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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:
weight of evidence
Reliability:
2 (reliable with restrictions)

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1975
Report Date:
1975

Materials and methods

Test guideline
Qualifier:
no guideline available
Principles of method if other than guideline:
A teratology and embryotoxicity study was conducted using pregnant rats exposed by inhalation to chloroprene vapour. The two studies were similar in design, differing mainly in the number of days the rats were exposed and in the period of gestation during which exposure occurred .
The teratology study was designed to investigate the potential for inducing groth abnormalities or foetal deaths following exposure to chloroprene in the period of organogenesis. The embryotoxicity study was designed to determine whether chloroprene exposure resulted in pre-implantation loss - an effect usually associated with days 1-6 of the rat's gestation period.
GLP compliance:
no
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report):
2 chlorobutadiene-1,3 or ß-chloroprene

Test animals

Species:
rat
Strain:
other: ChR-CD
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: See report HL-580-75 at point 7.8.1.001 - Charles River Laboratories
- Age at study initiation: See report HL-580-75 at point 7.8.1.001. The rats were delivered, time mated, half were two days pregnant and the remainder were three days pregnant
- Weight at study initiation: See report HL-580-75 at point 7.8.1.001
- Fasting period before study: Not applicable
- Housing: No data
- Diet (e.g. ad libitum): ad libitum except during exposure
- Water (e.g. ad libitum): ad libitum except during exposure
- Acclimation period:None - all animals exposed from day of delivery to gestation day 20


ENVIRONMENTAL CONDITIONS
- Temperature (°C): No data
- Humidity (%): No data
- Air changes (per hr): No data
- Photoperiod (hrs dark / hrs light):No data

Administration / exposure

Route of administration:
inhalation: vapour
Type of inhalation exposure (if applicable):
whole body
Vehicle:
other: nitrogen used as carrier for test material, mixed with room air
Details on exposure:
See report HL-580-75 at point 7.8.1.001 -
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: 1.4 m³ stainless steel chambers
- Method of holding animals in test chamber: Not stated
- Source and rate of air: Room air, no rate provided
- Method of conditioning air: Not stated
- System of generating particulates/aerosols: liquid chloroprene, allowed to reach room temperature
- Temperature, humidity, pressure in air chamber:
- Air flow rate: Not stated
- Air change rate: Not stated
- Method of particle size determination: Not stated
- Treatment of exhaust air: No details provided


TEST ATMOSPHERE
- Brief description of analytical method used: gas chromatography
- Samples taken from breathing zone: yes. Regular analysis completed during exposure periods

Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
See report HL-580-75 at point 7.8.1.001



For the teratology study the nominal concentrations of 1, 10 and 25 ppm were determined analytically to be 0.8, 8.6 and 22.7 ppm.

For the embryotoxicity study the nominal concentrations of 1, 10 and 25 ppm were determined analytically to be 1.3, 9.9 and 24.7 ppm.

Details on mating procedure:
For the teratology phase the rats were supplied as time-mated at the breeder.

For the embryotoxicity phase 200 ChR-CD rats were mated at the laboratory, with day 1 of gestation set as the time when sperm were observed in the vaginal smear
Duration of treatment / exposure:
For the teratology phase the rats were treated from day of arrival (gestation day 2 or 3) up to gestation day 20
For the embryotoxicity phase the rats were dosed from gestation day 1 to GD 12.
Rats were exposed to chloroprene vapour for four hours each day
Frequency of treatment:
daily
Duration of test:
Teratology phase terminated on gestation day 20. Embryotoxicity phase included a period of five days after the last exposure and the rats were terminated on gestation day 17
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 1, 10 or 25 ppm
Basis:
nominal conc.
No. of animals per sex per dose:
Teratology - 25 female rats per dose group
Embryotoxicity - 50 female rats per dose group
Control animals:
yes
Details on study design:
For the teratology study, 25 rats were allocated to each dose level, randomly by bodyweight. The animals were mated at the supplier and treatment commenced on the day of arrival. Daily exposure for 4 hrs per day continued to gestation day 20. After exposure on day 20 all rats were terminated by anaesthetic overdose and gross examination of the dams completed.


