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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
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Guideline study (OECD)
Cross-reference
Reason / purpose:
reference to same study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1995
Report Date:
1995

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
other: OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test) draft
GLP compliance:
yes
Remarks:
Department of Toxicology, BASF AG
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): 1,6-Hexandiol
- Test substance No. : 93/23 0
- Date of production : Dec. 17 - 21, 1993
- Physical state: solid - liquid/colorless
- Analytical purity: 97%
- Purity test date: February 9, 1994
- Lot/batch No.: Tank 19
- Storage condition of test material: room temperature; in a closed container due to the hygroscopic properties of the test substance


Test animals

Species:
rat
Strain:
Wistar
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Dr . K . THOMAE GmbH, Biberach an der Riss, Germany
- Age at study initiation: (P) 12 wks
- Weight at study initiation: (P) Males: 394.0 (369.4 - 414.0) g; Females: 234.7 (224.4 - 248.0) g
- Identification: ear tattoo; pups by skin tattoo
- Housing:individually in type DK III stainless steel wire mesh cages supplied by BECKER & CO., Castrop-Rauxel, Germany (floor area of about 800 cm2). For the overnight mating the females were put into the cages of the males; from day 18 pc until sacrifice, the pregnant animals and their litters were housed in Makrolon type MIII cages (floor area about 800 cma). The MIII cages were also supplied by BECKER & CO. Pregnant females were provided with nesting material (cellulose wadding) toward the end of pregnancy. The cages with the test animals were arranged on the racks in such a way that uniform experimental conditions (ventilation and light) were ensured. The bedding used throughout the study was Ssniff (type 3/4 ) supplied by SSN IFF S PEZIALDIATEN GmbH, Soest, Germany.
- Diet (e.g. ad libitum): ad libitum, ground Kliba maintenance diet rat/mouse/hamster GLP 343 meal, supplied by KLINGENTALNlOHLE AG, Kaiseraugst, Switzerland
- Water (e.g. ad libitum): Drinking water of tap water quality was supplied from water bottles
- Acclimation period: 7 d


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

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
Before start of study, the test substance was melted at 50°C and homogenated by stirring. Thereafter about 60 samples (one sample for one test
substance preparation) were bottled, numbered consecutively and stored at room temperature. Each day, one of the test substance samples was
melted at 50°C in a water bath, thereafter an appropriate amount of the test substance was weighed and subsequently dissolved in doubly distilled water with a magnetic stirrer for about 5 minutes.

VEHICLE
- Amount of vehicle (if gavage): 10 ml
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The analytical examinations mentioned below were carried out in the analytical department of BASF AG (Dr. P. Schmidt responsible):
- Analyses of test substance: Investigations to characterize the test substance in respect to purity and homogeneity were carried out before the start of the study (method: gas chromatography). The stability of the test substance over a period of 17 months was proven. Due to the short study duration, a reanalysis after the experimental phase of the study was not considered necessary. Detailed descriptions of the extent of the analytical
investigations and of the analytical methods employed are stored with BASF AG.
- Analyses of the solutions of test substance: analytical verifications of the stability of the
aqueous test substance solutions for a period of at east 4 hours at room temperature were carried out in study (32M0015/924088, BASF AG) before the beginning of this screening study. Due to the fact, that the test substance preparations were true solutions, it was not necessary to verify the homogeneous distribution by analysis. Samples of the aqueous test substance solutions were sent to the analytical laboratory twice during the study period for verification of the concentrations. The test substance solutions were analyzed by gas
chromatography.
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1/1
- Length of cohabitation: overnight; for max. 2 weeks
- Verification of same strain and source of both sexes: yes
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy
Duration of treatment / exposure:
Exposure period: throughout the whole study period (males: about 4 weeks; females: about 6 weeks)
Premating exposure period (males): at least 14 days
Premating exposure period (females): at least 14 days
Duration of test: until day 4 post partum of F1 generation
Frequency of treatment:
daily
Duration of test:
56 d
Doses / concentrations
Remarks:
Doses / Concentrations:
100, 400 or 1000 mg/kg/d
Basis:
nominal conc.
No. of animals per sex per dose:
10
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: The doses were chosen on the basis of the results from a previous 4-week oral toxicity study (Repeated dose oral toxicity study with 1,6-Hexandiol in Wistar rats; administration by gavage over 4 weeks (Project No . 31S0230/93052; BASF AG,Germany, 1995) in which 5 rats/group and sex received 1,6-Hexandio by gavage in doses of 100, ' 400 and 1,000 mg/kg body weight/day. In this 4-week study no clear substance-induced effects were recorded.

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
- Cage side observations were included: mortality, nesting, littering and lactation behavior


DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily


BODY WEIGHT: Yes
- Time schedule for examinations: weekly; during the mating period the parental females were weighed on the day of positive evidence of sperm
(day 0 p.c.) and on days 7, 14 and 20 post coitum; Females with litter were weighed on the day of parturition (day 0 p.p.) and on days 4 and 7 post partum


FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: No
- Number of corpora lutea: No
- Number of implantations: Yes
- Number of early resorptions: No
- Number of late resorptions: No
Fetal examinations:
- External examinations: Yes
- Soft tissue examinations: Yes
- Skeletal examinations: Yes
- Head examinations: Yes
Statistics:
The data were evaluated statistically using the computer systems of the Department of Toxicology of BASF AG (laboratory data processing, Dr. H.D. Hoffmann responsible):
The DUNNETT Test, two-sided: food consumption (parental animals), body weights and body weight change (parental animals and pups), number of mating days, duration of gestation, number of implantations, proportion of postimplantation loss and number of pups delivered per litter.
FISHER's Exact Test, one-sided: male and female mating index, male and female fertility index, gestation index, females with liveborn, stillborn and with all stillborn pups, pups liveborn, pups stillborn, pups died, pups cannibalized, pups sacrificed moribund, viability index, number of litters with affected pups is at necropsy.
The WILCOXON-Test one-sided: proportion of affected pups per litter with necropsy observations.
If the results of these tests were significant labels (* for p <= 0.05, ** for p <= 0.01) were printed in the Summary Tables.
Indices:
Males: mating and fertility indices were calculated
Females: mating, fertility and gestation indices and gestation loss were calculated

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:no effects

Effect levels (maternal animals)

open allclose all
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day
Basis for effect level:
other: developmental toxicity

Results (fetuses)

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

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Applicant's summary and conclusion