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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
one-generation reproductive toxicity
Remarks:
based on test type (migrated information)
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)

Data source

Reference
Reference Type:
publication
Title:
Quantitative Comparison of Maternal Ethanol and Maternal Tertiary Butanol Diet on Postnatal Development
Author:
Daniel, MA and Evans, MA
Year:
1982
Bibliographic source:
The Journal of Pharmacology and Experimental Therapeutics 222: 294-300

Materials and methods

Principles of method if other than guideline:
The published study was designed to evaluate the effects of maternal exposure to t-butanol during gestation or postnatal development. For that, pregnant mice were fed liquid diets containing tertiary butanol in concentrations of 0.50, 0.75 and 1 % (w/v) from day 6 to day 20 of gestation. Postnatal development was analyzed in regard to maternal nutritional and behavioral factors.
GLP compliance:
no
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent

Test animals

Species:
mouse
Strain:
Swiss Webster
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source:
- Age at study initiation: 8-10 weeks
- Weight at study initiation: (P) 18-20 g
- Fasting period before study: no
- Housing: housed in groups of 5
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22°C
- Humidity (%): 30-40 %
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
oral: drinking water
Vehicle:
other: Maltose/dextrin in water
Details on exposure:
Animals were fed standard dry Iab chow diet and water ad libitum until day six of gestation. Afterwards, the diet was presented in standard water bottles ad libitum to the 1 % t-butanol group from day 6 to day 20. The other four groups were pair-fed based upon the consumption of 1% t-butanol. Intake was calculated by subtracting the weight remairring in the water bottles between 7 and 8 P.M. from the total supplied the previous day.
Details on mating procedure:
- M/F ratio per cage: 1/3
- Proof of pregnancy: sperm plugs were taken as day 1 of pregnancy
- After successful mating each pregnant female was caged (how): no data
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
day 6 to 20 of gestation
Frequency of treatment:
daily
Doses / concentrations
Remarks:
Doses / Concentrations:
0.5, 0.75, 1 % (w/v)
Basis:
nominal in water
No. of animals per sex per dose:
15
Control animals:
yes, concurrent vehicle
Details on study design:
Within 24 hr of parturition, litter size, weight and viability were recorded. Approximately one-half of the maternal mice in each group were replaced with Iab chow-fed maternal animals which had delivered a litter within 24 hr of the time the treatment or control groups delivered. Litten were adjusted to a maximum of 5 per maternal animal. Subsequently, 4 fostered and 4 maintained with the original maternal animal were selected from each of the treatment groups for the behavioral tests. In the 1 % t-butanol group, only six litters, three fostered and three maintained with the original maternal animal, were selected for study.

Examinations

Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: Yes
- Cage side observations checked: mortality

BODY WEIGHT: Yes
- Time schedule for examinations: day 5, 10, 15 and 20 of pregnancy

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes, intake was determined by subtracting the weight remaining in the water bottles between 7 and 8 P.M. from the total supplied the previous day. All bottles were replaced with clean bottles and fresh diet every 24 hr.

Other: length of gestation was determined
Oestrous cyclicity (parental animals):
No data
Sperm parameters (parental animals):
no data
Litter observations:
Gross structural anomalies and number of deaths were recorded within 24 hr of parturition. Weight, pinna detachment, eye opening and behavior were recorded every two days from day 2 until day 10. Roto-rod evaluations were made every other day from day 14 to day 22, inclusive. The following endpoints were recorded: Righting reflex, negative geotaxis, open filed behavior, cliff avoidance, Roto-rod performance
Postmortem examinations (parental animals):
No data
Postmortem examinations (offspring):
Gross structural anomalies and number of deaths were recorded.
Statistics:
Statistical analyses were performed using each animal as the unit of analyses. The N value for each treatment group was 28 representing four litters with seven pups/ litter except for the 1 % t-butanol treatment group which had an N value of 15 (three Iitters with 5 pups/ liter). Linear regression
analyses was performed for each behavioral test procedure using the log dose of t-butanol diet (w/v) vs. the mean of the test score for each animal. The F test was used toassess the significance between the regression coefficients of scores from maternal and fostered pubs.

Results and discussion

Results: P0 (first parental generation)

Details on results (P0)

CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS): no mortalities occurred

BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS): A slight decrease in maternal diet intake occurred at the higher butanol concentrations (0.75 and 1 %) which resulted from difficulties in pair feeding and increased maternal sedation.

REPRODUCTIVE FUNCTION: ESTROUS CYCLE (PARENTAL ANIMALS): no data

REPRODUCTIVE FUNCTION: SPERM MEASURES (PARENTAL ANIMALS): no data

REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS): no data

ORGAN WEIGHTS (PARENTAL ANIMALS). no data

GROSS PATHOLOGY (PARENTAL ANIMALS): no data

HISTOPATHOLOGY (PARENTAL ANIMALS): no data

Results: F1 generation

Details on results (F1)

All values from pups exposed in utero to t-butanol were observed to correlate directly with increasing dose of t-butanol concentration and reflect a dose-response relationship. These include a decreased number of litters (control: 77 %; 0.5 % t-butanol: 80 %; 0.75 % t-butanol: 53 %; 1 % t-butanol: 47 %), decreased fetal weight (control: 1.78 g, 0.75 % t-butanol: 1.45 g; 1 % t-butanol 1.1 g) and increased number of total still borns (control: 3; 0.75 %: 14; 1 % t-butanol: 20).
Negative geotaxis was proved to be unreliable because circling occurred in all groups. Except for the righting reflex, no significant difference in postnatal hehavior scores could be detected between the pups of the control and treatment groups. Weight, cliff avoidance, righting reflex, open field behavior and roto-rod performance showed treatment-related effects. A statistically significant maternal behavior or postnatal nutrition-related developmental delay was detected in the 0.75 and 1 % t-butanol group regarding body weight gain.
The righting reflex of 0.75% t-butanol and 1 % t-butanol groups was not as well developed compared to the maltose/dextrin control. The righting reflex showed a dose-response correlation and a significant difference between fostered and nonfostered pups, indicating a significant postnatal maternal nutritional and behavioral effect. Similar results were obtained in the open field analysis.

Effect levels (F1)

Dose descriptor:
NOAEL
Generation:
F1
Effect level:
ca. 0.5 other: %
Based on:
test mat.
Sex:
male/female

Overall reproductive toxicity

Reproductive effects observed:
not specified

Applicant's summary and conclusion