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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:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study without detailed documentation
Justification for type of information:
Propan-2-ol (Isopropyl alcohol) is both reagents used in the manufacture of Reaction mass of O-isopropyl ethylthiocarbamate and n-butanol and propan-2-ol. Therefore, Propan-2-ol (Isopropyl alcohol) need to be considered in the assessment of Reaction mass of O-isopropyl ethylthiocarbamate and n-butanol and propan-2-ol .

Data source

Reference
Reference Type:
publication
Title:
Research Triangle Park report № 311C-4557 to CMA
Author:
Tyl, R.W., Masten, L.W., Marr, M.C., Myers, C.B., Slauter, R.W., Gardiner, T.H., Strother, D.E., McKee, R.H., and Tyler, T.R.
Year:
1994
Bibliographic source:
Fundam. Appl. Toxicol. 22:139- 151.

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
no
GLP compliance:
not specified
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Reaction mass of propan-2-ol and butan-1-ol and O-isopropyl ethylthiocarbamate
EC Number:
943-680-2
Molecular formula:
C6H13NOS
IUPAC Name:
Reaction mass of propan-2-ol and butan-1-ol and O-isopropyl ethylthiocarbamate
Test material form:
liquid
Details on test material:
- Name of test material (as cited in study report):isopropanol; isopropyl alcohol; 2-propanol
EC Name: propan-2-ol
CAS Number :67-63-0
EC Number:200-661-7
CAS Name: isopropyl alcohol
- Physical state: Colorless liquid
- Analytical purity: 99.95 ± 0.01%
- Lot/batch No.: Log number 6361-02-01.
Propan-2-ol (Isopropyl alcohol) is both reagents used in the manufacture of Reaction mass of O-isopropyl ethylthiocarbamate and n-butanol and propan-2-ol. Therefore, Propan-2-ol (Isopropyl alcohol) need to be considered in the assessment of Reaction mass of O-isopropyl ethylthiocarbamate and n-butanol and propan-2-ol .

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Inc., Raleigh, NC.
- Age at study initiation: Female rats = 10 weeks of age on Gestational Day 0
- Weight at study initiation: 213.6 - 274.6 g on Gestational Day 0
- Housing: Males were housed singly in solid bottom polycarbonate cages (5" x 11 1/2" x 7"), non-mated females were group housed (maximum 3/cage), and mated females were singly housed in solid bottom polycarbonate cages (6" x 19" x 10 1/2") with stainless steel wire lids
- Diet (e.g. ad libitum): #5002 Purina Certified Rodent Chow ad libitum
- Water (e.g. ad libitum): Deionized/filtered tap water ad libitum
- Acclimation period: 7-day quarantine period


ENVIRONMENTAL CONDITIONS
- Temperature: Reported in the study as 72.0 ± 0.5 °F (approximately 22.2 ºC)
- Humidity (%): . Mean relative humidity = 59.0 ± 0.55% with a range of 46.7 - 70.0%
- Photoperiod (hrs dark / hrs light): 12 hours: 12 hours

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: deionized/distilled water
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: The concentration of isopropanol in the dosing solutions varied with dose. Dilutions of isopropanol in deionized/distilled water were formulated independently for each concentration and were prepared in a quantity sufficient for the period of dosing.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
An aliquot of each formulation of isopropanol and vehicle was analyzed to verify the concentration of the test compound. Dosing formulations with assayed values of 90-110% of the nominal concentration were considered to be suitable for use in these studies. Personnel, other than the laboratory supervisor and those involved in analysis of dosage formulations for isopropanol concentration, were not informed of the formulation concentrations until all laboratory work had been completed.

