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-difluoroethane (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 LD0 = 2,000 mg/kg; rat dermal LD0 = 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 neurotoxicity and irritation; eye irritation based on

submitted test data; mutagenicity, oncogenicity, sensitization, and developmental

toxicity based on alkylation; cardiac sensitization based on other hydrofluorocarbons;

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liver 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 skin 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 (LD0 = 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 conjunctival 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 support a cancer concern for the PMN substance.

Carcinogenicity (see attached assessment by Dr. Woo) - Given the close structural

analogy between the PMN substance and bromoethane (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 containing 0, 100, 200, or 400 ppm bromoethane

for 6 hr/day, 5 days/wk, for 2 yr. With the 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 pheochromocytomas (8/23, 23/47, 18/50, 21/49);

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brain and lung neoplasms may also have been related to bromoethane exposure. 

There was equivocal evidence of carcinogenicity in female rats and male mice as

indicated by marginal increases in lung tumor 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 the PMN substance and concerns for cardiac

sensitization based on data on other 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 maternal body weights for the 2,000- and 5,000-

mg/kg/day groups were statistically significantly 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

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tubules contained cell debris and a decreased 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 literature, 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 structural 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 Inhalation 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 these exposures is 

Estimated Occupational Dermal Exposure, Manufacturing/Use

None; glove use is expected if dermal exposure 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 ,

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indicative 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 equipment, the PMN substance may cause eye

irritation, skin sensitization, and systemic toxicity (liver/kidney) in manufacturing and use

workers, but risks cannot be quantified with available 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 did 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.

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