1,2-epoxybutane

Toxicity to reproduction

Administrative data

Endpoint:

two-generation reproductive toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1983-04-04 to 1985-06-19

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

comparable to guideline study

Data source

Reference

Reference 1

Reference Type:

study report

Title:

Unnamed

Year:

1985

Report date:

1985

Reference 2

Reference Type:

publication

Title:

Effect of propylene oxide on reproductive parameters in Fischer 344 rats

Author:

Hayes WC, Kirk HD, Gushow TS and Young JT

Year:

1988

Bibliographic source:

Fundam. Appl. Toxicol. 10:82-88.

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 416 (Two-Generation Reproduction Toxicity Study)

GLP compliance:

yes

Remarks:

Mammalian and Environmental Toxicology Research Laboratory Health and Environmental Sciences, Dow Chemical, USA. Midland, Michigan 48640

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Methyloxirane

EC Number:

200-879-2

EC Name:

Methyloxirane

Cas Number:

75-56-9

Molecular formula:

C3H6O

IUPAC Name:

1,2-Epoxypropane

Test material form:

liquid

Test animals

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Breeding Laboratory, Kingston NY
- Age at study initiation: 7 weeks (P), 5 weeks (F1)
- Weight at study initiation: weight range of 128.3-129.6 g (males P) and
100.8-101.6 g (females P) ; weight range of 97.4-104.2g (males F1) and 86.1-88.1 g (females F1)
- Fasting period before study: no data
- Housing: singly in wire mesh-bottemed, stainless steel cages
- Diet: ad libitum (except during the exposure periods)
- Water: ad libitum (except during the exposure periods)
- Acclimation period: 2 weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22
- Humidity (%): 40 - 60
- Air changes (per hr): 6 h/day exposure to test material
- Photoperiod (hrs dark / hrs light): 12 hour photocycle

Administration / exposure

Route of administration:

inhalation: vapour

Type of inhalation exposure (if applicable):

whole body

Vehicle:

unchanged (no vehicle)

Details on exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
Exposures were conducted in 14.5 cubic meter chambers with stainless steel pyramidal shaped ceilings and epoxy resin coated floors and walls. All chambers were operated under dyhamic airflow conditions at a slight negative pressure relative to the surrounding area. Control animals were placed in an identical chamber. Air supplied to the chambers was controlled by a system designed to control temperature (approximately 22°C) and relative humidity (approximately 50%). These data were recorded each exposure day.

Propylene oxide test atmospheres were generated by vaporizing the liquid at controlled rates using glass J-tubes (Miller et al., 1980). The vapors were swept from the J-tubes with compressed air into the air inlet ducts of the chambers where there was further dilution to the desired concentration. The compressed air was preheated wlth a flameless heat torch (Master, Model FHT-4) at approximately 34 degrees C, in order to facilitate complete vaporization of the liquid test material. Total chamber airflow was maintained at approximately 2200 liters per minute.

The concentration of the test material in each chamber was determined at least once per hour by a MIRAN I infrared spectrophotometer at a wavelength of 11.95 microns. The nominal concentration (ratio of the amount of test material to the total anount of air through the chamber) was calculated for each chamber on a daily basis.

Details on mating procedure:

- M/F ratio per cage: 1:1
- Length of cohabitation: two 5 day cohabitation periods
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy
- After successful mating each pregnant female was caged: individually and during late gestation the cages contained ground corn cob bedding
- Any other deviations from standard protocol: avoiding brother-sister matings

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Once an hour by MIRAN 1 infrared spectrophotometer at a wavelength of 11.95 microns. The nominal concentration was calculated for each chamber on a daily basis.

