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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:
06.10.2004 - 02.03.2005
Reliability:
1 (reliable without restriction)

Data source

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

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
GLP compliance:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid

Test animals

Species:
rat
Strain:
other: Han Wistar
Details on test animals and environmental conditions:
Acclimatization: Five days prior to pairing under test conditions with an evaluation of the health status
Number of animals: 88 mated females*, 22 per group (*In order to complete mating within a reasonable time period, 98 female rats were obtained from the breeder. The surplus females were killed after commencement of treatment tor the last mated females.)
Age at pairing: 11 weeks
Body weights (day 0 post coitum): 196 - 240 grams
Identifiation (day 0 post coitum): Individual cage card and animal number tattooed on the pinnae.

HUSBANDRY
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 Makroion cages (type-3) with wire mesh tops and standardized granulated softwood bedding (Lignocel, Schill AG, CH-4132 Muttenz/Switzerland).

Diet:
Pelleted standard Kliba-Nafag 3433 rat/mouse main­tenance diet (Provimi Kliba AG, CH-4303 Kaiseraugst/ 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 mUkg body weight with a daily adjustment to the actual body weight was used.
Duration of treatment / exposure:
Day 6 through to day 20 post coitum, inclusive.
Frequency of treatment:
once daily
Duration of test:
21 days (post coitum)
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day (nominal)
Remarks:
Group 1 (vehicle control)
Dose / conc.:
50 mg/kg bw/day (nominal)
Remarks:
Group 2
Dose / conc.:
100 mg/kg bw/day (nominal)
Remarks:
Group 3
Dose / conc.:
200 mg/kg bw/day (nominal)
Remarks:
Group 4
No. of animals per sex per dose:
22 mated female rats
Control animals:
yes, concurrent vehicle

Results and discussion

Results: maternal animals

Effect levels (maternal animals)

Key result
Dose descriptor:
NOEL
Effect level:
50 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
clinical signs
mortality
body weight and weight gain
food consumption and compound intake
water consumption and compound intake
ophthalmological examination
haematology
clinical biochemistry
urinalysis
behaviour (functional findings)
organ weights and organ / body weight ratios
gross pathology
histopathology: neoplastic
maternal abnormalities
number of abortions
pre and post implantation loss
total litter losses by resorption
effects on pregnancy duration
early or late resorptions
dead fetuses
changes in pregnancy duration
changes in number of pregnant
necropsy findings

Results (fetuses)

Effect levels (fetuses)

Key result
Dose descriptor:
NOEL
Effect level:
200 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
reduction in number of live offspring
changes in sex ratio
fetal/pup body weight changes
changes in litter size and weights
changes in postnatal survival
external malformations
skeletal malformations
visceral malformations

Overall developmental toxicity

Key result
Developmental effects observed:
no
Treatment related:
no
Dose response relationship:
no
Relevant for humans:
not specified

Applicant's summary and conclusion

Conclusions:
In order to detect effects on the pregnant female and on embryonic and fetal development A 130 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 100 and 200 mg/kg body weight/day resulted in clinical signs (ruffled fur), dose-dependently reduced mean food consumption and body weight gain.
Based on these results the NOEL (no observed effect level) for maternal organisms was considered to be 50 mg/kg body weight/day.
The NOEL (no observed effect level) for fetal organisms was considered to be 200 mg/kg body weight/day.
Up to and including the high dose of 200 mg/kg body weight/day, A 130 revealed no teratogenic potential.
Executive summary:

The purpose of this study was to assess the effects of A 130 on the pregnant female rat and development of the embryo and fetus 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. A 130 was administered once daily at dose levels of:

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

Group 2: 50 mg/kg body weight/day

Group 3: 100 mg/kg body weight/day

Group 4: 200 mg/kg 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 necropsy.

At 100 and 200 mg/kg/day, ruffled fur and signs of discomfort following administration were noted for all females on most days of the treatment period.

No test item-related macroscopic findings were noted during necropsy of dams.

Food Consumption and Body Weights

At 100 and 200 mg/kg/day, mean food consumption and body weight gain was dose­dependently reduced during the treatment period. Also corrected body weight gain (corrected for gravid uterus weight) was dose-dependently reduced at these dosages.

Reproduction Data

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

Sex Ratios and Body Weights

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

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

External Examination

No abnormalities that were considered to attributable to treatment with the test item were noted during fetal external

examination.

Visceral Examination

No test item-related findings were noted during fetal visceral examination.

Skeletal and Cartilage Examination

No test item-related findings were noted during fetal skeletal and cartilage examination.