Registration Dossier

Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: OECD guideline study TG 415

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2000
Report Date:
2000

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
other: OECD Guideline 415
Principles of method if other than guideline:
One-Generation Reproduction Toxicity Study
GLP compliance:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Basisch Gelb 8511
- Physical state: powder
- Analytical purity: 98,9%
- Lot/batch No.: ZD 00969/086

Test animals

Species:
rat
Strain:
Wistar
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Boehringer Ingelheim Pharma KG
- Age at study initiation: 37 +- 1 day at the beginning of treatment
- Weight at study initiation: Males: 148.0 - 184.8 g (mean 168.0 g); Females: 116.7 - 155.9 g (mean 138.0g);
- Housing: DK III stainless steel wire mesh cages, Becker A& Co.; floor area of about 800 cm²
- Dieta: ad libitum
- Water: ad libitum
- Acclimation period: 9 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 24°C
- Humidity (%): 30 - 70 %
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
olive oil
Details on exposure:
As the test substance is sensitive to hydrolysis, it was administered as a suspension in olive oil (EAB, 1997; pharmaceutical). To prepare the suspension, the appropriate amount of test substance was weighed, depending on the dose group. Then the olive oil was filled up to the desired volume and mixed using an Ultra Turrax. During the administration the test substance preparations were kept homogenous with a magnetic stirrer. In respect to the proven stability the test substance preparations were prepared twice a week before dosing.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The stability of the substance in olive oil was demonstrated for a period of 4 days at room temperature before the start of the study. Homogeneity analyses were performed at the start of the administration period in samples of the high and low concentration drawn from bottom, middle and top of the substance preparations. These samples also served for concentration control analyses for these groups. Additional concentration control analyses were performed at the start of the administration period with samples from the mid concentration drawn from the middle of the substance preparation, at the middle and towards the end of the administration period with samples from all concentrations.
Details on mating procedure:
- M/F ratio per cage: 1:1
- Length of cohabitation: overnight for a maximun of 3 weeks
- Proof of pregnancy: sperm in vaginal smear] referred to as day 0 of pregnancy
- Any other deviations from standard protocol: exception in few matings a ration of 1:2 (males:females) due to premature mortalities of single males.
Duration of treatment / exposure:
Premating exposure period: min. 74 days
Frequency of treatment:
daily
Duration of test:
d 21 pp
Doses / concentrations
Remarks:
Doses / Concentrations:
2, 10, 60 mg/kg bw/d
Basis:

No. of animals per sex per dose:
25
Control animals:
yes, concurrent vehicle

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
General effects in the F0 parental animals were limited to abnormal clinical findings. Respiratory sounds, discolored urine and a single case of fur smeared with urine were seen at 60 mg/kg body weight/day. The discoloration of the urine was related to the physical properties of the test compound (dye stuff) indicative for systemic availability. The affection of the respiratory system was probably due to an unintentional aspiration of the test substance as a consequence of attempts to vomit the test substance.

Effect levels (maternal animals)

Dose descriptor:
NOAEL
Effect level:
60 mg/kg bw/day
Basis for effect level:
other: developmental toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
Substance-induced signs of developmental toxicity were not observed in progeny of the F0 parents at any dose level. The NOAEL for developmental toxicity (growth and development of the offspring) could be fixed at 60 mg/kg body weight/day for the F1 progeny.

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
The NOAEL for developmental toxicity (growth and development of the offspring) could be fixed at 60 mg/kg body weight/day for the F1 progeny.