2,2-dichloro-1,1,1-trifluoroethane

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: High because a scientifically defensible and guideline method was used. Critical study for SIDS endpoint. Only study summary reviewed from secondary source.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1989

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

GLP compliance:

yes

Test material

Test material information

Constituent 1

Reference substance name:

2,2-dichloro-1,1,1-trifluoroethane

EC Number:

206-190-3

EC Name:

2,2-dichloro-1,1,1-trifluoroethane

Cas Number:

306-83-2

Molecular formula:

C2HCl2F3

IUPAC Name:

2,2-dichloro-1,1,1-trifluoroethane

Constituent 2

Reference substance name:

Ethane, 2, 2-dichloro- 1, 1, 1-trifluoro-

IUPAC Name:

Ethane, 2, 2-dichloro- 1, 1, 1-trifluoro-

Details on test material:

- Name of test material (as cited in study report): Ethane, 2, 2-dichloro- 1, 1, 1-trifluoro-, HCFC-123
- Purity = 99.8%

Test animals

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

Female rabbits were 4 to 5 months old at receipt and weighed between 2967 and 4123 g
Food and water were available ad libitum except during exposures.
Rabbits were housed individually except during mating.
A 12 hour light/dark cycle was controlled via an automatic timer.
Temperature and relative humidity were monitored throughout the study.

Administration / exposure

Route of administration:

inhalation: vapour

Type of inhalation exposure (if applicable):

whole body

Vehicle:

not specified

Details on exposure:

A chamber-exposed sham-air treated control group of comparable size was also tested. Animals were exposed in Wahmann glass and stainless steel exposure chambers which had a total volume of 6 m3. HCFC-123 was vaporized using heated nitrogen in a counter-current volatization chamber.The HCFC-123 was delivered by a metered pump, via tubing, to the coiled glass rod in the volatization chamber.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Exposure levels evaluated were 500, 1500, and 5000 ppm. Samples for determination of HCFC-123 exposure levels were performed using gas chromatography. Chamber temperature, relative humidity, and air flow were also monitored in the exposure chamber.

Details on mating procedure:

Rabbits were naturally mated. Each female was placed into the male rabbits' cage. When coitus was observed, the female was removed and returned to her original cage. Following an interval of 1 to 2 hours, the female was placed into the cage of a second, different male. When coitus was observed with the second male, the female was considered mated and returned to her cage. The day on which evidence of mating was observed with both males was defined as day 0 of gestation.

Duration of treatment / exposure:

Days 6 through 18 of gestation

Frequency of treatment:

Daily

Duration of test:

6 hours

Control animals:

yes

Examinations

Maternal examinations:

In-life observations included periodic measurements of body weight, food consumption, and clinical findings.

Ovaries and uterine content:

Animals were sacrificed on day 30 of gestation and given a gross postmortem evaluation. Corpora lutea were counted and the uteri evaluated for the number of implantation sites and the number of live, dead, and resorbed fetuses.

Fetal examinations:

Fetuses were weighed, evaluated for external irregularities, and processed for soft tissue and skeletal evaluations.

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:

Maternal toxic effects:yes

Details on maternal toxic effects:
The low mortality rate (4.2%, 1/24 females) seen at 5000 ppm was not considered to represent a treatment-related response. Maternal toxicity was evident at all exposure levels evaluated (500, 1500, and 5000 ppm). Over the entire day 6-18 exposure interval of gestation, a mean weight loss was seen in each of the treated groups in comparison to a slight mean weight gain seen in the concurrent control group. A clear exposure relationship was evident and differences from control were statistically significant. Mean daily food consumption values for the exposure groups during the day 6-18 gestation interval were lower than control data, and statistically significant differences were seen for the following intervals: 500 ppm (days 8-10 and 13), 1500 ppm (days 6-14 and 16) and 5000 ppm (days 6-13 and 16). No other maternal toxicity was seen among the exposure groups.