For analysis of the dosing formulations, triplicate 0.100 mL samples of the vehicle control solution (deionized/distilled water) and of the dosing formulations were pipetted into separate GC auto-sampler vials each containing 0.80 mL of methanol. An 0.10 mL aliquot of the internal standard solution, 0.493 g of butanol/mL of water was added for each vial. The samples were mixed and analyzed by gas chromatography. Standards encompassing the range of dosing formulation concentrations were prepared in the same way and also analyzed.
Details on mating procedure:
- Impregnation procedure: Cohoused
- If cohoused:
- M/F ratio per cage: Individual females were placed in the home cage of singly housed males (i.e., 1:1)
- Length of cohabitation: Overnight
- Proof of pregnancy: Sperm in vaginal smear referred to as day 0 of pregnancy
Duration of treatment / exposure:
Gestational Days 6 through 15
Frequency of treatment:
Single-dose administration
Duration of test:
From Feb. 26, 1990 to March 28, 1990
No. of animals per sex per dose:
25 females/group
Control animals:
yes, concurrent vehicle

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Once daily on Gestational Day 0-5 (prior to dosing period) and on Gestational Day 16-20 (after dosing period) and twice daily, at dosing and 1-2 hours after dosing, throughout the dosing period (Gestational Day 6 through 15).

DETAILED CLINICAL OBSERVATIONS: Yes

BODY WEIGHT: Yes

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day # 20
- Organs examined: At sacrifice, the body, liver and uterus of each sperm-positive female were weighed
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
- Number of early resorptions: Yes
- Number of late resorptions: Yes
Fetal examinations:
- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: all per litter
- Skeletal examinations: Yes: half per litter
- Head examinations: Yes: half per litter
Statistics:
Analyses of Variance(ANOVA) and Bartlett’s test for homogeneity of variance. A one-tailed test (i.e., Williams’ Test and/or Dunnett’s Test) was used for all pairwise comparisons except that a two-tailed test was used for maternal body and organ weight parameters, maternal food consumption, fetal body weight, and percent males per litter. Nominal scale measures were analyzed by Chi-Square Test for Independence for differences among treatment groups.
Indices:
Not reported
Historical control data:
Not reported

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
No pregnant surviving female aborted, delivered early or was removed from study. Two females (8%) died in the 1200 mg/kg bw/day group and one female (4%) died in the 800 mg/kg bw/day group. Maternal body weights were equivalent across all groups and for all timepoints. The statistically reduced maternal weight gain (Gestational Days 0-20) in the 1,200 mg/kg bw/day group was likely due to significantly reduced gravid uterine weights. Corrected maternal weight gain for Gestational Days 0-20 was statistically equivalent across all groups. There were no treatment related clinical signs apparent in maternal animals. Maternal food consumption was statistically equivalent across all groups for all intervals evaluated although a significant downward trend for Gestational Days 6-9 and 6-15 (treatment period) with no significant pairwise comparisons was evident.

Effect levels (maternal animals)

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

Results (fetuses)

Fetal body weight changes:
no effects observed
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
A total of 22-25 litters were evaluated per group. No litter was fully resorbed. All gestational parameters were equivalent across groups, including pre- and post-implantation loss. Fetal body weights/litter were significantly reduced in the 800 and 1,200 mg/kg bw/day groups. There were no treatment-related increased incidences in individual or pooled external, visceral, skeletal or total fetal malformations or variations.

Effect levels (fetuses)

Basis for effect level:
other:
Remarks on result:
other: Embryotoxic / teratogenic effects:no effects

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
There were no adverse maternal or developmental effects at 400 mg/kg. No evidence of increased teratogenicity was observed at any dose tested. Therefore, isopropanol was not teratogenic to CD rats.
Propan-2-ol (Isopropyl alcohol) as a main constituent of Reaction mass of O-isopropyl ethylthiocarbamate (85%-98%) and n-butanol (1%-10%) and propan-2-ol (1%-5%) and need to be considered in the assessment of Reaction mass of O-isopropyl ethylthiocarbamate and n-butanol and propan-2-ol .
Executive summary:

There were no adverse maternal or developmental effects at 400 mg/kg. No evidence of increased teratogenicity was observed at any dose tested. Therefore, isopropanol was not teratogenic to CD rats.

Propan-2-ol (Isopropyl alcohol) as a main constituent of Reaction mass of O-isopropyl ethylthiocarbamate (85%-98%) and n-butanol (1%-10%) and propan-2-ol (1%-5%) and need to be considered in the assessment of Reaction mass of O-isopropyl ethylthiocarbamate and n-butanol and propan-2-ol .