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Toxicological information

Developmental toxicity / teratogenicity

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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other: GLP-compliant guideline study, availalble as unpublished report, no restrictions, fully adequate for assessment.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1994
Report Date:
1994

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Qualifier:
according to
Guideline:
other: EPA (TSCA) Guideline 798.4900
Qualifier:
according to
Guideline:
other: Japanese Ministry of International Trade and Industry Guidelines for Developmental Toxicity Studies
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): FM-200, HP HFC 227-ea (1,1,1,2,3,3,3-heptafluoropropane)
- Physical state: gaseous
- Purity: 99.99%
- Cylinder serial No.: 23537, 25368
- Cylinder Lot No.: 93-200-176B, 93-200-176B
- Stability under test conditions: stable

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories, Inc., Portage, Michigan
- Age upon receipt: 11 weeks
- Weight at study initiation: 228-277 g on day 0 of gestation
- Housing: individually in clean, wire-mesh cages suspended above cage-board
- Diet (e.g. ad libitum): Purina Certified Roden Chow #5002, ad libitum, except during the exposure periods
- Water (e.g. ad libitum): municipal water, ad libitum, except during the exposure periods
- Acclimation period: 13 days

ENVIRONMENTAL CONDITIONS
- Temperature (°F): 66-83
- Humidity (%): 32-72
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
inhalation: gas
Type of inhalation exposure (if applicable):
whole body
Vehicle:
unchanged (no vehicle)
Details on exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: 0.5 cubic meter stainless steel and glass whole body inhalation chamber
- Temperature, humidity, pressure in air chamber: 22 +/- 2 C, 40-60%
- Air change rate: 12 to 15 per hour
- Treatment of exhaust air: treatment of the exhaust air consisted of drawing the air through an activated charcoal bed, a HEPA filter, and a water-spray fume scrubber.

TEST ATMOSPHERE
- Brief description of analytical method used: gas chromatography
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Exposure concentrations within each chamber were measured by a gas chromatographic method at least at the beginning, at an intermediate time and at the end of each daily exposure period. Mass air flow, temperature, humidity and oxygen levels were monitored continuously and were recorded at least every 30 min. Nominal chamber concentrations were determined. Test atmosphere homogeneity data were generated during pre-study method development and validated as necessary during the study. The concentration of the test substance was measured by gas chromatography with thermal conductivity detector.
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1
- Length of cohabitation: until the evidence of mating was identified
- Verification of same strain and source of both sexes: yes
- Proof of pregnancy: vaginal plug or sperm in vaginal smear, referred to as day 0 of pregnancy
Duration of treatment / exposure:
6 hours/day
Frequency of treatment:
10 consecutive days
Duration of test:
Gestation days 6-15, with laparohysterectomy performed on all surviving animals on gestation day 20
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
139370, 348420 and 731690 mg/m3 (20000, 50000 and 105000 ppm)
Basis:
other: target concentration
Remarks:
Doses / Concentrations:
20002, 50021 and 104924 ppm
Basis:
analytical conc.
Remarks:
Doses / Concentrations:
18265, 45390 and 76611 ppm
Basis:
nominal conc.
No. of animals per sex per dose:
24 females/dose
Control animals:
yes
Details on study design:
- Dose selection rationale: Exposure levels were selected based on the results of an inhalation range-finding developmental toxicity study in rats (WIL-12313)

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily for moribundity and mortality. Animals were also observed for signs of toxicity during the exposure period and approximately one hour following completion fo the exposure period.


DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: individually from days 0 through 20 of gestation prior to exposure during the treatment period.


BODY WEIGHT: Yes
- Time schedule for examinations: individual maternal body weights were recorded on gestation days 0, 6, 16, 18 and 20. A groupr mean body weight was calculated for each of these days. Mean body weight changes were calculated for each corresponding interval and also for gestation days 6-9, 9-12, 12-16, 6-16, 16-20 and 0-10


FOOD CONSUMPTION AND COMPOUND INTAKE: Yes
- Individual maternal food consumption was recorded on the corresponding gestation body weight days. The amounts of food consumed were calculated for the corresponding body weight gain intervals and were reported as g/animal/day and g/kg/day.


POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day # 20
- Organs examined: the lungs, kidneys and liver from each maternal animal were excised, weighed and preserved in 10% neutral buffered formalin for possible future histopathological evaluation.
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of fetuses: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
Fetal examinations:
- External examinations: Yes: all per litter
- Soft tissue examinations: Yes, half per litter
- Skeletal examinations: Yes, all per litter
- Head examinations: Yes, half per litter
Furthermore, the fetuses were weighed and sexed.
Statistics:
All analyses were conducted using two-tailed tests for a minimum significance level of 5 % comparing each treated group to the control group. Each mean was presented with the standard deviation (S.D.) and the number of animals (N) used to calculate the mean.
The following tests were used:
- CM-square test with Yates' correction factor: Fetal Sex Ratios
- Fisher's Exact test: Malformations and Variations
- Mann-Whitney U-test: Early and Late Resorptions, Dead Fetuses, Post-implantation Losses
- ANOVA (two-tailed) with Dunnett' s test: Corpora Lutea, Total Implantations, Viable Fetuses, Fetal Body Weights, Maternal Body Weights and Weight Changes, Maternal Net Body Weight Changes and Gravid Uterine Weights, Maternal Food Consumption, Organ Weights
- Kruskal-Wallis test: Litter Proportions of Intrauterine Data (Considering the Litter, Rather than the Fetus, as the Experimental Unit)

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:no effects

Details on maternal toxic effects:
All animals survived up until the scheduled necropsy on gestation day 20. In treated animals, salivation or red material around the nose occurred at similar incidence when compared with the control group.
There were no changes observed in the mean body weights, mean gravid uterine weights or net body weights in any treated groups. A non-treatment related increase in mean body weight gain in the high dose group was observed during gestation days 13-14. All other values were comparable between the treated and control groups. Food consumption in the treated and control groups was comparable.
At scheduled necropsy, there was no treatment related internal findings at any dose. Nematodes were observed in both treated and control groups. Mottled lungs were observed in the control and high dose groups. No treatment related organ weight differences were observed between the treated and controls animals.

Effect levels (maternal animals)

open allclose all
Dose descriptor:
NOAEC
Effect level:
731 690 mg/m³ air
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEC
Effect level:
731 690 mg/m³ air
Basis for effect level:
other: developmental toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
Intrauterine growth and survival of foetuses were unaffected by treatment at any concentration tested. Parameters evaluated included pre- and post-implantation loss, live litter size, foetal sex ratios, foetal body weights and numbers of corpora lutea and implantation sites. There were no statistically significant differences observed between the treated and control groups. External malformations, soft tissue and skeletal malformations were observed in 1(1), 1(1), 6(4) and 2(2) foetuses (litters) in the control, low dose, mid dose and high dose groups, respectively. The malformations were considered to be of spontaneous origin. None of the malformation differences or developmental variations was statistically significant between the treated and control groups on either an incidence or proportional basis. There were no treatment-related trends in comparisons of numbers of malformations or specific types of anomalies.

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Applicant's summary and conclusion