For the embryotoxicity study, 50 rats were allocated to each dose level, randomly by bodyweight. The females were co-housed with males in a ratio of two to one. Mating was confirmed by the presence of sperm in the vaginal smear, defied as gestation day 1. Treatment commenced on gestation day 12 and continued for five days. Daily exposure was for 4 hrs per day. After exposure on day 17 all rats were terminated by anaesthetic overdose and gross examination of the dams completed.


Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily

BODY WEIGHT: No data

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20 for teratology investigation or gestation day 17 for embryotoxicity
- Organs examined:

For teratology study dams:
Uterine horns opened and examined, foetuses removed and the number of corpora lutea in each ovary counted; number of implantation sites in each horn; number and location of live and dead foetuses; number and location of late and early resorptions; weights and crown-to-rump lengths for all live foetuses; foetal examination for gross anomalies
For embryotoxicity dams:
Uterine horns opened and examined, foetuses removed and the number of corpora lutea in each ovary counted; number of implantation sites in each horn; number and location of live and dead foetuses; number and location of late and early resorptions
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
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
Fetal examinations:
- External examinations: Yes: all per litter in teratology study. No data for embryotoxicity study
- Soft tissue examinations: Yes: circa one third of foetuses examined in teratology study
- Skeletal examinations: Yes: circa two thirds of foetuses examined in teratology study
- Head examinations: No data
Statistics:
No data
Indices:
See attached tables
Historical control data:
Tabulated results contain breeder's information for various teratology and embryotoxicity parameters from historical records

Results and discussion

Results: maternal animals

Maternal developmental toxicity

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

Results (fetuses)

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

Effect levels (fetuses)

Dose descriptor:
NOEC
Effect level:
> 25 ppm (nominal)
Basis for effect level:
other: teratogenicity

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
In teratology and embryotoxicity assessments conducted in pregnant female rats of the CD strain, inhalation exposure during gestation at concenttrations up to 25 ppm resulted in no adverse effects on the mothers. There were no effects on bodyweight or gravid uterus weight, pre- and post-implantation losses were similar in test and control groups as were fertilised ova losses and the number of live foetuses per litter.
Embryo development based on weight and size was unaffected by maternal inhalation of 25 ppm atmospheric concentration. No major external, skeletal or soft tissue malformations were observed at concentrations up to 25 ppm.

ß-Chloroprene was not found to be teratogenic or embryotoxic to CD rats under the conditions of the two investigations included in this report.
Executive summary:

or the teratology study, 25 rats were allocated to each dose level, randomly by bodyweight. The animals were mated at the supplier and treatment commenced on the day of arrival. Daily exposure for 4 hrs per day continued to gestation day 20. After exposure on day 20 all rats were terminated by anaesthetic overdose and gross examination of the dams completed. For the embryotoxicity study, 50 rats were allocated to each dose level, randomly by bodyweight. The females were co-housed with males in a ratio of two to one. Mating was confirmed by the presence of sperm in the vaginal smear, defied as gestation day 1. Treatment commenced on gestation day 12 and continued for five days. Daily exposure was for 4 hrs per day. After exposure on day 17 all rats were terminated by anaesthetic overdose and gross examination of the dams completed.

No clinical signs of reaction to exposure to chloropene at 1, 10 or 25 ppm were observed in either the teratology or embryotoxicity studies, during exposure or in the post-exposure period.

No gross pathological changes were observed in the uterine horns, ovaries or any other organs at termination of the two studies.

Neither study showed any treatment related differences between test and contro groups in respect of implantation sites per litter, litter size, fertilised ova losses, foetal resorptions (early or late) or the number of females with partial resorptions.

The teratology investigation revealed no differences in foetal length/ crown-to-rump length. The incidence and type of foetal anomalies showed no effect of treatment. The majority of gross anomalies were minute subcutaneous heamatomas or petechial heamorrhages, also commonly observed in the controls.

No major skeletal or soft tissue abnormalities were identified in foetuses rom chloroprene treated mothers that were also observed inthe control group. The number of unossified sternebrae and thoracic centra was slightly lower in test groups than controls. Ossfication was unaffected by chloroprene treatment.

Spontaneous congenital variants such as supernumary and wavy ribs or hydronephrosis were observed but are not a reaction to treatment.