The number of corpora lutea per pregnant female was comparable between the control and each treated group. The mean number of uterine implantations per pregnant female were comparable between the control, 500, and 5000 ppm groups. In the 1500 ppm group, a slight, albeit statistically significant reduction in the mean number of uterine implants was seen. This incidence, while lower than concurrent control data, was within the range of historical control data for the laboratory and in absence of a similar reduction in the high-dose group, this response was not considered indicative of a treatment-related effect. Historical control data for implantations (for 17 studies conducted between 1982-1987) was 8.8 (range of 7.5 - 10.5). The incidence of females with resorptions among their in utero litters was slightly higher than control in each of the treated groups; however, these differences were not statistically significant. The mean number of live fetuses per pregnant female was comparable between the control, 500, and 5000 ppm groups. This incidence in the 1500 ppm group was slightly lower than control and this difference was statistically significant. The mean number of live fetuses in the 1500 ppm group was within the range recent control historical control data. In absence of a similar reduction in mean number of live fetuses at the high-dose level, the slight, albeit statistically significant reduction in this parameter at 1500 ppm was not considered indicative of a treatment-related response. Historical control data for number of live fetuses (for 17 studies conducted between 1982-1987) was 8.0 (range of 6.3-8.9).

Effect levels (maternal animals)

Dose descriptor:

NOAEL

Effect level:

< 500 ppm

Basis for effect level:

other: maternal toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
No embryotoxic, fetotoxic, or teratogenic effects were seen at the exposure levels evaluated. Pregnancy rates for the 0, 500, 1500, and 5000 ppm groups were 87.5% (21/24), 95.8% (23/24), 91.7% (22/24), and 87.5% (21/24), respectively. No evidence of aborted fetuses was seen among the 0, 500, or 5000 ppm groups. In the 1500 group, two females aborted. In the absence of aborted females at the highest concentration level, the low incidence of aborted fetuses in the mid-exposure level was not considered indicative of a direct treatment-related response. A summary of reproductive outcomes (means/litter unless otherwise noted) is provided in the table below:

No dead fetuses were recovered in utero for control or treated females. Mean fetal weights as a composite for both sexes and distinguished by sex, were considered comparable between the control, 500, and 1500 ppm groups. In the 5000 ppm group, mean fetal weights were slightly lower than control (-6.4% for composite fetal weight data, -6.9% for male fetuses, and -5.5% for female fetuses); however, these differences were not statistically significant. Mean fetal weight data for the 5000 ppm group were within the range of recent historical control data (1982-1987) for the laboratory. Therefore, the slight decrease in mean fetal weight seen at 5000 ppm was not considered indicative of a treatment-related effect. Historical control data for mean male fetal weights was 46.7 g (range of 40.0 - 50.4 g). Historical control data for mean female fetal weights was 45.5 g (range of 39.6 - 48.1 g). Historical control data for mean composite fetal weight was 46.3 g (range of 40.5 - 49.6 g). The mean number of male and female fetuses per litter was considered comparable between the control and treated groups. Likewise, the ratio of male/female fetuses was similar between these same groups. No compound-related statistically significant external, visceral, or skeletal variations or malformations were observed in the fetal examinations.

Effect levels (fetuses)

Dose descriptor:

NOAEL

Effect level:

5 000 ppm

Basis for effect level:

other: teratogenicity

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

not specified

Any other information on results incl. tables

The mean daily analytical concentrations were 502, 1469, and 4828 ppm for the 500, 1500 and 5000 ppm groups, respectively. Chamber distribution analyses indicated that there was no significant gradient within each exposure chamber. The mean chamber temperature was 21±2, 22±2, 21±2, and 21±2ºC for the 0, 500, 1500, and 5000 ppm groups, respectively. Mean chamber relative humidity was 42±11, 34±12, 45±9, and 34±10% for the 0, 500, 1500, and 5000 ppm groups, respectively. Although chamber temperature and relative humidity deviated from the specified ranges on occasion, these levels were considered acceptable. No mortality occurred in the 0, 500, or 1500 ppm groups.

A summary of reproductive outcomes (means/litter unless otherwise noted)is provided in the table below:
   
Concentration (ppm):0   500   1500   5000
Corpora lutea:   10.0   10.4   9.1   9.3
Implantations:    9.4   9.3    7.8   8.9
No. of Resorptions:0.2  0.7    0.4   0.6
Total No. of Fetuses:9.1 8.6   7.4   8.3
Total No. of Live Fetuses: 
                    9.1   8.6   7.4   8.3
Mean Fetal Weight (g):47.72  49.06  49.47  44.68
Sex Ratio (total males/total females):
                   0.9  1.0   1.2    1.0

Applicant's summary and conclusion

Conclusions:

A NOAEL for maternal toxicity of <500 ppm was established.
A NOAEL for teratogenicity of 5000 ppm was established.