NATIONAL TOXICOLOGY PROGRAM EXECUTIVE SUMMARY OF SAFETY AND TOXICITY INFORMATION BENZOPHENONE CAS Number 119-61-9 October 4, 1991 Submitted to: NATIONAL TOXICOLOGY PROGRAM Submitted by: Arthur D. Little. Inc. Board of Scientific Counselors Draft Report NATIONAL TOXICOLOGY PROGRAM EXECUTIVE SUMMARY OF SAFETY AND TOXICITY INFORMATION BENZOPHENONE CAS Number 119-61-9 October 4, 1991 Submitted to: NATIONAL TO:X'lCOLOGY PROGRAM Submitted by: Arthur D. Little, Inc. Board of Scientific Counselors Draft Report TABLE OF CONTENTS I. NOMINATION HISTORY AND REVIEW . II. CHEMICAL AND PHYSICAL DATA . , .......... 3 III. PRODUCTION/USE . .................. 5 IV. EXPOSURE/REGULATORY STATUS .......................11 V. TOXICOLOGICAL EFFECTS ............................15 VI. STRUCTURE ACTIVITY RELATIONSHIPS ................. .33 VII. REFERENCES...................................... .34 APPENDIX I, ON-LINE DAT A BASES SEARCHED .............40 APPENDIX II, SAFETY INFORMATION. ....................42 OVERVIEW! Nomination History: Benzophenone was nominated by the National Institute of Environmental Health Sciences (N/EHS) in 1987 for toxicity and carcinogenicity testing based on the potential for occupational and consumer exposure, and the lack of chronic toxicity data" NIOSH originally nominated this chemical for Salmonella testing. Chemical and Physical Properties: Benzophenone is a white solid with the appearance of orthorhombic bisphenoidal prisms. This compound has a melting range of 48.0-51°C (118­ 124 °F) and a boiling point of- 305 °C (-581 'F). Benzophenone is insoluble in l't:ater, but is soluble in alcohol, acetone, acetic acid, ether, chloroform, and benzene. This compound is photochemically reactive, incompatible with strong oxidizing and reducing agents. and may attack some unspecified plastics. The decomposition of benzophenone may produce carbon monoxide and carbon dioxide. ProductionNses/Exposure: The production of benzophenone was reported in the public file of the EPA Toxic Substances Control Act (TSCA) Inventory in 1983 by four manufacturers to range from 300,000-3,001,000 pounds. No production data were available from the United States International Trade Commission's (US/TC) publication, Synthetic Organic Chemicals. or from SRI's Chemical Economics Handbook. Four companies listed as importers in the EPA TSCA Inventory reported a total import volume ranging from 3 ,000-31,000 pounds. The US/TC reported an import volume range of2 ,646-1,709 pounds for the years 1979-1982, respectively. Benzophenone is a component of many consumer products. It is primarily used as a photoinitiator and as a fragrance enhancer. It is also used as an ultraviolet curing agent, flavor ingredient, as a polymerization inhibitor, and in the manufacture of insecticides, agricultural chemicals, hypnotics, and other pharmaceuticals. Data from the National Occupational Exposure Survey (NOES) conducted during 1981-1983, estimated that 41,520 workers, including 18,162 females, were potentially exposed to benzophenone. 1 The information contained in this Executive Summary of Safety and Toxicity Information (ESSTI) is based on data from current published literature. The summary represents information provided in selected sources and is not claimed to be exhaustive. u Benzophenone has been detected in the environment in soil, water, and air. It readily adsorbs to soil at a rate proportional to the amount oforganic matter in the soil. It has been found in surface and ground water, primarily from the discharge of untreated domestic and industrial sewage and waste water into rivers. streams. and other waterways. Benzophenone has been detected in the atmosphere as either a product ofcombustion or a secondary product ofatmospheric degradation. The FDA has approved the used of benzopenone as a flavoring substance and adjuvant. The EPA regulates process units that produce benzophenone. OSHA has not established a permissible exposure limit (PEL); ACGIH has not recommended an exposure limit (TLV); and NIOSH has not recommended an exposure limit (REL) for this compound. Toxicological Effects: Human: Benzophenone inhalation induced purulent bronchitis, allergic asthma, and erythema in one case report. This compound l1-'as positive in patch test results in 1-2% ofpatients tested by the North American Contact Dermatitis Research Group. In one case study, benzophenone did not induce photosensitization. In another study, benzophenone was negative in patch tests on five subjects with allergic contact dermatitis. No data were found in the literature on chemical disposition, or the carcinogenic, reproductive, or teratogenic effects ofbenzophenone in humans. Animal: In rats orally administered benzophenone, p-hydroxybenzophenone ( 1% of administered dose) was detected