TI: L. Randecker RAD Disposition Meeting: 3/10/04 NM: Darlene Jones

RISK ASSESSMENT: PMN 04-244

I. BACKGROUND Structure -

Identity - 2-Bromo-1,1-difluoroet hane (BDFE; CAS 359-07-9) Formula - C2H3BrF2 SAT Concerns - Eye irritation, sensitization (dermal/cardiac), mutagenicity, oncogenicity, liver/kidney toxicity, developmental toxicity, male reproductive toxicity, neurotoxicity Submitters - Dow Chemical Co., Midland, MI 48674/Great Lakes Chemical Corp., West Lafayette, IN 47996 Manufacturing Site - Production Volume -
Use - Chemical intermediate for the manufacture of an herbicide intermediate PC Properties - The substance is a liquid with a MW of 145, vapor pressure of 233 torr, and water solubility of 1.1 g/l Exposures of Concern - Occupational, inhalation/dermal Toxicity Data Provided - Rat oral LD 0 = 2,000 mg/kg; rat dermal LD 0 = 2,000 mg/kg; moderate eye irritation but not skin irritation in rabbits SAT Report - Absorption all routes based on analogue. Substance expected to be alkylating agent. Concern for solvent neurotox icity and irritation; eye irritation based on submitted test data; mutagenicity, oncogeni city, sensitization, and developmental toxicity based on alkylation; cardiac sens itization based on otherhydrofluorocarbons;

1liver and kidney toxicity based on the bromine moiety and alkylation; and male reproductive toxicity based data in (1,2-dichloro-1,1-difluoroethane). This analogue has a rat inhalation NOAEL = 500 pm (598 mg/kg), and it produced effects on testes at 2,000 ppm (2,390 mg/kg) and 5, 000 ppm (5980 mg/kg), including bilateral aspermatogenesis.

II. HEALTH ASSESSMENT SUMMARY Absorption/Metabolism (see attached assessment by Dr. Keifer) -The PMN substance is expected to be absorbed via all routes. However, unless applied under an occlusive covering, absorption from the ski n may be negligible since the vapor pressure is so high. Estimated percent absorbed : SKIN: 100% (if occluded; otherwise, 0%) LUNG: 100% GI TRACT: 100% . The PMN substance is expected to act as an alkylating agent. Acute Toxicity, Irritation (see attached assessment by Dr. Anderson) - The acute oral and acute dermal test data on the PMN substance (LD 0 = 2,000 mg/kg for both) are consistent with a low order of toxicity. The substance was not a skin irritant but it was an eye irritant (moderate to slight conjunctiva l irritation); however, the eye irritation study is unacceptable because only one animal was tested, there was no evaluation of the test substance in unwashed eyes, and Draize scores were not reported. Mutagenicity (see attached assessment by Dr. Cimino) -Based on mutagenicity data on alkyl halide analogues, the PMN substance may be (1) a gene mutagen in bacteria, lower eukaryotes, and insects but not in mammalian cells in vitro; (2) a chromosome mutagen in human cells in vitro and in mammals in vivo but not in insects; and (3) an inducer of DNA effects in lower eukaryotes and in human and nonhuman mammalian cells in vitro. These data suppor t a cancer concern for the PMN substance. Carcinogenicity (see attached assessment by Dr. Woo) -Given the close structural analogy between the PMN substance and br omoethane (a rodent carcinogen), there is sufficient basis to support a cancer concern. However, the PMN substance should have a lower carcinogenic potential than bromoethane. In the NTP study on bromoethane, groups of 50 rats and mice of each sex were given whole-body exposure to atmospheres contai ning 0, 100, 200, or 400 ppm bromoethane for 6 hr/day, 5 days/wk, for 2 yr. With t he exception of high-dose female mice, there were no significant differences in survival and body weight gains. In male rats there were increased incidences of adrenal pheochr omocytomas (8/23, 23/47, 18/50, 21/49);

