Registration Dossier

Administrative data

Endpoint:
developmental toxicity
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Guideline study according to OECD GL 414 (“Prenatal Developmental Toxicity Study”)

Data source

Referenceopen allclose all

Reference Type:
other company data
Title:
Unnamed
Year:
1997
Report Date:
1997
Reference Type:
secondary source
Title:
Unnamed
Year:
2000
Reference Type:
secondary source
Title:
SIDS Initial Assessment Report - 2-Methylbut-3-yn-ol
Author:
BASF AG
Year:
2002
Bibliographic source:
OECD SIDS

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Qualifier:
according to
Guideline:
EU Method B.31 (Prenatal Developmental Toxicity Study)
Version / remarks:
Cited as Directive 87/302/EEC, part B, p. 24
GLP compliance:
yes
Remarks:
Dept. of Toxicology, BASF AG
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
other: Liquid
Details on test material:
Please refer to the section "confidential details on test material" below.

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: 70 days old
- Identification: ear tattoo
- Housing: singly, from day 0 - 20 p.c. in type DK III stainless steel wire mesh cages supplied by BECKER & CO ., Castrop-Rauxel, FRG (floor area about 800 cm^2). Underneath the cages, waste trays were fixed containing absorbent material (type 3/4 dustfree embedding, supplied by SSNIFF, Soest, Germany)
- Diet: ad libitum, ground Kliba 343 feed rat/mouse/hamster supplied by KLINGENTAIMOHLE AG, Kaiseraugst, Switzerland
- Water: ad libitum, drinking water of tap water quality from water bottles
- Acclimation period: at least 5 days

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

Food and water analysis:
- The food used in the study was assayed for chemical and for microbiological contaminants
- The drinking water is regularly assayed for chemical contaminants by the municipal authorities of Frankenthal and the Technical Services of BASF Aktiengesellschaft as well as for the presence of microorganisms by a contract laboratory.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
- The test substance solutions were prepared in intervals of not more than 3 days during the administration period, because the stability of test substance solution over a period of 96 hours had been verified analytically .
- For the preparation of the solutions, an appropriate amount of the test substance was weighed in volumetric flasks, subsequently topped up with doubly distilled water and intensively shaken.


VEHICLE
- Concentration in vehicle: 4.5, 13, 40 mg/mL
- Amount of vehicle (if gavage): 10mL/kg bw
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
- Analytical verifications of the stability of the test substance in Milli-Q-water for a period of 96 hours at room temperature were carried out for the same batch in a previous study (BASF Aktiengesellschaft, Project No.: 26M0231/934206).
- As the test substance preparations were true solutions, the homogeneity had not be proven analytically.
- Samples of the test substance solutions were sent to the analytical laboratories twice during the study period for verification of the concentrations
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1/2
- Length of cohabitation: ca. 13.5 h
- Further matings after two unsuccessful attempts: no
- 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:
day 6 through day 15 post coitum
Frequency of treatment:
daily, in the morning
Duration of test:
21 days
Doses / concentrations
Remarks:
Doses / Concentrations:
45, 130, 400 mg/kg/day
Basis:
analytical conc.
No. of animals per sex per dose:
25 females/dose
Control animals:
yes, concurrent no treatment
Details on study design:
- Dose selection rationale: The selection of doses for the present examination was based on the results of a subacute oral toxicity study in rats and a preceding range-finding prenatal toxicity study (BASF AG, 1994) in Wistar rats.
- Other: Due to technical reasons, the study was carried out in 3 sections. Each dose group was represented in each section. A treatment interval of 1 - 2 days elapsed before the next section.

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice a day on working days or once a day (Saturday, Sunday or on public holidays) (days 0 - 20 pc).


DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: at least once a day, or more often when clinical signs of toxicity were elicited (days 0 - 20 pc).

BODY WEIGHT: Yes
- Time schedule for examinations: All animals were weighed on days 0, 1, 3, 6, 8, 10, 13, 15, 17 and 20 pc.


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: No


WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No


POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day # 20
- Organs examined: uterus
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
- Other: number of dead fetuses, calculations of conception rate and pre- and postimplantation losses
Fetal examinations:
- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: half per litter
- Skeletal examinations: Yes: half per litter
- Head examinations: No data
Statistics:
- two-sided Dunetts test: Food consumption, body weight, body weight changes, corrected body weight gain (net maternal body weight change), carcass weight, weight of unopened uterus, number of corpora lutea, number of implantations, number of resorptions, number of live fetuses, proportion of preimplantation loss, proportion of postimplantation loss, proportions of resorptions, proportion of live fetuses in each litter, litter mean fetal body weight, litter mean placental weight
- two-sided Kruskal-Wallis test: liver weights
one-sided Fisher's Exact test: female mortality, number of females pregnant at terminal sacrifice, number of litters with fetal findings
- one-sided Wilcoxon test: proportions of fetuses with malformations, variations and/or unclassified observations in each litter

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
400 mg/kg bw/day:
- Transient, statistically significant reduction of food consumption from day 6 to day 8 p.c. (-15% compared to control group).
- Transient, statistically significant body weight loss at beginning of treatment period (days 6 to 8 p.c.). On the following days weight gains in the highest dose group exceeded control values considerably.
- Clinical symptoms of apathy, unsteady gait and/or piloerection during entire or part of treatment period. Symptoms appeared shortly after treatment and persisted for several hours. After cessation of treatment these signs were not seen any more.

130 mg/kg bw/day: - no substance-related effects on dams, gestational parameters

45 mg/kg bw/day: - no substance-related effects on dams, gestational parameters

Effect levels (maternal animals)

open allclose all
Dose descriptor:
NOAEL
Effect level:
130 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEL
Effect level:
130 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: developmental toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:yes

Details on embryotoxic / teratogenic effects:
400 mg/kg bw/day:
- Statistically significant (ca. 6%) reduction of mean fetal weights
- Statistically significant increased occurence of rudimentary cervical or accessory 14th rib(s).
- Statistically significant increased rate of affected fetuses/litter showing skeletal retardations (poor or missing ossification of skull bones, thoracic vertebral bodies and/or sternebra). Statistically or biologically relevant fetal malformations with proven dose correlation were not found.

130 mg/kg bw/day: - no substance-related effects on fetuses

45 mg/kg bw/day: - no substance-related effects on fetuses

Effect levels (fetuses)

Dose descriptor:
NOAEL
Effect level:
400 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: teratogenicity

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Any other information on results incl. tables

Thus, under the conditions of this prenatal toxicity study, the oral administration (by gavage) of 3-Methyl-1 -butyn-3 -ol elicited clear signs of maternal and developmental toxicity at 400 mg/kg body weight/day, but was not toxic to the adult females and their fetuses at 45 or 130 mg/kg body weight/day. There were, however, no indications for substance induced teratogenicity up to and including the high dose level (400 mg/kg body weight/day), as the accessory 14th and/or rudimentary cervical rib(s) in the fetuses are assessed as an embryotoxic effect representing a manifestation of a non-specific stress on the dams. Based on these results, the no observed adverse effect level (NOAEL) for the dams and the fetal organism is 130 mg/kg bw/d. Thus, developmental toxicity occurred only in the presence of maternal toxicity.

Applicant's summary and conclusion