Registration Dossier

Administrative data

Endpoint:
two-generation reproductive toxicity
Remarks:
based on test type (migrated information)
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1983-04-04 till 1985-06-19
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP near guideline study , accepatable for assessment.

Data source

Referenceopen allclose all

Reference Type:
study report
Title:
Unnamed
Year:
1985
Report Date:
1985
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:
OECD Guideline 416 (Two-Generation Reproduction Toxicity Study)
Principles of method if other than guideline:
test animals: male and female Fisher 344 rats
exposure to 30, 100 or 300 ppm of PO or room air, for 6 hours a day.
Exposure started at 7 weeks of age, after 14 weeks the animals were mated. From the F1 30 males and 30 females from every treatment group were selected. After 17 weeks the F1 were bred to produce F2. The F0 and F1 animals were exposed until they were sacrificied.
During the premating phase F0 and F1 rats were exposed for 6 hours/day and for 5 days/week. During the rest of the period they were exposed for 6 h/day and 7d/week.
there was no exposure between day 21 of gestation and the 4th day postpartum. During lactation the neonatal rats were deprived from their mother for 6 h/day , from day 5 till day 28
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

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Propylene oxide: lot nr 30215 III, was supplied by ARCO
composition analysis was performed by gaschromatography and electron impact gas chromatography-mass spectometry.
purity: >99.9 %

Test animals

Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratory, Kingston NY
- Age at study initiation: P 7 weeks F1 4 weeks
- Weight at study initiation: no data
- Fasting period before study: no data
- Housing: individualy
- Diet :ad libitum
- Water :ad libitum
- 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 (how): 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 chamberon 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 / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
0, 30 , 100 and 300 ppm
Basis:
nominal conc.
Remarks:
Doses / Concentrations:
0, 70, 240 and 710 mg/m3
Basis:
analytical conc.
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 (if not random): 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
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
The tissues indicated in Table [#] were prepared for microscopic examination and weighed, respectively.
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: 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
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Organ weight findings including organ / body weight ratios:
not specified
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Other effects:
not examined

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
not specified
Reproductive function: sperm measures:
not specified
Reproductive performance:
effects observed, treatment-related

Details on results (P0)

CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS): no effect


BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS): 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


TEST SUBSTANCE INTAKE (PARENTAL ANIMALS): not examined


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

REPRODUCTIVE FUNCTION: SPERM MEASURES (PARENTAL ANIMALS) no data


REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS): see reproductive indices abov e
Mating indices: 87-100%

Conception indices: 81, 85, 59 and 70 % respictively in the 0, 30, 100 and 300 ppm groups

The litter size on day 1 was lower in the 100 ppm group than the control value: 7.5 vs. 10.5

Gestation survival index: was 99.6 - 100%
The survival indices on days 1, 4, 7, 14, 21 and 28 for the 3 exposure ranged from 94 tot 100 %


ORGAN WEIGHTS (PARENTAL ANIMALS) no data


GROSS PATHOLOGY (PARENTAL ANIMALS) no lesions in relation to treatment

HISTOPATHOLOGY (PARENTAL ANIMALS) no lesions in relation to treatment

Effect levels (P0)

Dose descriptor:
NOAEC
Remarks:
toxicity
Effect level:
100 ppm
Sex:
male/female
Basis for effect level:
other: body weight decreased at 300 ppm

Results: F1 generation

General toxicity (F1)

Clinical signs:
no effects observed
Mortality / viability:
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Sexual maturation:
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
effects observed, treatment-related
Histopathological findings:
effects observed, treatment-related

Details on results (F1)

VIABILITY (OFFSPRING)94 -100 %


CLINICAL SIGNS (OFFSPRING): no effects


BODY WEIGHT (OFFSPRING):males from all 3 test groups had a lower bodyweight
females from the 300 ppm group decreased from week 4 onward


SEXUAL MATURATION (OFFSPRING): no data


ORGAN WEIGHTS (OFFSPRING): no data


GROSS PATHOLOGY (OFFSPRING): no lesions in relation to treatment


HISTOPATHOLOGY (OFFSPRING): no lesions in relation to treatment

Effect levels (F1)

open allclose all
Dose descriptor:
NOAEC
Remarks:
toxicity
Generation:
F1
Effect level:
100 ppm
Sex:
male/female
Basis for effect level:
other: body weight decreased at 300 ppm
Dose descriptor:
NOAEC
Remarks:
fertility
Generation:
F1
Effect level:
> 300 ppm
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.

Overall reproductive toxicity

Reproductive effects observed:
not specified

Any other information on results incl. tables

No effect on reproduction in two generation of rats who were exposed to 30, 100 or 300 ppm

Applicant's summary and conclusion