3-amino-2-chlor-6-methylphenol

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

07.03. - 05.04.1988

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1988

Report date:

1988

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

GLP compliance:

yes

Test material

Test material information

1

Reference substance name:

3-amino-2-chlor-6-methylphenol

EC Number:

283-144-9

EC Name:

3-amino-2-chlor-6-methylphenol

Cas Number:

84540-50-1

Molecular formula:

C7H8ClNO

IUPAC Name:

3-amino-2-chloro-6-methylphenol

Test material form:

solid: crystalline

Details on test material:

cream colored

Test animals

Species:

rat

Strain:

other: Wistar/HAN

Details on test animals or test system and environmental conditions:

Number of animals: 100 mated females
Age: 11 weeks, minimum
Body weight: 186-234 g
Acclimatization: 7 days minimum
Conditions:
The animals were housed under standard laboratory conditions:
air-conditioned with 10-15 air changes per hour; the environment monitored continuously with hourly recordings of temperature
(range 22 +/- 3 degrees Centigrade) and humidity (range 40 - 70 1.); 12 hours artificial fluorescent light/12 hours dark with background music (Schweizerischer Telefonrundspruch) played at a centrally defined low volume for at least 8 hours during the light period.

Accommodation:
The animals were housed individually in Makrelen cages (type-3) with wire mesh tops and standardised granulated softwood
bedding Clignocel, Schill AG, CH 4132 Muttenz I Switzerland).

Diet:
N Pelleted standard Kliba 343 rat/mouse maintenance diet c·Kliba Klingentalmuehle AG, CH 4303 Kaiseraugst/Switzerland) was available ad libitum (Batch no. 91/88). Results of analyses for contaminants are attached Cpp. 90,91).

Water:
Tap water in bottles was available ad libitum.

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

other: distilled water

Details on exposure:

dose volume of 10 ml/kg body weight

Details on mating procedure:

After acclimatization, the females were paired overnight with sexually mature males, in the ratio of 1 male: 1 female. The day on which spermatozoa were found in the vaginal smear or a vaginal plug was observed was designated day 0 post coitum.

Duration of treatment / exposure:

day 6 through to day 15 post coitum

Frequency of treatment:

daily

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

0 mg/kg bw/day (nominal)

Remarks:

group 1 (vehicle control)

Doses / concentrations 2

Dose / conc.:

30 mg/kg bw/day (nominal)

Remarks:

group 2

Doses / concentrations 3

Dose / conc.:

90 mg/kg bw/day (nominal)

Remarks:

group 3

Doses / concentrations 4

Dose / conc.:

270 mg/kg bw/day (nominal)

Remarks:

group 4

No. of animals per sex per dose:

25

Control animals:

yes, concurrent vehicle

Results and discussion

Results: maternal animals

Effect levels (maternal animals)

Key result

Dose descriptor:

NOEL

Effect level:

90 mg/kg bw/day (nominal)

Based on:

test mat.

Basis for effect level:

body weight and weight gain

food consumption and compound intake

Results (fetuses)

Effect levels (fetuses)

Key result

Dose descriptor:

NOEL

Effect level:

270 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

fetal/pup body weight changes

external malformations

skeletal malformations

visceral malformations

Fetal abnormalities

Key result

Abnormalities:

effects observed, non-treatment-related

Overall developmental toxicity

Key result

Developmental effects observed:

no

Treatment related:

no

Applicant's summary and conclusion

Conclusions:

Oral administration of Ro 543 to pregnant female rats between days 6 and 15 post coitum caused slightly reduced food consumption and body weight gain at the highest dose level of 270 mg/kg body weight/day.

Based on these results, the no-observable effect level for the maternal organism was 90 mg/kg body weight/day.

Ro 543 did not reveal any embryotoxic or teratogenic potential up to the highest dose level of 270 mg/kg body weight/day when administered to pregnant Wistar rats under the conditions described for this study .

Executive summary:

The purpose of this study was to assess the effects of Ro 543 on embryonic and fetal development in pregnant Wistar/HAN rats. Each group consisted of 25 mated female rats. Ro 543 was administered orally by gavage once daily from day 6 through to day 15 post coitum, at dose levels of:

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

Group 2:        30 mg/kg body weight/day

Group 3:        90 mg/kg body weight/day

Group 4:        270 mg/kg body weight/day

The dosages were based on the results of the dose range­finding study (RCC Project 204480). 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 (distilled water).

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

The following results were obtained:

Treatment with Ro 543 did not influence the viability or the behavior and appearance of the animals in any dose group during the entire study. At necropsy, no abnormal findings were observed which could be attributed to treatment with the test article.

Oral administration of Ro 543 caused significantly reduced mean food consumption in the dams of group 4 (270 mg/kg) during the treatment period. In correlation with this finding, mean body weight gain of the group 4 dams was slightly reduced (mainly in the early days of the treatment period). The marginally reduced mean corrected body weight gain was also considered to be treatment-related.

No treatment-related differences between the vehicle control group and any dose group were noted for any of the reproduction parameters. During external examination of the fetuses, no malformations or anomalies were noted which could be attributed to treatment with the test article. The single fetus with malrotated hind limbs in group 3 (90 mg/kg) and the runt with palatoschisis in group 4 (270 mg/kg) were considered to be incidental.

Visceral and skeletal examination of the fetuses gave no indication of treatment-related effects. The differences noted were within the normal range of variation for this rat strain.