in enzyme-treated urine samples, but not in unhydrolyzed urine. No p-hydroxybenzophenone was detected in the feces. The primary pathway of benzophenone metabolism follo·wing oral administration to rabbits was reported to be reduction of the keto group to benzhydrol which was excreted, at concentrations 41-61 % of the administered benzophenone dose, as a labile glucuronide in the urine. The amount ofpercutaneous absorption in monkeys was found to be 43 and 68% of the applied benzophenone dose for unoccluded and occluded sites. respectively. m Acute oral (dosed feed) exposure in rats, caused a dose-dependent increase in the absolute and the relative weights of the liver. and the relative weight of the kidney. and an increase in serum glutamic pyruvic transaminase (SGPT). In addition, mild degenerative effects were observed in the liver and bone marrow of animals in the high dose group, indicating that the liver may be the primary target organ, and that the bone marrow may also represent a site of toxic action. The oral Wsofor benzophenone has been reported to range from 1,900 - >10,000 mg/kg in rats and 1,600­ 2 ,895 mg/kg in mice. The dermal W so l1.'aS found to be 3 ,535 mg/kg and > 1 glkg in rabbits and guinea pigs, respectively. Benzophenone has produced slight to moderate skin irritation in guinea pigs, Benzophenone was not found to cause sensitization among guinea pigs by a variety of tests, including the maximization test. Jn one study, this compound was determined to have a medium dermal, and a slight ocular, irritancy potential, and in another it was reported that this compound failed to induce skin or eye irritation in rabbits. Benzophenone did not induce a significant increase in skin tumors in mice that received topical applications of benzophenone for 120 weeks, or until death compared to animals treated with acetone or 7, 12-dimethylbenzanthracene, and non-treated controls. However, decreased survival rate was observed in benzophenone-treated animals compared to untreated controls. Topical application to rabbits for 160 weeks did not result in a treatment-related decrease in survival rates or local changes. No tumors were observed in rabbits exposed to benzophenone. Benzophenone did not have an effect on limb regeneration in Japanese newts. No other data were found on the teratogenic effects, and no data were found on reproductive toxicology. Genetic Toxicology: Benzophenone has been found to be negative in all strains of Salmonella tested. Benzophenone was also negative in the E. coli Pol A assay. Structure Activity Relationships: Benzophenone is structurally related to acetophenone. Acetophenone did not affect growth or hematological parameters, or produce macroscopic or microscopic changes in rats fed this compound in the diet for 17 weeks. Acetophenone has been found to be negative in the Salmonella and in the E. coli pol A assays, but was genotoxic in cultured hamster lung cells. No data were found on the carcinogenicity ofacetophenone. iv I. NOMINATION HISTORY AND REVIEW A. Nomination History 1. Source: National Institute of Environmental Health Sciences (NIEHS) [NIEHS. 1987] 2. Date: December, 1987 3. Recommendations: • Toxicity • Carcmogenicity 4. Priority: -­ 5. Rationale/Remarks: • Originally nominated by NIOSH for Salmonella testing • Potential for occupational exposure • Used in a variety of consumer products • Lack of chronic toxicity data B. Chemical Evaluation Committee Review 1. Date of Review: August 8, 1991 2. Recommendation: • Toxicity • Carcinogenicity • Teratogenicity 3. Priority: • Moderate for toxicity and carcinogenicity • High for teratogenicity 4. NTP Chemical Selection Principle(s): 3, 6, 8 5. Rationale/Remarks: • High production • Potential for occupational and consumer exposure • Air and water pollutant • Lack of toxicity data • Structural interest as an aromatic ketone C. Board of Scientific Counselors Review 1. Date of Review: 2. Recommendations: 3. Priority: 4. Rationale/Remarks: 1 D. Executive Committee Review 1. Date of Review: 2. Decision: 2 II. CHEMICAL AND PHYSICAL DATA A. Chemical Identifiers BENZOPHENONE CAS No.119-61-9 RTECS No. D/9950000 Molecular formula: C13H100 Molecular weight: 182.21 B. Synonyms and Trade Names Synonyms: benzophenone (8CI); methanone, diphenyl- (9CI); alpha­ oxodiphenylmethane; alpha-oxoditane; benzoylbenzenephenyl; benzene, benzoyl; benzoylbenzene; diphenyl ketone; diphenylmethanone; phenyl ketone Trade Names: No information was found. C. Chemical and Physical Properties Description: Off-white chips [Lenga, 1988]; orthorhombic bisphenoidal prisms [Budavar1, 1989; Weast, 1988] or white crystalline powder [J.T.Baker, 1990] with a geranium [Budavari, 1989] floral [J. T. Baker, 1990] or rose­ like odor [Sax and Lewis, 1989; Furia and Bellanca,