOAEC 90-Day Inhalation (mg/L) Reproductive Toxicity In the 90-Dav repeated-dose toxicity studies, no Ircalmcni-rclatcd effects on reproductive tissues and organs in mice and rats were observed during lvislopalhological examinations. (RA) In the 90-Day repeated-dose toxicity studies, no treatment-related effects on reproductive tissues and organs in mice and rats were observed during histopathological examinations. Developmental Toxicity NOAEL/LOAEL Diet (mg/kg-bw/day) Maternal Toxicity Developmental Toxicity NOAEL ~ 750 NOAEL ~ 750 (rat) (RA) NOAEL ~ 750 NOAEL ~ 750 (rat) Genetic Toxicity - Gene Mutation In vitro Positive Genetic Toxicity - Chromosomal Aberrations In vivo Negative ------- U.S. Environmental Protection Agency Hazard Characterization Document Additional Information Eye Irritation Positive Skin Irritation Positive Respiratory Tract Irritation Positive Carcinogenicity Has the potential to induce tumors. Bold = experimental data (i.e., derived from testing); (RA) = Read Across December, 2012 17 ------- U.S. Environmental Protection Agency Hazard Characterization Document December, 2012 4. Hazard to the Environment A summary of aquatic toxicity data submitted for SIDS endpoints is provided in Table 4. Acute Toxicity to Fish Benzoyl chloride (CASRN 98-88-4) (1) Fathead minnow (Pimephalespromelas) were exposed to benzoyl chloride at unspecified, measured concentrations under static conditions for 96 hours. 96-h LC50 = 34.1 mg/L (2) Fathead minnow (.Pimephales promelas) were exposed to benzoyl chloride at unspecified concentrations under static conditions for 96 hours. Benzoyl chloride reacted with water in aquatic tests producing benzoic acid and hydrochloric acid, causing an average decrease in pH to 5.2 in freshwater and detrimental effects to the biological oxygen demand. 96-h LC50 = 34.7 mg/L Benzoic acid (CASRN 65-85-0, supporting chemical) (1) Bluegill (Lepomis macrochirus) were exposed to benzoic acid at nominal, unspecified concentrations under unspecified conditions for 96 hours. http ://www. chem .unep. ch/irptc/ sids/OECD SID S/BENZO ATES. pdf 96-h LC50 = 44.6 mg/L (2) Rainbow trout (Salmo gairdneri) were exposed to benzoic acid at nominal, unspecified concentrations under unspecified conditions for 96 hours. http ://www. chem .unep. ch/irptc/ sids/OECD SID S/BENZO ATES .pdf 96-h LC50 = 47.3 mg/L Acute Toxicity to Aquatic Invertebrates Benzoic acid (CASRN 65-85-0, supporting chemical) Water fleas (Daphnia magna) were exposed to benzoic acid at unspecified concentrations under unspecified conditions. The water was vigorously aerated and determined to have a pH of 8.45. http ://www. chem .unep. ch/irptc/ sids/OECD SID S/BENZO ATES .pdf 48-h EC50 > 100 mg/L Toxicity to Aquatic Plants Benzoyl chloride (CASRN 98-88-4) Green algae (Pseudokirchnerella subcapitata) were exposed to benzoyl chloride at nominal concentrations of 21.3, 47.0, 103, 227, or 500 mg/L and were tested in triplicate. The test substance was found to hydrolyze to HC1 and benzoic acid after 10 minutes in the test solution, thus only nominal concentrations were used. The pH was not adjusted and no abnormal development of the cells was observed. Further details of the test conditions were not provided. http://echa.europa.eu/web/guest/information-on-chemicals/registered-substances 72-h EC50 = 96 mg/L (growth rate) ------- U.S. Environmental Protection Agency Hazard Characterization Document December, 2012 72-h EC50 = 45 mg/L (biomass) NOEC = 21.3 mg/L Conclusion: For benzoyl chloride, the 96-hour LC50 for fish is 34.1 mg/L. Based on the supporting chemical, benzoic acid, the 48-h EC50 for aquatic invertebrates is > 100 mg/L. The72-h EC50 of benzoyl chloride for aquatic plants is 96 and 45 mg/L for growth rate and biomass, respectively. Table 4. Summary of Environmental Effects - Aquatic Toxicity Data Endpoints SPONSORED CHEMICAL Benzoyl Chloride (98-88-4) SUPPORTING CHEMICAL Benzoic Acid (65-85-0) Fish 96-h LC50 (mg/L) 34.1 46.0 Aquatic Invertebrates 48-h EC50 (mg/L) No Data > 100 (RA) > 100 Aquatic Plants 72-h EC50 (mg/L) (Growth Rate) (Biomass) 96 45 No Adequate Data Bold = experimental data (i.e., derived from testing); (RA) = Read Across 19 ------- |