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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:
1990
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions

Data source

Reference
Reference Type:
publication
Title:
AY23 - STUDY OF THE TERATOGENIC POTENTIAL OF FD & C YELLOW NO. 5 WHEN GIVEN BY GAVAGE TO RATS
Author:
T. F. X. COLLINS, T. N. BLACK, L. H. BROWN and P. BULHAC
Year:
1990
Bibliographic source:
Fd Chem. Toxic. Vol. 28, No. 12, pp. 821-827, 1990

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
not specified
GLP compliance:
not specified
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid: particulate/powder
Details on test material:
No data

Test animals

Species:
rat
Strain:
Osborne-Mendel
Remarks:
FDA strain
Details on test animals and environmental conditions:
Male and female Osborne- Mendel (FDA strain) rats were obtained from the FDA rat breeding colony. At the start of the study, female rats were 13-21 wk old and weighed 210-270 g. This strain of rats was selected because of the availability of historical data. The general appearance and well-being of the rats were monitored daily. Food (Purina Laboratory Chow, Ralston Purina Company, St Louis, MO, USA) and distilled water were available ad lib.The rats were weighed daily and food consumption was measured weekly. Water intake was not measured. All rats were identified by numbered metal ear tags and were housed in stainless-steel hanging cages. The foetuses were grouped by litter for identification. Hygrothermographs monitored temperature (20.5-25°C) and humidity (30-50%).An automatic light provided a 12-hr light/dark cycle (8.00 am-8.00 pm).

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
Fresh solutions were prepared daily and administered by gavage in a volume of 1 ml/100 g body weight at approximately the same time each day. Controls received an equivalent amount of distilled water.
Analytical verification of doses or concentrations:
not specified
Details on mating procedure:
On mating days, two females were randomly mated with one male at approximately 4.30 pm. The following morning, the presence of sperm in the vaginal smear was con- sidered to be evidence of copulation and the sperm- positive females were considered to be at day 0 of gestation. Then 40-41 of the females presumed to be pregnant were placed in each dosage group by random number: 0 (distilled water only), 60, 100, 200, 400, 600 or 1000 mg/kg body weight/day. Each rat was treated daily from day 0 to day 19 to simulate human consumption that occurs throughout gestation. On day 20 of gestation, starting at 1.00 pm, the females were examined for gross abnormalities for the last time before being killed by CO2 asphyxiation.
Frequency of treatment:
daily
Duration of test:
20 days
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day (nominal)
Remarks:
negative control
Dose / conc.:
60 mg/kg bw/day (nominal)
Dose / conc.:
100 mg/kg bw/day (nominal)
Dose / conc.:
200 mg/kg bw/day (nominal)
Dose / conc.:
400 mg/kg bw/day (nominal)
Dose / conc.:
600 mg/kg bw/day (nominal)
Dose / conc.:
1 000 mg/kg bw/day (nominal)
No. of animals per sex per dose:
not specified
Control animals:
yes, concurrent vehicle
Details on study design:
Caesarean sections were performed, corpora lutea were counted and the uteri were opened and exam- ined in situ. The uterine positions of all implantation sites were noted and their condition (early or late resorptions, alive or dead foetuses) was determined. Each live foetus was promptly weighed, sexed and examined for gross external malformations, and the crown-rump length was measured. Any foetus that weighed less then 70% of the average weight of the concurrent male or female controls was considered to be a runt (Leuschner and Czok, 1973). Approximately half of the foetuses were examined for skeletal variations after being fixed in alcohol, cleared and stained with Alizarin Red S by a modifi- cation of Dawson's method (Dawson, 1926). The remaining foetuses were fixed in Bouin's solution and sectioned according to the method of Wilson (Wilson, 1973; Wilson and Warkany, 1965) in order to detect internal visceral variations. Each sperm-positive female was given a random test number, which was carried over as a litter number after the female was killed. To preclude the possibility of bias, evaluations of the dams and foetuses during caesarean sections and during skeletal or visceral analysis were done without the evaluators knowing the dose group to which the animal belonged.

