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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
one-generation reproductive toxicity
Remarks:
based on test type (migrated information)
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP, guideline compliant, unpublished study, no restrictions, fully adequate for assessment

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2004
Report Date:
2004

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Type:
Constituent
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): pyrolysis C5
- Substance type: complex mixture of hydrocarbons
- Physical state: clear, colourless liquid
- Lot/batch No.: QA1001A100
- Expiration date of the lot/batch: Not provided by Sponsor
- Stability under test conditions: The 3 major components analysed were shown to be stable for the duration of the study
- Storage condition of test material: cool, dry well-ventilated area in the dark under nitrogen
- The sample tested consisted of isoprene (18%), cis- and trans-pentadiene-1, 3 (16%), cyclopentadiene + dicyclopentadiene (14%), n-pentane (10%), cyclopentene (7%), 2-methy1-2-butene (3%) and cyclopentane (1%)
- The balance consists of other hydrocarbons with similar boiling point (primarily C5s)

Test animals

Species:
rat
Strain:
other: Crl:CD®(SD)IGS BR
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River (UK) Ltd., Margate, Kent, England.
- Age at study initiation: 8-9 weeks
- Weight at study initiation: 199-240 g (females)
- Housing: 1:1 (male:female) during mating phase in polypropylene cages with stainless steel grid floor; females housed individually after mating.
- Diet: pelleted UAR VRF1 certified diet ad libitum except during exposure
- Water: ad libitum except during exposure
- Acclimation period: 12 days

ENVIRONMENTAL CONDITIONS
- Temperature: 19-25°C
- Humidity: 40-70%
- Air changes: positive pressure, filtered fresh air, not recirculated
- Photoperiod: 12 hrs dark / 12 hrs light):

IN-LIFE DATES: From: 2 April 2002 To: 13 May 2002

Administration / exposure

Route of administration:
inhalation: vapour
Type of inhalation exposure (if applicable):
whole body
Vehicle:
other: air
Details on exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: 0.75 m3 stainless steel and glass exposure chambers
- System of generating test atmosphere: the test substance was metered into glass vapour generators through which dried air was passed at a group-dependent flow rate of 50-150 L/min
- The test atmosphere (except for group 4) was further diluted with air to give a total flow rate of 150 L/min
- Temperature and humidity in air chamber: mean range: 23.5-23.9°C; 30.4-34.7%
- Air flow rate: verified by calibrated in-line tapered tube gas flow meters
- Treatment of exhaust air: vented to atmosphere

TEST ATMOSPHERE
- Brief description of analytical method used: gas chromatography (GC)
Details on mating procedure:
- M/F ratio per cage: 1:1
- Length of cohabitation: no data
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy
- After successful mating each pregnant female was caged: individually. From day 14 of gestation, wood flake bedding was provided.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Mean analysed concentrations of Pyrolysis C5 were 98, 302 and 1012 ppm
Duration of treatment / exposure:
Two weeks prior to breeding, during breeding, and continuing through day 19 of gestation. Total of 34-38 days.
Frequency of treatment:
6 hours/day, 7 days/week
Details on study schedule:
The dams were allowed to deliver their litters, which were retained until lactation day 4
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
100, 300 or 1000 ppm
Basis:
nominal conc.
Remarks:
Doses / Concentrations:
98, 302 or 1012 ppm
Basis:
analytical conc.
No. of animals per sex per dose:
12
Control animals:
yes, sham-exposed

Examinations

Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: At least twice daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: weekly

BODY WEIGHT: Yes
- Time schedule for examinations: on the day treatment commenced (week ) and then weekly

FOOD CONSUMPTION:
- Mean weekly food consumption for each animal (g/rat/week) was calculated per cage.
Oestrous cyclicity (parental animals):
- Dry vaginal smears were taken from all females for 10 days before pairing, to assess the regularity and duration of oestrus cycles.
Sperm parameters (parental animals):
Males used for mating were from the toxicity phase of the study. At termination, testes were evaluated histopathologically with regard to stage in the spermatogenic cycle and the integrity of the various cell types present within the different stages.
Litter observations:
STANDARDISATION OF LITTERS
- Performed on day 4 postpartum: no - litters killed on day 4.

