Propan-2-ol

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

1990

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Well documented, according to accepted guidelines

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1990

Report date:

1990

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Deviations:

no

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Propan-2-ol

EC Number:

200-661-7

EC Name:

Propan-2-ol

Cas Number:

67-63-0

Molecular formula:

C3H8O

IUPAC Name:

propan-2-ol

Details on test material:

- Name of test material (as cited in study report):isopropanol; isopropyl alcohol; 2-propanol
- Physical state: Colorless liquid
- Analytical purity: 99.95 ± 0.01%
- Lot/batch No.: Log number 6361-02-01.

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

Doses / concentrations

Doses / concentrations 1

Remarks:

Doses / Concentrations:
400 mg/kg bw
Basis:
actual ingested

Doses / concentrations 2

Remarks:

Doses / Concentrations:
800 mg/kg bw
Basis:
actual ingested

Doses / concentrations 3

Remarks:

Doses / Concentrations:
1200 mg/kg bw
Basis:
actual ingested

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)

1

Dose descriptor:

NOAEL

Effect level:

400 mg/kg bw/day (actual dose received)

Basis for effect level:

other: maternal toxicity

2

Dose descriptor:

NOAEL

Effect level:

400 mg/kg bw/day (actual dose received)

Basis for effect level:

other: developmental toxicity

Results (fetuses)

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)

Dose descriptor:

NOAEL

Effect level:

400 mg/kg bw/day

Sex:

male/female

Basis for effect level:

fetal/pup body weight changes

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

not specified