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Developmental toxicity / teratogenicity

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developmental toxicity
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: well-documented, guideline-like study report

Data source

Reference Type:
study report
Report date:

Materials and methods

Test guideline
according to guideline
other: NTP Protocol
GLP compliance:
testing lab.

Test material

Constituent 1
Chemical structure
Reference substance name:
EC Number:
EC Name:
Cas Number:
Molecular formula:
Details on test material:
purity: > 99%

Test animals

Details on test animals or test system and environmental conditions:
Female outbred Swiss albino mice (CD-1 mice) (Charles River Laboratories, Inc., Raleigh, NC) were individually identified by tail tattoo. Male breeders of the same strain (Charles River Laboratories, Inc., Raleigh . NC) were individually identified by eartag. Plug-positive females were individually housed in solid-bottom polycartonate cages with stainless steel wire lids (Laboratory Products, Rochelle Park, NJ) and Ab-Sorb-Orig cage litter (Laboratory Products, Garfield, NJ). Ground Purina Certified Rodent Chow and deionized/filtered water were available ad libitum throughout gestation. Lights in the animal rooms were on from 07.00h to 19.00h. Environmental conditions (temperature and relative humidity) were monitored and controlled by computer. The average temperature was 72°F (range 69-75°F), and the average relative humidity was 55% (range 44-64%).

Administration / exposure

Route of administration:
oral: gavage
Details on exposure:
Timed-mated mice were given 1.4-butanediol in aqueous solution on the mornings of gestational days 6 through 15. Analysis of dose formulations by gas chromatography prior to use indicated that formulations were within 97-105% of their theoretical concentrations. Dose formulations were stored at room temperature in amber glass containers, and used within the period of proven stability for these storage conditions. Treatment and examination of animals was performed without knowledge of dose levels.
Analytical verification of doses or concentrations:
Details on analytical verification of doses or concentrations:
Aqueous solutions of 1.4-butanediol (10 mg/ml) were stable for 28 days at room temperature when stored in the dark and were also stable under simulated conditions of use (ie. in an open beaker at room temperature when exposed to light and air in a laboratory hood tor 3 hours.
Details on mating procedure:
After a seven-day quarantine period, individual breeding pairs were cohabited overnight. The morning of vaginal plug detection was designated as gestational day (gd) 0. On gd 0, plug-positive females were assigned to experimental groups by stratified randomization so that body weights did not differ among groups within any individual replicate. The study was performed in two replicates with 4 consecutive breeding dates in each replicate. The last breeding date for the first replicate and the first breeding date for the second replicate were 18 days apart. The body weight range for females on gd
0 was 24-31 g.
Duration of treatment / exposure:
gd 6 through 15
Frequency of treatment:
Duration of test:
until gd 17
Doses / concentrations
Doses / Concentrations:
0 (control), 100, 300 or 600 mg/kg/day

No. of animals per sex per dose:
Control animals:
yes, concurrent no treatment
Details on study design:
In a dose range-finding study, Swiss mice were exposed to 1.4-butanediol (0, 100, 400, 600, 800 or 1000 mg/kg/day p.o. on gd 6-15; 8 pregnancies/group). At 100 mg/kg/day, dams were alert, but slightly less active than controls. Maternal toxicity was expressed as reversible maternal sedation (ie. diminished activity followed by recumbancy or immobility) at 2400 mg/kg/day, and as reduced corrected gestational weight gain at >600 mg/kg/day. Gravid uterine weight (gd 17) appeared lower and prenatal mortality appeared to be higher than controls at 1400 mg/kg/day, but these differences were not statistically significant. Fetal body weight was significantly reduced relative to controls at >800 mg/kg/day.
Based upon the dose range finding study described above, dose levels of 0 (control), 100, 300 or 600 mg/kg/day were selected for the present study. The low dose was expected to be pharmacologically active (ie. mild maternal sedation), but to produce no other maternal or developmental effects. The mid dose was expected to produce moderate, reversible maternal sedation (<4 hours duration) and possible reductions in fetal body weight and prenatal viability. The high dose was expected to produce reversible maternal sedation (<4 hours duration), reduction of maternal body weight gain (gestation and corrected), possible changes in maternal hepatic or renal histology, and possible reduction in fetal body weight and prenatal viability.


Maternal examinations:
Timed-mated females were weighed in life on the mornings of gd 0, 3, 6-15 and 17. On treatment days (gd 6-15), each animal was observed for clinical signs of toxicity as follows: immediately before treatment, approximately 45-60 minutes after treatment and approximately 4 hours after treatment. On gd 16 and 17, each animal was observed for clinical signs of toxicity once in the morning. The times of observation and dosing were recorded for each animal. Measurements of food and water were taken on gd 0, 3, 6, 9, 12, 15, and 17. Animals were killed by cervical dislocation on gd 17.
At necropsy on gd 17, the maternal body, liver, kidneys and intact uterus were weighed and corpora lutea were counted. Maternal livers and kidneys were fixed in neutral buffered 10% formalin and saved for optional histopatholgy.
At necropsy on gd 17, uterine contents were examined to determine the number of implantation sites, resorptions, dead fetuses and live fetuses, uteri
which had no visible implantation sites were stained with ammonium sulfide (10%) to detect very early resorptions (Salewski,1964).
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
Fetal examinations:
On gd 17, live fetuses were dissected from the uterus and anesthetized on ice (Blair, 1971; Lumb and Jones, 1973). They were weighed, examined for
external morphological abnormalities and dissected for visceral examination by a fresh tissue dissection technique (Staples, 1974; Stuckhardt and Poppe, 1984). Half of the fetuses were decapitated prior to dissection; the heads were fixed in Bouin's solution and then examined by a free-hand sectioning technique (Wilson, 1965). All fetal carcasses (50% without heads) were stained with Alcian Blue/Alizarin Red S and examined for skeletal malformations (Marr et al., 1988).
Historical control data:

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Details on maternal toxic effects:
There were no maternal deaths in this study. No maternal or developmental effects were observed at the low dose. Dams (60-100 %/group/day) at the mid and high doses exhibited signs of central nervous system intoxication (hypoactivity, immobility, loss of righting reflex and/or prone posture) during the first 4 hr following daily administration. Maternal effects at the mid and high doses also included reduced food intake (treatment and post treatment periods), reduced body weight, and reduced weight gain (treatment period, gestation period and corrected weight gain).

Effect levels (maternal animals)

open allclose all
Dose descriptor:
Effect level:
100 mg/kg bw/day
Basis for effect level:
other: maternal toxicity
Dose descriptor:
Effect level:
300 mg/kg bw/day
Basis for effect level:
other: maternal toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Details on embryotoxic / teratogenic effects:
The only definitive expression of developmental toxicity was a reduction in average fetal body weight at the middle and high doses (92% and 83% of control weight, respectively) .

Effect levels (fetuses)

open allclose all
Dose descriptor:
Effect level:
100 mg/kg bw/day
Basis for effect level:
other: fetotoxicity
Dose descriptor:
Effect level:
300 mg/kg bw/day
Basis for effect level:
other: fetotoxicity

Fetal abnormalities

not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Applicant's summary and conclusion