Examinations

Maternal examinations:
No unusual behaviour or remarkable external maternal findings were noted.
Statistics:
All analyses for statistical significance were performed by the Division of Mathematics at the FDA. Data on maternal initial body weight and maternal food consumption were analysed by straight analysis of variance (ANOVA) and a two-tailed t-test, and by regression analysis. Data on litters having one or more, or two or more, resorptions were analysed by Fisher's exact test.

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
not specified
Dermal irritation (if dermal study):
not examined
Mortality:
mortality observed, non-treatment-related
Description (incidence):
One female in the group given 60mg/kg body weight/day died at day 13 of gestation of gavage difficulties unrelated to dosage.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
Initial body weight at day 0 and maternal body-weight gain during gestation did not vary significantly between treated and control groups
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Throughout gestation, the mean daily food consumption of the rats given 1000mg/kg body weight/day was significantly greater than that of the controls. Overall mean daily food consumption by the rats treated with 6-600mg/kg body weight/day was not significantly different from that of the controls, although consumption in some individual weeks was significantly higher than that of the controls.
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
not specified
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
not specified
Other effects:
not specified

Maternal developmental toxicity

Number of abortions:
no effects observed
Description (incidence and severity):
The pregnancy rate was high in all groups, ranging from 87.5 to 95.0%.
Pre- and post-implantation loss:
no effects observed
Description (incidence and severity):
Implantation efficiency was similar in all groups.
Total litter losses by resorption:
not specified
Early or late resorptions:
not specified
Dead fetuses:
not specified
Changes in pregnancy duration:
not specified
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): not specified
Changes in number of pregnant:
not specified

Effect levels (maternal animals)

Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
mortality

Maternal abnormalities

Abnormalities:
no effects observed
Localisation:
other: -

Results (fetuses)

Fetal body weight changes:
not specified
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): not specified
Reduction in number of live offspring:
not specified
Changes in sex ratio:
not specified
Changes in litter size and weights:
not specified
Changes in postnatal survival:
not specified
External malformations:
effects observed, non-treatment-related
Description (incidence and severity):
Examination of offspring for external variations yielded one foetus with a string tail in the control group and three hydrocephalic pups in a single litter in the 200 mg/kg body weight/day group. The three hydrocephalic foetuses have been added to and analysed with the visceral variations. Foetuses with haemorrhages were observed in all treated and control groups. These external haemorrhages, not shown in the table, were seen on all parts of foetuses and their incidence was not correlated with dosage.In the control group, two litters, each with one foetus, were affected. In the 1000mg/kg body weight/day group, four foetuses from three litters were affected. In the remaining five treated groups, the number of litters affected ranged from one to seven without relation to dosage.
Skeletal malformations:
no effects observed
Description (incidence and severity):
No dose-related increase in sternebral variations occurred among the foetuses with reduced ossification, bipartite, missing or malaligned sternebrae. No dose-related increase occurred among the foetuses with skeletal variations.The incidences of foetuses with skeletal variations and of litters containing those foetuses were similar in all groups
Visceral malformations:
not specified
Other effects:
not specified
Details on embryotoxic / teratogenic effects:
No teratogenic effects were observed.

Effect levels (fetuses)

Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: general consideration about exminations

Fetal abnormalities

Abnormalities:
effects observed, non-treatment-related
Localisation:
other: brain
Description (incidence and severity):
see details in the related field

Overall developmental toxicity

Developmental effects observed:
no
Lowest effective dose / conc.:
1 000 mg/kg bw/day (nominal)
Treatment related:
yes

Applicant's summary and conclusion

Conclusions:
Not teratogenic
NOAEL = 1000 mg/kg bw
Executive summary:

The tested substance appears to be neither developmentally toxic nor teratogenic.