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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
06 Aug 2012 - 27 Feb 2013
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP guideline study.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2013
Report Date:
2013

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
other: OECD 421
Deviations:
yes
Remarks:
20 animals per sex were used
Qualifier:
according to
Guideline:
other: EPA OPPTS 870.3550, July 2000
GLP compliance:
yes (incl. certificate)
Remarks:
BASF SE Experimental Toxicology and Ecology 67056 Ludwigshafen, Germany
Limit test:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Physical state: orange solid
- Analytical purity: > 99%
- Expiration date of the lot/batch: unlimited
- Storage condition of test material: room temperature

Test animals

Species:
rat
Strain:
Wistar
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Research Models and Services, Germany GmbH
- Age at study initiation: (P) 1 - 11 wks
- Housing: individually in Makrolon type M III cages, except during mating and postnatal days 0 - 4
- Diet: ground Kliba maintenance diet mouse-rat “GLP”, meal, supplied by Provimi Kliba SA, Kaiseraugst, Switzerland; ad libitum
- Water: ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 24
- Humidity (%): 30 - 70
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
Paliotol Gelb K 2142 was applied as a suspension. To prepare this suspension, the appropriate amount of test substance was weighed out depending on the desired concentration. Then, deionized water was filled up to the desired volume, subsequently released with a high speed homogenizer. During administration of the test substance, preparations were kept homogeneous by stirring with a magnetic stirrer.

VEHICLE
- Amount of vehicle (if gavage): 10 mL/kg
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The analyses of the test substance preparations were carried out as a separate study at the test facility Competence Center Analytics of BASF SE, 67056 Ludwigshafen, Germany, under the responsibility of a Study Director of this test facility. The study was carried out in compliance with the Principles of Good Laboratory Practice.

The stability of the test substance in deionized water for a period of 5 days at room temperature was proven before the start of the study.

Homogeneity analyses of the test substance preparations were performed in samples of the highest and lowest concentrations at the start of the administration period. These samples also served for concentration control.
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1:1
- Length of cohabitation: up to two weeks
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy
Duration of treatment / exposure:
40 to 55 days
Frequency of treatment:
daily, 7 days/week
Duration of test:
males: 2 weeks premating and during mating
females: 2 weeks premating, during mating, gestation and 4 days lactation
Doses / concentrations
Remarks:
Doses / Concentrations:
1000 mg/kg bw/d
Basis:
actual ingested
No. of animals per sex per dose:
20
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: limit test with 1000 mg/kg bw was done based on unexpected total implantation loss at that dose in another OECD 421 study (80R0323/08X008)

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice a day during work days and once on weekends

DETAILED CLINICAL OBSERVATIONS: Yes / No / No data
- Time schedule: twice a day during work days and once on weekends

BODY WEIGHT: Yes
- Time schedule for examinations: males: on the first day of dosing and weekly thereafter; females: on the first day of dosing and once weekly during the premating period, on days 0, 7, 14 and 20 of gestation and during lactation on the same day as litters (days 0 and 4 postnatal)

FOOD CONSUMPTION:
- Time schedule: weekly during premating, during gestation and lactation periods on days 0, 7, 14 and 20 (gestation) and 0 and 4 (lactation), no food consumption was determined for males during mating and postmating periods and for females without positive evidence of sperm and without litter

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on lactation day 4
- Organs examined: all gross lesions, ovaries, uterus and oviducts

Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Number of corpora lutea: Yes
- Number of implantations: Yes
Fetal examinations:
- External examinations: Yes: all per litte
- Soft tissue examinations: Yes: all per litter
Statistics:
For the hypothesis of equal means student's t-test (two-sided) was performed. For the hypothesis of equal proportions Fisher's exact test (one-sided) was applied. For the hypothesis of equal medians one-sided Wilcoxon test was performed. Results were found to be significant at p<0.05.
Indices:
Live birth index (%) = (number of liveborn pups at birth/total number of pups born) x 100
Post implanatation loss (%) = (number of implantations - number of pups delivered/number of implantations) x 100
Viability index (%) = (number of live pups on day 4 after birth/number of live pups on the day of birth) x 100

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Details on maternal toxic effects:
Neither parental mortality nor clinical signs were observed during the study.

Effect levels (maternal animals)

open allclose all
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: developmental toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Details on embryotoxic / teratogenic effects:
No substance related embryotoxic/teratogenic effects were observed until lactation day 4. Slight effects on viability index (96.5% in control and 99.6% in 1000 mg/kg bw/day group) were deemed to be incidental and the rates of liveborn and stillborn pups were evenly distributed about both groups.

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Applicant's summary and conclusion