2brain and lung neoplasms may also have been related to bromoethane exposure. There was equivocal evidence of carcinogenici ty in female rats and male mice as indicated by marginal increases in lung tu mor incidences. For female mice, there was clear evidence of carcinogenicity as indicated by increased incidences of adenomas, adenocarcinomas, and squamous cell carcinomas of the uterus/cervix (0/50, 4/50, 5/47, 27/48). Systemic Toxicity - The SAT raised concerns for liver and kidney toxicity based on the bromine moiety and alkylation potential of t he PMN substance and concerns for cardiac sensitization based on data on ot her hydrofluorocarbons. Specific data, including the nature of the effects and effect levels, however, could not be found. Developmental Toxicity (see attached assessment by SRC) - Data on the developmental effects of the PMN substance were not available; however there are data on analogues, primarily 2-chloro-1,1,1-trifluoroethane with supporting data on 1,2-dichloro-1,1-difluoroethane and ethyl chloride. In the 2-chloro-1,1,1-trifluoroethane study , mated female rats (25/group) were exposed to 0, 500, 2,000, or 5,000 ppm (0, 500, 2,000, or 5,000 mg/kg/day) 6 hr/day on gestation days 6-15. Mean final mater nal body weights for the 2,000- and 5,000- mg/kg/day groups were statistically significant ly lower than those of controls. Compared to controls, there were statistically significant decreases in the number of corpora lutea and implantations per litter the 5,000-mg/kg/day group, decreases in the number of live fetuses per litter and mean fetal crown-rump length in the 2,000- and 5,000-mg/kg/day groups, increases in the number of litters with early resorptions and in the number of resorptions per litter in the 2,000- and 5,000-mg/kg/day groups, an increase in the percentage of litters that were resorbed in the 5,000- mg/kg/day group, and depressed mean fetal body weight in the 500-, 2,000-, and 5,000-mg/kg/day groups. The NOAEL and LOAEL for maternal toxicity were 500 and 2,000 mg/kg/day, respectively. Based on depressed mean fetal body weight, the LOAEL for developmental toxicity was 500 mg/kg/day. Reproductive Toxicity (see attached assessment by SRC) - Data on the reproductive effects of the PMN substance were not available; however there are data on analogues, primarily 1,2-dichloro-1,1-difluoroethane with supporting data on 2- chloro-1,1,1-trifluoroethane. In the 1,2-dichloro-1,1-difluoroethane study , male and female rats (20/sex/group) were exposed to 0 (air only), 500, 2,000, or 5,000 ppm (0, 408, 1,634, or 4,085 mg/kg/day) 6 hr/day 5 days/wk for up to 90 days. In males, bilateral disruption of spermatogenesis, manifested by disorganization of the seminiferous tubular epithelium and degeneration of germ cells leading to aspermatogenesis, was noted at all concentrations at both the interim and 90-day sacrifices. Gross examination revealed that some of the affected testes were smaller than expected. Affected epididymal

3tubules contained cell debris and a decreas ed sperm number and/or disappearance of sperm in the lumen. The NOAEL value for reproductive toxicity was 408 mg/kg/day. Immunotoxity (see attached assessment by Dr. Ward) - Based on structure-activity relationships and analogue data from the literat ure, the PMN substance may be a skin sensitizer. A recent analysis has shown that the relative skin-sensitizing potential of a series of alkylating agents was related to their ability to alkylate cutaneous proteins. Since the PMN substance penetrates the skin and is an alkylating agent, it may be a skin sensitizer. Further support for this conclusion derives from the fact that “haloalkanes” is a skin-sensitization structur al alert in the rule base for identifying contact allergens, although not all haloalkanes are sensitizers. However, in the absence of direct test data, this PMN substance would have to be classified as a possible skin sensitization hazard. Neurotoxicity (see attached assessment by Dr. Norris) - Acute oral toxicity data on the PMN substance show no neurotoxic effect on rats exposed to a single dose of 500 mg/kg, but those exposed to a single dose of 2,000 mg/kg showed clinical signs of decreased actiity, incoordination, salivation, and perineal soiling. These are signs of solvent neurotoxicity.

III. RISK ASSESSMENT Estimated Occupational Inhalati on Exposure, Manufacturing/Use In the absence of protective equipment, The exposure assessor states that these exposure levels are “pretty conservative.” The approximate absorbed dose for thes e exposures is Estimated Occupational Dermal Exposure, Manufacturing/Use None; glove use is expected if dermal exposur e is possible (CFC substitutes study), and the use of drylok equipment (submission) is expected to mitigate most possible dermal exposures (Engineering Report). Inhalational Risk of Carcinogenicity -

Inhalational Risk of Developmental Toxicity -Taking the LOAEL of 500 mg/kg/day from the rat inhalation developmental study with 2-chloro-1,1,1-trifluoroethane and the manufacturing/use inhalation dose of mg/kg/day produces a MOE of ,

4indicative of concern. Inhalational Risk of Reproductive Toxicity - Taking the NOAEL of 408 mg/kg/day from the rat inhalation developmental study with 1,2-dichloro-1,1-difluoroethane and the manufacturing/use inhalation dose o mg/kg/day produces a MOE of , indicative of some concern. Inhalational Risk of Systemic Toxicity and Immunotoxicity - Risks cannot be quantified with available toxicity data. IV. CONCLUSIONS

L In the absence of protective equipmen t, the PMN substance may cause eye irritation, skin sensitization, and systemic toxi city (liver/kidney) in manufacturing and use workers, but risks cannot be quantified with ava ilable data. In the absence of protective equipment, the PMN substance may pose a risk of carcinogenicity and reproductive/developmental toxicity in manufacturing and use workers exposed by inhalation.

V. TEST RECOMMENDATIONS

Carcinogenicity- A 2-yr bioassay in rats by the inhalation route. Cardiac Sensitization - The protocol for cardiac sensitization testing will be designed by the submitter. Systemic/Developmental Toxicity - OECD test guideline 422 in rats by the inhalation route but with a 10-wk dosing period prior to mating. Reproductive Toxicity - OECD test guideline 415 in rats by the inhalation route.

VIII. SUBSTITUTES/BENEFITS Substitutes - The Dow contact did not know of any substitutes for the PMN substance in its intended use. Benefits - The PMN substance is to be used only to make an herbicide (penoxsulam) not yet on the market, and the Dow contact di d not know of other ways to manufacture the herbicide. The benefit would derive from the benefit of the herbicide, which is a low usage rate of only 35 g/hectare.

5