Duration of treatment / exposure:

6 hours a day

Frequency of treatment:

5 days a week during the premating period
7 days a week during mating, gestation and lactation

Details on study schedule:

- F1 parental animals not mated until 17 weeks after selected from the F1 litters.
- Selection of parents from F1 generation when pups were 4 weeks of age.
- Age at mating of the mated animals in the study: 21 weeks

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

30 ppm (nominal)

Remarks:

70 mg/m3 (analytical)

Doses / concentrations 2

Dose / conc.:

100 ppm (nominal)

Remarks:

240 mg/m3 (analytical)

Doses / concentrations 3

Dose / conc.:

300 ppm (nominal)

Remarks:

710 mg/m3 (analytical)

No. of animals per sex per dose:

30

Control animals:

yes

Details on study design:

- Dose selection rationale: based on the results of the chronic study in Wistar Rats (Reuzel and Kuper, 1982)
- Rationale for animal assignment: random

Positive control:

none

Examinations

Parental animals: Observations and examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: at least once a day

DETAILED CLINICAL OBSERVATIONS: No data

BODY WEIGHT: Yes
- Time schedule for examinations: weekly, and for the sperm positive females on day 1, 7, 14 and 21 of lactation, body weights of maternal animals were recorded on Days 1, 4, 7, 21, and 28 postpartum

Oestrous cyclicity (parental animals):

no information

Sperm parameters (parental animals):

no information

Litter observations:

STANDARDISATION OF LITTERS
- Performed on day 4 postpartum: yes
- If yes, maximum of 8 pups/litter 4/sex/litter as nearly as possible; excess pups were killed and discarded.

PARAMETERS EXAMINED
The following parameters were examined in F1 / F2 offspring:
number and sex of pups, stillbirths, live births, postnatal mortality, presence of gross anomalies, weight gain, physical or behavioural abnormalities,

GROSS EXAMINATION OF DEAD PUPS:
yes, for external and internal abnormalities; possible cause of death was determined for pups born or found dead

Postmortem examinations (parental animals):

SACRIFICE
- Male animals: All surviving animals as soon as the last litter of F1 or F2 pups were weaned
- Maternal animals: All surviving animals as soon as the last litter of F1 or F2 pups were weaned

GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations including the cervical, thoracic, and abdominal viscera.

HISTOPATHOLOGY / ORGAN WEIGHTS: yes

Postmortem examinations (offspring):

SACRIFICE
- The F1 offspring not selected as parental animals and all F2 offspring were sacrificed at 28 days of age.

Statistics:

Body weights were evaluated by Barlett's test and ANOVA, Littersize by ANOVA,
Mating and conception indices by Fisher Exact Probability test, Evaluation of neonatal sex ratio by Binomial distribution test, Survival indices by censored Wilcoxon test

Reproductive indices:

Mating index: number of females with a vaginal plug or sperm positive vaginal smear expressed as percentage of the total number of mated females
Conception index: number of females delivering a litter expressed as a percentage of the number of mated (sperm positive) females.
Gestation index: Number of females delivering a live litter expressed as a percentage of the number of females delivering a litter.

Offspring viability indices:

gestation survival index: percentage of newborn pups that were alive at birth.
1-28 day survival index: percentage of liveborn pups that survived for 1-28 days.

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:

no effects observed

Description (incidence and severity):

No treatment-related alterations in demeanor or physical appearance were observed.

Mortality:

mortality observed, non-treatment-related

Description (incidence):

One P0 male rat in the 30 ppm group was found dead after exposure on Day 72 of the study. A second P0 male in this group was found dead on Day 166. The findings on these animals did not indicate a treatment-related effect.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Decreases in body weight were observed in all 3 male exposure groups from week 17 until sacrifice. There was also an decrease in bodyweight in the 300 ppm females beginning after week 1.

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

not specified

Clinical biochemistry findings:

not specified

Endocrine findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

not specified

Histopathological findings: non-neoplastic:

effects observed, non-treatment-related

Histopathological findings: neoplastic:

not examined

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:

not examined

Reproductive function: sperm measures:

not examined

Reproductive performance:

effects observed, non-treatment-related

Description (incidence and severity):

Mating indices: 90, 87, 97 and 100% respectively in the 0, 30, 100 and 300 ppm groups,
Conception indices: 81, 85, 59 and 70 % respectively in the 0, 30, 100 and 300 ppm groups
Gestation survival index: was 99.6 - 100%
The conception index in the 100 ppm group was lower than the control (59% vs
81%) though the difference was not significant. However, the conception index in the 300 ppm group was 70% and thus there was no apparent dose-response.

