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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
Study period:
1992
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: 1a GLP Guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1992

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
GLP compliance:
yes

Test material

Constituent 1
Chemical structure
Reference substance name:
Pentafluoroethane
EC Number:
206-557-8
EC Name:
Pentafluoroethane
Cas Number:
354-33-6
Molecular formula:
C2HF5
IUPAC Name:
1,1,1,2,2-pentafluoroethane
Details on test material:
- Name of test material (as cited in study report): HFC-125
- Physical state: gasseous
- Analytical purity: >99% w/w
- Impurities (identity and concentrations): not reported
- Isomers composition: n/a
- Lot/batch No.: BR 1212
- Expiration date of the lot/batch: 1 year from receipt of the lab
- Stability under test conditions: stable
- Storage condition of test material: Pressurised gas at ambient temperature

Test animals

Species:
rabbit
Strain:
New Zealand White
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Interfauna UK Ltd.
- Age at study initiation: 16-24 weeks old
- Weight at study initiation: 3-4 kg
- Fasting period before study: No
- Housing: 1 animal/cage (about 1 cubic m)
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: No


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21
- Humidity (%): 55
- Air changes (per hr):
- Photoperiod (hrs dark / hrs light): 14/10

Administration / exposure

Route of administration:
inhalation
Type of inhalation exposure (if applicable):
whole body
Vehicle:
unchanged (no vehicle)
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Concentration of the test substance in the exposure chambers was measured hourly during the exposure period by means of GC analysis
Details on mating procedure:
mated female rabbits were purchased. No information on the mating procedure is reported
Duration of treatment / exposure:
day 6-18 of pregnancy
Frequency of treatment:
6 hrs/day
Duration of test:
29 days (day 0-29 of pregnancy)
No. of animals per sex per dose:
24
Control animals:
yes, concurrent no treatment
Details on study design:
Sex: female

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily during the exposure period

BODY WEIGHT: Yes
- Time schedule for examinations: day 0, 2, 6, 8, 10, 14, 19, 23 and 29


FOOD CONSUMPTION: Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day # 29
- Organs examined: reproductive organs


OTHER:
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes / No / No data
Examinations included:
- Gravid uterus weight: No
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
- Other: individual foetal weight
Fetal examinations:
- External examinations: Yes: [all per litter]
- Soft tissue examinations: Yes: [all per litter]
- Skeletal examinations: Yes: [all per litter]
- Head examinations: Yes: [all per litter]
Statistics:
Analysis of variance followed by Williams' test and Kursal-Wallis test  followed by Shirley's test were used to analyse parametric and  non-parametric data, respectively. For Litter data and foetal changes the litter was considered the basic  sample unit and non-parametric analyses were routinely used.  Where 75% or more of the values for a given variable are the same, a  Fisher's exact test was used, when considered necessary.
Indices:
litter weight
pre-implantation loss
post-implantation loss
sex ratio
Historical control data:
A group of 9 studies performed in 1991 was used for historical control data in the study report. The historical control database was increased up to
35 studies performed between 1990 and 1993 by HLS in the framework of the OECD SIDS dossier for HFC-125

Results and discussion

Results: maternal animals

Maternal developmental toxicity

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

Details on maternal toxic effects:
One animal of control group and one of 5000 ppm groups were killed due to  poor condition. One animal of control group produced a litter
on day 29  of pregnancy and was excluded from the study. One animal of 5000 ppm  group showed weight loss and aborted on days 20/21
of pregnancy. No other  instances of abortion were present in the study.  Animals showing cold ears during the exposure period was higher in all  the treated groups, in comparison with control group. This finding
was  considered a response to stress, not directly related to exposure. Statistically significant reduction in food consumption of animals of  50000 ppm-group was observed during the exposure period. However,
no difference in food consumptions was observed between the 5000 and the  15000 ppm groups and the control group, and the effect was
considered no  treatment-related. No differences were observed in body weight among the  treated and the control groups.
No treatment-related findings were  observed at terminal autopsy.

