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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:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Data is from peer reviewed publication

Data source

Reference
Reference Type:
publication
Title:
Teratogenicity and in Vitro Mutagenicity Studies on Nonoxynol-9 and -30
Author:
O. Meyer, P. Haubro Andersen, E. V. Hansen and J. C. Larsen
Year:
1988
Bibliographic source:
Pharmacology & Toxicology 1988, 62, 236-238

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
other: as below
Principles of method if other than guideline:
Teratology study of Nonoxynol 9 by the oral route on rats was carried out
GLP compliance:
not specified

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Nonoxynol-9/ Antarox CO 630
- Molecular formula (if other than submission substance): (C2-H4-O)mult-C15-H24-O
- Molecular weight (if other than submission substance): 264.406 g/mol
- Substance type: Organic
- Physical state: No data available
- Impurities (identity and concentrations): No data available

Test animals

Species:
rat
Strain:
other: Mob: WIST
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Møllegårds Breeding Center Ltd., DK-4623 Skensved, Denmark
- Sex: Male/female
- Age at study initiation: 11 weeks
- Weight at study initiation: No data available
- Fasting period before study: No data available
- Housing: No data available
- Diet (e.g. ad libitum): Powdered chow (chow 101) ad libitum
- Water (e.g. ad libitum): Acidified water (citric acid, pH 3.5) ad libitum
- Acclimation period: 2 weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 1⁰C
- Humidity (%): 60 ± 5%
- Air changes (per hr): 6-8 air changes/hr
- Photoperiod (hrs dark / hrs light): electric light from 07 p.m. to 07 a.m

IN-LIFE DATES: From: To: No data available

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Remarks:
distilled
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: The test substances were dissolved in distilled water
Analytical verification of doses or concentrations:
not specified
Details on mating procedure:
- M/F ratio per cage: 1:1
- Length of cohabitation: No data available
- Proof of pregnancy: [vaginal plug / sperm in vaginal smear] referred to as [day 0 / day 1] of pregnancy - Proof of pregnancy: The presence of a plug was checked every evening (designated day 0) and morning (designated day 1).
- After … days of unsuccessful pairing replacement of first male by another male with proven fertility. No data available
- Further matings after two unsuccessful attempts: [no / yes (explain)] No data available
- After successful mating each pregnant female was caged (how): No data available
- Any other deviations from standard protocol: No data available
Duration of treatment / exposure:
Gestational days 6-15
Frequency of treatment:
Daily from days 6-15
Duration of test:
21 days
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 50, 250, 500 and 500 mg/Kg bw/day
Basis:
no data
No. of animals per sex per dose:
No. Of pregnant rats: 25, 22, 25, 24 and 21 at 0, 50, 250, 500 and 500 mg/Kg bw/day respectively
Control animals:
yes, concurrent vehicle
Details on study design:
No data available

Examinations

Maternal examinations:
The rats were weighed on day 21
Ovaries and uterine content:
Weight of the intact uterus and ovaries, number of corpora luteae, implantations and foetuses, live and dead was observed.
Fetal examinations:
The foetuses were weighed, their sex was determined and they were examined for gross external malformations. Half of the foetuses were examined for skeletal anomalies. The remaining foetuses were fixed in Bouins solution and sectioned according to the method of Wilson.
Statistics:
Weight gain of the dams, sex ratio of foetuses and pre- and post-implantation losses were calculated (Meyer & Hansen 1975).

Student’s t-test was performed on body weight F0, weight gain F0, litter size, sex ratio, body weight F1, mean weight of the intact uteri (inclusive ovaries), pre- and post-implantation loss.

The “Quick Test-chi-square” was used for special parameters in the teratogenicity test.
Indices:
No data available
Historical control data:
No data available

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
A statistically significant, lower average litter size was observed in group 250 mg/Kg bw/day (P< 0.05) and an increase in pre-implantation loss (250 mg/Kg bw/day and 500 mg/kg/day on days 6-15, P< 0.05).
A statistically significant dose-related increase in extra ribs, and rudiments of ribs was observed.
Dams treated with 250 mg or 500 mg of NP-9/Kg bw/day orally exhibited statistically significant decreases in weight gains.

Effect levels (maternal animals)

open allclose all
Dose descriptor:
NOAEL
Effect level:
50 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Dose descriptor:
LOAEL
Effect level:
250 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: maternal toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:yes

Details on embryotoxic / teratogenic effects:
An increased incidence in fetuses showing slightly dilated pelvic cavity was observed in the group treated with 500 mg/kg bw/day of NP-9 orally from day 1 to 20 (12/21 litters compared to 5/25 in the controls, P < 0.05).

Effect levels (fetuses)

open allclose all
Dose descriptor:
NOAEL
Effect level:
50 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: teratogenicity
Dose descriptor:
LOAEL
Effect level:
250 mg/kg bw/day
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:
The No Observed Adverse Effect Level (NOAEL) for the test compound Nonoxynol 9 is found to be 50 mg/ Kg bw/day and the Low Observed Adverse Effect Level (LOAEL) is found to be 250 mg/Kg bw/day.
Executive summary:

As part of the safety evaluation of PA a teratology study with nonoxynol-9 (NP-9) administered perorally was performed. Pregnant rats given 250 mg or 500 mg NP-9/Kg bw/day orally exhibited a statistically significant decrease in weight gain. A concominant effect in these dams on reproduction, and an increase in the incidence of extra ribs and dilated pelvic cavity in their foetuses was interpreted as a consequence of a toxic effect of high doses of NP-9.

 

The No Observed Adverse Effect Level (NOAEL) for the test compound Nonoxynol 9 is found to be 50 mg/ Kg bw/day and the Low Observed Adverse Effect Level (LOAEL) is found to be 250 mg/Kg bw/day.