Effect levels (P0)

1

Key result

Dose descriptor:

NOAEC

Remarks:

systemic toxicity

Effect level:

100 ppm (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

body weight and weight gain

2

Key result

Dose descriptor:

NOAEC

Remarks:

fertility

Effect level:

> 300 ppm (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No effects on fertility were observed at the highest dose. 300 ppm is considered equivalent to 710 mg/m3.

Target system / organ toxicity (P0)

Key result

Critical effects observed:

no

Results: P1 (second parental generation)

General toxicity (P1)

Clinical signs:

no effects observed

Mortality:

no mortality observed

Description (incidence):

No deaths occurred during treatment.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

A significant decrease in body weight was observed in males and females exposed to 300 ppm beginning at Week 3 and continuing until the end of the study. Body weights of the males exposed to 100 ppm were also lower, though
the difference was significant only at Week10. Significant decreases in body weight were observed in males exposed to 30 ppm beginning at Week 5 and continuing throughout the rest of the study.

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Endocrine findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

effects observed, non-treatment-related

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

effects observed, non-treatment-related

Histopathological findings: neoplastic:

not examined

Reproductive function / performance (P1)

Reproductive function: oestrous cycle:

not examined

Reproductive function: sperm measures:

not examined

Reproductive performance:

effects observed, non-treatment-related

Description (incidence and severity):

Mating indices: 87, 93, 93 and 100% respectively in the 0, 30, 100 and 300 ppm groups,
Conception indices: 77, 86, 82 and 93 % respectively in the 0, 30, 100 and 300 ppm groups
Gestation survival index: was 98.6 - 100%

Effect levels (P1)

1

Key result

Dose descriptor:

NOAEC

Remarks:

systemic toxicity

Effect level:

100 ppm (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

body weight and weight gain

2

Key result

Dose descriptor:

NOAEC

Remarks:

fertility

Effect level:

> 300 ppm (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No effects on fertility were observed at the highest dose. 300 ppm is considered equivalent to 710 mg/m3.

Target system / organ toxicity (P1)

Key result

Critical effects observed:

no

Results: F1 generation

General toxicity (F1)

Clinical signs:

no effects observed

Mortality / viability:

mortality observed, non-treatment-related

Description (incidence and severity):

The litter size on day 1 was lower in the 100 ppm group than the control value: 7.5 vs. 10.5. However, the litter size in the 300 ppm group was comparable to control group.
The survival indices on days 1, 4, 7, 14, 21 and 28 for the 3 exposure ranged from 94 to 100 %

Body weight and weight changes:

effects observed, non-treatment-related

Description (incidence and severity):

No significant differences were observed in mean pup body weights on days 1, 4, 7, 21, or 28 postpartum.

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Sexual maturation:

not specified

Anogenital distance (AGD):

not specified

Nipple retention in male pups:

not specified

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

effects observed, non-treatment-related

Histopathological findings:

effects observed, non-treatment-related

Developmental neurotoxicity (F1)

Behaviour (functional findings):

not examined

Developmental immunotoxicity (F1)

Developmental immunotoxicity:

not examined

Effect levels (F1)

Key result

Dose descriptor:

NOAEC

Generation:

F1

Effect level:

> 300 ppm (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No adverse effects observed at highest dose.

Target system / organ toxicity (F1)

Key result

Critical effects observed:

no

Results: F2 generation

General toxicity (F2)

Clinical signs:

no effects observed

Mortality / viability:

mortality observed, non-treatment-related

Body weight and weight changes:

effects observed, non-treatment-related

Description (incidence and severity):

No significant differences were observed in mean pup body weights on days 1, 4, 7, 21, or 28 postpartum.

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Sexual maturation:

not specified

Anogenital distance (AGD):

not specified

Nipple retention in male pups:

not specified

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

effects observed, non-treatment-related

Histopathological findings:

effects observed, non-treatment-related

Developmental neurotoxicity (F2)

Behaviour (functional findings):

not examined

Developmental immunotoxicity (F2)

Developmental immunotoxicity:

not examined

Effect levels (F2)

Key result

Dose descriptor:

NOAEC

Generation:

F2

Effect level:

> 300 ppm (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No adverse effects observed at highest dose.

Target system / organ toxicity (F2)

Key result

Critical effects observed:

no

Overall reproductive toxicity

Key result

Reproductive effects observed:

no