PARAMETERS EXAMINED
- The following parameters were examined: number, sex and bodyweight of pups at day 1; stillbirths, live births, postnatal mortality, presence of gross anomalies; bodyweight gain by day 4.

GROSS EXAMINATION OF DEAD PUPS:
- yes, for external abnormalities
Postmortem examinations (parental animals):
- On day 4 of lactation all animals were injected with sodium pentobarbitone and exsanguinated.
- Detailed necropsy was performed with a range of tissues taken and preserved.
- The following organs were weighed: brain, kidneys, liver, lungs and bronchi
Postmortem examinations (offspring):
- On day 4 of lactation all animals were injected with sodium pentobarbitone
- All offspring (scheduled kill and intercurrent deaths) were subject to macroscopic external examination and then discarded.
Statistics:
Appropriate statistical analyses were conducted on all parameters.
Reproductive indices:
Percentage mating, conception rate and fertility index were calculated separately for males and females.
Offspring viability indices:
Survival indices for each group were calculated based on individual litter values.

Results and discussion

Results: P0 (first parental animals)

General toxicity (P0)

Clinical signs:
no effects observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
not examined
Other effects:
no effects observed

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
no effects observed
Reproductive function: sperm measures:
not examined
Reproductive performance:
no effects observed

Details on results (P0)

BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS)
There were no statistically significant differences in bodyweight
- Bodyweight gain during gestation was slightly lower in high dose female compared to controls.
- Bodyweight gain was higher in treated animals compared to controls during the first 4 days of lactation.

REPRODUCTIVE PERFORMANCE:
There was no evidence of any reproduction toxicity. The oestrous cycle was unaffected by exposure, and mating performance, fertility indices and gestation length were similar in all groups.

ORGAN WEIGHTS (PARENTAL ANIMALS)
- Kidney weight adjusted for bodyweight was slightly higher in high dose females.

Effect levels (P0)

Dose descriptor:
NOAEC
Effect level:
1 012 ppm (analytical)
Sex:
male/female
Basis for effect level:
other: no evidence of reproduction toxicity at highest concentration tested

Results: F1 generation

General toxicity (F1)

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

Details on results (F1)

- There were no adverse effects upon survival or growth of the offspring in utero or up to day 4 of lactation.

Overall reproductive toxicity

Reproductive effects observed:
not specified

Any other information on results incl. tables

Summary of parental female intergroup kidney weight (g) – adjusted for final bodyweight

0 (control)

98 ppm

302 ppm

1012 ppm

2.08

2.14

2.14

2.24*

*=p<0.01 (Williams’ test)

Applicant's summary and conclusion

Conclusions:
Inhalation exposure to CAS 68476-55-1 via inhalation for 2 weeks prior to pairing and up to day 19 of gestation had no effects on reproduction. A NOAEC of 1012 ppm (highest dose tested) was established.
Executive summary:

Groups of 12 male and female rats were exposed for a 2-week pre-mating period and throughout mating. Females were then exposed until Day 19 of gestation. The females were allowed to litter and rear their offspring to Day 4 of lactation. Animals were exposed to Pyrolysis C5 (CAS 68476 -55 -1) by whole body inhalation exposure at concentrations of 0, 100, 300 or 1000 ppm, 6 h/day for 7 days/week. Records of clinical condition, bodyweight, food consumption, oestrous cycles, mating performance, litter data, organ weights and macroscopic pathology were undertaken.

There was no evidence of any reproduction or developmental toxicity. The oestrous cycle was unaffected by exposure, and mating performance, fertility indices and gestation length were similar in all groups. There were no adverse effects upon survival or growth of the offspring in uterus or up to Day 4 of lactation.

The no effect level for reproductive toxicity in this screening study was 1012 ppm.