Effect levels (maternal animals)

Dose descriptor:
NOAEL
Effect level:
>= 50 000 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 treatment-related findings were observed in litter size, embryofoetal  loss and litter and foetal weight in the 5000 ppm- and 15000
ppm-groups. A slightly increased incidence of early and late in utero deaths was  observed in the 50000 ppm-group, in comparison to control.
However, the  in utero loss incidence at 50000 ppm felt within the historical range (originally 9 studies performed on 1991, refined up to 35
studies from the period 1990 -1993) and  was not conclusively considered treatment-related.
At lower  concentrations there was no related effect on post-implantation losses or  litter size. Although the mean incidence of both early and late in  utero deaths at 50,000 ppm falls within concurrent background, the total  number of in utero deaths at this concentration is slightly greater than
expected (Means reported in Table 1). There were no significant effects on litter weights or mean foetal  weights. The incidence of foetal malformations was 2/165, 1/193, 7/215  and 2/169 in control group, 5000, 15000 and 50000 ppm HFC-125,  respectively.  No statistically significant differences in the incidence of 
anomalies  and variants were observed during visceral and skeletal examinations of foetuses among the control and the treated groups

Effect levels (fetuses)

Dose descriptor:
NOAEL
Effect level:
>= 50 000 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

Table 1: litter data including historical control

 

Litter size

N. corpora lutea

Implants

Pre-implant loss (%)

Embryonic deaths

Post-implant loss (%)

Live young

early

late

total

Control

21

11.4

8.7

22.2

0.4

0.4

0.8

9.0

7.9

5,000 ppm

21

11.2

10.2

10.9

0.6

0.4

1.0

9.9

9.2

15,000 ppm

24

11.5

9.9

13.0

0.5

0.4

1.0

8.4

9.0

50,000 ppm

21

11.8

9.5

18.6

0.7

0.8

1.5

15.8

8.1

Background control range#

0.4-0.8

0.1-0.9

0.7-1.4

Extended background control range##

9.8 (3.6-17.5)

            # from 9 studies perfomed on 1991; ## from 35 studies performed between 1990 and 1993: means of individual study means’ (range of the means)

Applicant's summary and conclusion

Conclusions:
HFC-125 did not show adverse effect on reproduction in rabbits exposed up to 50,000 ppm by inhalation
Executive summary:

Groups 24 mated female rabbits were exposed to 5000, 15000 and 50000 ppm  HFC-125 in the day 6-18 of pregnancy for 6 hrs/day.

Animals were housed  individually in metal cages and exposed whole body in chambers. HFC-125 concentrations was monitored at 1 hour intervals during the exposure periods. 

EXAMINED PARAMETHERS:
Adult females:
All animals were subjected to daily examination for clinical signs of  toxicity. Body weight gain and food consumption were measured

regularly  during exposure.
On day 20 of pregnancy the animals were killed and examined for  pathological changes.

Litter and foetuses:
developmental and teratogenic potential of HFC-125 was assessed by  examination of the typical parameters:
-number of corpora lutea
-number and distribution of live young
-number and distribution of embryofoetal deaths
-individual and litter foetal weight
-foetal abnormalities.

Results:
Adult females:
No treatment-related adverse effects were recorded in the study.



Litters:
No treatment-related findings were observed in litter size, embryofoetal  loss and litter and foetal weight in the 5000 ppm- and 15000

ppm-groups. A slightly increased incidence of early and late in utero deaths was  observed in the 50000 ppm-group, in comparison to control.

However, the  in utero loss incidence at 50000 ppm felt within the historical range and  was not conclusively considered treatment-related.
There were no significant effects on litter weights or mean foetal  weights. 
No statistically significant differences in the incidence of anomalies  and variants were observed during visceral and skeletal examinations

of foetuses among the control and the treated groups.

50,000 ppm was judged as the maternal and foetal NOAEC of the study.