Propiononitrile

Toxicity to reproduction

Administrative data

Endpoint:

fertility, other

Type of information:

experimental study

Adequacy of study:

key study

Study period:

16 December 1981 - 23 March 1982

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

test procedure in accordance with national standard methods with acceptable restrictions

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1984

Report date:

1984

Materials and methods

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

Male Sprague-Dawley rats were exposed by the inhalation route (6 hours/day, 5 days/week) to the substance at target exposure levels of 60, 120 and 210 ppm for 57 exposure days and mated to untreated females to assess male fertility.

GLP compliance:

yes

Test material

Test material information

Constituent 1

Reference substance name:

Propiononitrile

EC Number:

203-464-4

EC Name:

Propiononitrile

Cas Number:

107-12-0

Molecular formula:

C3H5N

IUPAC Name:

propanenitrile

Test material form:

liquid

Specific details on test material used for the study:

Purity: 96%
Physical state: Liquid
Specific gravity: 0.78
Colour: Dark brown

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

Male rats were 28 days of age at receipt with body weights (measured on 10 males) ranging from 80-103g.
Female rats were 50 days of age at receipt with body weights (measured on 15 females) ranging from 155-181g.
Animals were quarantined for 7-10 days and examined for general health status.

Administration / exposure

Route of administration:

inhalation: vapour

Type of inhalation exposure (if applicable):

whole body

Vehicle:

air

Details on exposure:

Exposures were conducted in 10m3 Rochester-style stainless steel and glass inhalation chambers for 6 hours per day, five days per week.
Deviation: Due to building equipment failures, two exposure days (xposure days 33 and 43) were only about 4 hours of exposure and one exposure day (day 32) was about 5 hours duration. These exposure days were counted.
The substance vapour was generated using bubbler systems.

Details on mating procedure:

After sufficient time on study to cover the spermatogenesis cycle of the rat (46 exoosure days, 69 on study) males were mated consecutively to three females. Mated females were sacrificed at about mid-term (gestation days 13-15) and pregnancy status and pre- and post-implantation loss were determined.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Analytical concentrations were recorded four times per chamber per day throughout the study with the exception of exposure day 43 when the exposure was limited to 4 hours. Additional concentrations were recorded three different times during the study period from 9 specified locations in each chamber to demonstrate the uniformity of distribution of hte substance vapour.

Duration of treatment / exposure:

57 days

Frequency of treatment:

6 hours/day, 5 days/week

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

0 ppm (nominal)

Doses / concentrations 2

Dose / conc.:

60 ppm (nominal)

Doses / concentrations 3

Dose / conc.:

120 ppm (nominal)

Doses / concentrations 4

Dose / conc.:

210 ppm (nominal)

No. of animals per sex per dose:

15 animals per concentration.

Control animals:

yes, concurrent no treatment

Examinations

Parental animals: Observations and examinations:

Clinical analyses, body weights, physical examinations, mortality, gross necropsy.

Postmortem examinations (parental animals):

The tissues and organs of the thoracic, abdominal and scrotal cavities were examined and testes, epididymides, prostate glands ad seminal vesicles were removed and preserved in 10% neutral buffered formalin.

Reproductive indices:

Mating indices (copulations/mating opportunities), number and percent of mated animals determined to be pregnant, live implants, resorptions, and corpora lutea per dam, Percent pre- and post-implantation loss and number of females with post-implantation loss.

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

High exposure level males exhibited a number of clinical signs including hypoactivity, signs of salivation, arched back and laboured breathing.

Mortality:

mortality observed, treatment-related

Description (incidence):

One male of the high exposure level group died during the study after two exposure days. On the previous day this animal exhibited laboured breathing, hypoactivity, poor control of hind limbs, difficulty in standing, body tremours and involuntary movements. The study authors cautiously attribute the death to treatment, however, no unusual findings were observed at gross necropsy and no other males died prior to scheduled sacrifice.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

The high exposure level produced some reduction in body weight gain. Body weights of the high exposure level group males were lower than controls by about 6-9% during most of the exposure period. This difference remained at the end of the exposure period, but the difference was not statistically significant.

Body weights of males in the low and mid exposure groups were not signifcantly different from control groups.

Ophthalmological findings:

effects observed, treatment-related

Description (incidence and severity):

Infrequent signs of eye irritation was observed in about 25% of the animals of the high exposure group.

Organ weight findings including organ / body weight ratios:

effects observed, non-treatment-related

Histopathological findings: non-neoplastic:

not examined

Histopathological findings: neoplastic:

not examined

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:

not examined

Reproductive function: sperm measures:

not examined

Reproductive performance:

no effects observed

Details on results (P0)

There was no effect of treatment on mating efiiciency, pregnancy rate, number of live implants (pre- and post-implantation loss), number of resorptions, total nidations or number of copora lutea.

Effect levels (P0)

Key result

Dose descriptor:

NOAEL

Effect level:

60 ppm

Based on:

test mat.

Sex:

male

Basis for effect level:

clinical signs

mortality

body weight and weight gain

Target system / organ toxicity (P0)

Key result

Critical effects observed:

yes

Lowest effective dose / conc.:

160 ppm

System:

other: Body weight gain, signs of clinical toxicity and mortality

Treatment related:

yes

Dose response relationship:

yes

Relevant for humans:

not specified

Results: F1 generation

Effect levels (F1)

Key result

Remarks on result:

other: There was no F1 generation because the pregnant females were termainated mid gestation so that examination of live pups was not possible. However, foetuses were normal in regards to size and pre- and post-implantation losses.

Overall reproductive toxicity

Key result

Reproductive effects observed:

no

Applicant's summary and conclusion

Conclusions:

Male rats exposed to 0, 60, 120 or 210 ppm of the substance for 6 hours/day 5 days/week for 10 weeks via inhalation. These males were then mated with untreated females. Based on an evaluation of the resulting pregnancies exposure to the substance did not affect the fertility of the male rats in this study.

Executive summary:

Male Sprague-Dawley rats were exposed to 0, 60, 120 or 210 ppm of the substance for 6 hours/day 5 days/week via whole body inhalation exposure. After 10 weeks of exposure these males were then mated with unexposed females. Females were sacrificed at mid gestation. The number of corpora lutea, implantation sites, resorptions and live implants were determined. No mortality was observed at 60 or 120 ppm. One male died in the group of rats exposed to 210 ppm. Males in this group had a reduced body weight gain and exhibited clinical signs of toxicity. These signs included hypoactivity, laboured breathing, signs of salivation and arched backs. A few of these signs were also seen in the mid dose group but there was no effect on body weight gain. None of these observations were reported in males from the low dose group. Females that mated with males exposed to the substance produced litters that were normal in regards to size and pre- and post-implantation losses. Based on an evaluation of the resulting pregnancies exposure to the substance did not affect the fertility of the male rats in this study.