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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:
25.08.2004 - 24.09.2004
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2005
Report date:
2005

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:
4-chlororesorcinol
EC Number:
202-462-0
EC Name:
4-chlororesorcinol
Cas Number:
95-88-5
Molecular formula:
C6H5ClO2
IUPAC Name:
4-chlorobenzene-1,3-diol
Test material form:
other:
Remarks:
beige powder
Details on test material:
Molecular weight: 144.65

Test animals

Species:
rat
Strain:
Wistar
Details on test animals or test system and environmental conditions:
Age at pairing: 11 weeks minimum

Body weights (day 0 post coitum): 190 - 236 grams

Acclimatization: five days prior to pairing under test conditions with an evaluation of the health status

Conditions: animals were housed under standard laboratory conditions: air-conditioned with 10-15 air changes per hour; the environment monitored continuously with recordings of temperature (target range 22 +/- 5°C) and relative humidity (target range 30 - 70%), 12 hours artificial fluorescent light / 12 hours dark with background music played at a centrally defined low volume for at least 8 hours during the light period

Accomodation: animals were housed individually in Makrolon cages (type-3) with wire mesh tops and standardized granulated softwood bedding (Lignocel, Schill AG, CH-4132 MuttenzlSwitzerland)

Diet: pelleted standard Kliba-Nafag 3433 rat/mouse maintenance diet (Provimi Kliba AG, CH-4303 Kaiseraugstl Switzerland) was available ad libitum

Water: community tap water from Füllinsdorf in bottles was available ad libitum

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: ultrapure water
Details on exposure:
A standard dose volume of 10 ml/kg body weight with a daily adjustment to the actual body weight was used.
Details on mating procedure:
After acclimatization, females were housed with sexually mature males (1:1) in special automatic mating cages, i.e. with synchronized timing to initiate the nig htly mating period, until evidence of copulation was observed. This system reduced the variation in the copulation times of the different females.

The females were removed and housed individually, if:
a) the daily vaginal smear was sperm positive. or
b) a copulation plug was observed.

The day of mating was designated day 0 post coitum. Male rats of the Same source and strain were used for mating only. These male rats were in the possession of RCC, and were not considered part of the test system. The fertility of these males had been proven and was continuously monitored.
Duration of treatment / exposure:
from day 6 through to day 20 post coitum
Frequency of treatment:
once daily
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day
Remarks:
group 1 (vehicle control)
Dose / conc.:
50 mg/kg bw/day
Remarks:
group 2
Dose / conc.:
100 mg/kg bw/day
Remarks:
group 3
Dose / conc.:
200 mg/kg bw/day
Remarks:
group 4
No. of animals per sex per dose:
22 mated female rats
Control animals:
yes

Examinations

Maternal examinations:
General Tolerability
All females survived until scheduled Caesarean section.
In group 4, following administration of the test item clonic spasms or tremor were noted for all females on all treatment days. In group 3, following administration of the test item tremor was noted for all females during the first six to eleven treatment days. These clinical signs were considered to be test item related. No test item-related macroscopic findings were noted at necropsy.

Food Consumption and Body Weights
No test item-related effects on mean food consumption or body weight gain were noted at any dosage applied.
Also corrected body weight gain (corrected for gravid uterus weights) did not give an indication of test item-related effects.

Reproduction Data
The pregnancy rate was 100% and the mean numbers of Corpora lutea and implantation sites were similar in all groups. Post-implantation losses and the mean number of fetuses per dam were unaffected by treatment with the test item at all dose levels.
Fetal examinations:
Body Weights and Sex Ratios
Mean fetal body weights were similar in all groups and gave no indication of a test itemrelated effect.
No test item-related effects on fetal Sex ratios were noted in any group.

External Examination
No abnormalities were noted during external examination of fetuses.

Visceral and Skeletal Examination
No test item-related findings were noted during fetal visceral, skeletal or cartilage examination.

Results and discussion

Results: maternal animals

Effect levels (maternal animals)

Key result
Dose descriptor:
NOEL
Effect level:
50 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
body weight and weight gain
clinical signs
food consumption and compound intake
number of abortions
pre and post implantation loss

Results (fetuses)

Effect levels (fetuses)

Key result
Dose descriptor:
NOEL
Effect level:
200 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
changes in sex ratio
fetal/pup body weight changes
external malformations
skeletal malformations
visceral malformations

Overall developmental toxicity

Developmental effects observed:
no

Applicant's summary and conclusion

Conclusions:
In order to detect effects on embryonic and fetal development in pregnant rats, A 012 was administered orally by gavage once daily from day 6 through to day 20 post coitum at dose levels of 0, 50, 100 and 200 mg/kg body weight/day.

Treatment with the test item at 200 and 100 mg/kg body weightlday resulted in dose dependent clinical signs following administration of the test item (clonic spasms and tremor).

Based on these results the NOEL (no observed effect level) for maternal organisms was considered to be 50 mg/kg body weight/day.
Based on these results the NOEL (no observed effect level) for embryo-fetal organisms was considered to be 200 mg/kg body weight/day.

Under the conditions described for this study A 012 did not reveal any teratogenic potential up to and including the highest dose level of 200 mg/kg body weight/day.
Executive summary:

The purpose of this study was to assess the effects of A 012 on embryonic and fetal development when administered orally by gavage once daily to mated female rats from day 6 through to day 20 post coitum, inclusive.

Each group consisted of 22 mated female rats and A 012 was administered at dose levels of :

Group 1 : 0 mglkg body weight/day (vehicle control)

Group 2: 50 mglkg body weight/day

Group 3: 1 00 mglkg body weight/day

Group 4: 200 mglkg body weight/day

A standard dose volume of 10 ml/kg body weight with a daily adjustment to the actual body weight was used. Control animals were dosed with the vehicle alone (ultrapure water).

All females were sacrificed on day 21 post coitum and the fetuses were removed by Caesarean section. Examination of dams and fetuses was performed in accordance with international recommendations.

The following results were obtained:

MATERNAL DATA

General Tolerability

All females survived until scheduled Caesarean section.

In group 4, following administration of the test item clonic spasms or tremor were noted for all females on all treatment days. In group 3, following administration of the test item tremor was noted for all females during the first six to eleven treatment days. These clinical signs were considered to be test item related.

No test item-related macroscopic findings were noted at necropsy.

Food Consumption and Body Weights

No test item-related effects on mean food consumption or body weight gain were noted at any dosage applied.

Also corrected body weight gain (corrected for gravid uterus weights) did not give an indication of test item-related effects.

Reproduction Data

The pregnancy rate was 100% and the mean numbers of Corpora lutea and implantation sites were similar in all groups. Post-implantation losses and the mean number of fetuses per dam were unaffected by treatment with the test item at all dose levels.

FETAL DATA

Body Weights and Sex Ratios

Mean fetal body weights were similar in all groups and gave no indication of a test itemrelated effect.

No test item-related effects on fetal Sex ratios were noted in any group.

External Examination

No abnormalities were noted during external examination of fetuses.

Visceral and Skeletal Examination

No test item-related were noted during fetal visceral, skeletal or cartilage examination.