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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:
test procedure in accordance with generally accepted scientific standards and described in sufficient detail

Data source

Referenceopen allclose all

Reference Type:
study report
Title:
Unnamed
Year:
1993
Report date:
1993
Reference Type:
other: abstract
Title:
Developmental toxicity studies with octamethylcyclotetrasiloxane (D4) in CD rats and rabbits
Author:
York R, Schardein JL
Year:
1994
Bibliographic source:
The toxicologist 14: 160 abs 572

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
yes
Remarks:
some details missing, but this does not affect the quality of the study
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Octamethylcyclotetrasiloxane
EC Number:
209-136-7
EC Name:
Octamethylcyclotetrasiloxane
Cas Number:
556-67-2
Molecular formula:
C8H24O4Si4
IUPAC Name:
2,2,4,4,6,6,8,8-octamethyl-1,3,5,7,2,4,6,8-tetroxatetrasilocane

Test animals

Species:
rabbit
Strain:
New Zealand White
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Hazleton Research Products, Inc. Kalamazoo, Michigan.
- Age at study initiation: Approx. 27.5 weeks
- Weight at study initiation: 2871-3569 g at insemination
- Fasting period before study: No data
- Housing: Suspended stainless steel cages
- Diet (e.g. ad libitum): Ad libitum
- Water (e.g. ad libitum): Ad libitum
- Acclimation period: 37 days


ENVIRONMENTAL CONDITIONS
- Temperature (°F):60-69
- Humidity (%): 49-79
- Air changes (per hr): No data
- Photoperiod (hrs dark / hrs light): 12/12


IN-LIFE DATES: From: 08.09.1992 To: 09.10.1992

Administration / exposure

Route of administration:
inhalation
Type of inhalation exposure (if applicable):
whole body
Vehicle:
unchanged (no vehicle)
Details on exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: All animals were exposed simultaneously in four stainless steel and glass exposure chambers with a volume of approximately 16 cubic meters each. One chamber was used for each group for the duration of the study, and the animals remained in the chamber 24 hours per day.
- Source and rate of air: HVAC system separate from the general laboratory system.
- Method of conditioning air: filtered
- Temperature, humidity, pressure in air chamber: Controlled, but no further details
- Air flow rate: No data
- Air change rate: No data
- Treatment of exhaust air: No data

TEST ATMOSPHERE
- Brief description of analytical method used: Gas-phase infrared spectrometry using a MIRAN 1A
- Samples taken from breathing zone: yes
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Each chamber was sampled by drawing the exposure atmosphere into the MIRAN through Teflon sample lines. A solenoid valve-based sampling system and the recording of exposure concentrations from the MIRAN were controlled by a Hewlett-Packard 3388A laboratory computer system such that each chamber was analysed once per hour.
Details on mating procedure:
- Impregnation procedure: artificial insemination
- Verification of same strain and source of both sexes: No data
- Day of insemination referred to as day 0 pregnancy
Duration of treatment / exposure:
day 6 - 18 of gestation
Frequency of treatment:
daily for 6 h
Duration of test:
29 days
Doses / concentrationsopen allclose all
Dose / conc.:
100 ppm (nominal)
Dose / conc.:
300 ppm (nominal)
Dose / conc.:
500 ppm (nominal)
No. of animals per sex per dose:
20 females
Control animals:
other: yes, concurrent treatment with filtered air
Details on study design:
- Dose selection rationale: Based on range-finding study results

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Twice daily throughout the study for mortality and signs of overt toxicity.


DETAILED CLINICAL OBSERVATIONS: No


BODY WEIGHT: Yes
- Time schedule for examinations: Individual maternal body weights were recorded on gestation days 0, 6, 9, 12, 15, 19, 24 and 29.


FOOD CONSUMPTION: Yes
- Individually for the following intervals: 0-6, 6-9, 9-12, 12-15, 15-19, 19-24, 24-29, 6-19 and 0-29.


WATER CONSUMPTION: No


POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 29
- Organs examined: The uterus and ovaries were exposed and pregnancy status was determined. The abdominal and thoracic cavities and organs of the females were examined for gross adverse changes. Gross lesions were preserved for possible histopathological examination. Uteri from females that appeared nongravid were opened and examined for detection implantations. Maternal liver weights were also measured and recorded.

OTHER: Females showing signs of abortion were euthanised on the day such evidence was observed and the aborted tissue examined and preserved for possible histopathological examination.
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 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: half per litter
- Head examinations: No data
Statistics:
All statistical analyses compared the exposure groups with the control group; mean values were noted where p≤0.05 and p≤0.01 occurred. All means were accompanied by standard deviations. All statistical tests were performed by a VAX computer, SAS statistical software, as well as in-house software, were utilised for analyses.
Indices:
No indiced calculated
Historical control data:
No data described

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects: yes

Details on maternal toxic effects:
No substance related mortality; no adverse antemortem or necropsy findings; no substance related effects on body weight gain at any exposure group.
Statistically significant reductions in maternal food consumption were noted in the highest exposure group during the first and second exposure intervals (gestation days 6-9 and 9-12) when compared with the controls. Food consumption was also slightly reduced, relative to the control group, in that group during the third interval (gestation days 12-15) and during the overall exposure interval (gestation days 6-19). These reductions were considered to be treatment-related.

Effect levels (maternal animals)

Dose descriptor:
NOAEL
Effect level:
300 ppm
Based on:
test mat.
Basis for effect level:
other: maternal toxicity

Results (fetuses)

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

Details on embryotoxic / teratogenic effects:
Mean postimplantation loss (resorptions) was slightly increased in the highest exposure group when compared with the controls, but were well within the historical control range. This finding was not attributed to treatment. There were no treatment-related differences in the number of viable fetuses per dam or mean fetal body weight. There were no treatment-related malformations or developmental variations.

Effect levels (fetuses)

Dose descriptor:
NOAEL
Effect level:
>= 500 ppm
Based on:
test mat.
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 the key inhalation developmental toxicity study in rabbits, conducted using a protocol comparable to OECD 414 and GLP (reliability score 1), D4 did not affect fetal developmental and the NOAEC for this endpoint was therefore greater than the highest concentration tested (500 ppm). The NOAEC for maternal toxicity was 300 ppm based on reduced food consumption in the highest dose group.