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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
screening for reproductive / developmental toxicity
Remarks:
based on test type (migrated information)
Type of information:
experimental study
Adequacy of study:
key study
Study period:
02.12.2003 to 27.05.2005
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: The study was conducted according to the appropriate OECD test guideline, and in compliance with GLP.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2005
Report Date:
2005

Materials and methods

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

Test material

Reference
Name:
Unnamed
Type:
Constituent

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Inc.
- Age at study initiation: 9 weeks minimum
- Weight at study initiation: Males: 289.6 to 339.7 g; females: 183.3 to 244.1 g.
- Fasting period before study: No
- Housing: Individually in suspended wire-mesh cages.
- Diet (e.g. ad libitum): Ad libitum
- Water (e.g. ad libitum): Ad libitum
- Acclimation period: Six days


ENVIRONMENTAL CONDITIONS
- Temperature (°F): 64-79
- Humidity (%): 30-70
- Air changes (per hr): 10-15
- Photoperiod (hrs dark / hrs light): 12/12


IN-LIFE DATES: From: 19.04.2004 To: 09.08.2004

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
- Exposure apparatus: 2000 l stainless steel and glass Rochester-style inhalation chambers.
- Method of holding animals in test chamber: stainless steel exposure caging (four layers of 20 animal compartments).
- Source and rate of air: Room air
- Method of conditioning air: Air passed through HEPA and activated charcoal filters before delivery to the chamber. Moisture was added to maintain relative humidity.
- System of generating particulates/aerosols: Not applicable
- Temperature, humidity, pressure in air chamber: 22±3oC, 50±20%,
- Air flow rate: No data
- Air change rate: 10-15 air changes/hour
- Method of particle size determination: Not applicable.
- Treatment of exhaust air: No data


TEST ATMOSPHERE
- Brief description of analytical method used: gas chromatograph with flame ionisation detection
- Samples taken from breathing zone: yes
Details on mating procedure:
- M/F ratio per cage: 1/1
- Length of cohabitation: Continuous until proof of mating.
- Proof of pregnancy: vaginal plug or sperm in vaginal smear referred to as day 0 of pregnancy.
- Further matings after two unsuccessful attempts: No
- After successful mating each pregnant female was caged (how): Individually in home cage.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The test atmosphere from each chamber was sampled by an automated sampling system. The test atmosphere was continuously pulled from the chamber and delivered to the analyser. Analysis was by gas chromatograph with flame ionisation detection (GC/FID) and each chamber was evaluated at least once per hour during the exposure period.
Duration of treatment / exposure:
6 hours/day
Males: 29 days (including 14 days premating).
Females: 14 days premating, through mating, gestation and up to day for postpartum.
Females, toxicity group: 28 days
Frequency of treatment:
Daily
Details on study schedule:
Not applicable to screening study.
Doses / concentrations
Remarks:
Doses / Concentrations:
200, 1000, 5000 ppm
Basis:
other: target concentrations
No. of animals per sex per dose:
Ten
Control animals:
yes
Details on study design:
- Dose selection rationale: Based on the results of a range-finding study.
- Rationale for animal assignment (if not random): Random
Positive control:
None

Examinations

Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Mortality, morbidity and moribundity noted at least twice daily (all animals). Clinical observations made once per day (all animals).


DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Once before the first exposure, and weekly thereafter (all animals).


BODY WEIGHT: Yes
- Time schedule for examinations: Individual body weights were determined before the first exposure and at least weekly thereafter, and the day of necropsy. Pregnant females were weighed on gestation days 0, 7, 14 and 20, within 24 hours after parturition, and on day 4 postpartum.


FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes


FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No


WATER CONSUMPTION: No
Estrous cyclicity (parental animals):
Not examined.
Sperm parameters (parental animals):
Parameters examined in all P male parental generations: testis weight, epididymis weight, prostate weight.
Litter observations:
STANDARDISATION OF LITTERS
- Performed on day 4 postpartum: no, study terminated on Day 4 post-partum as screening study only.


PARAMETERS EXAMINED
The following parameters were examined in F1 offspring: number and sex of pups, stillbirths, live births, runts, presence of gross anomalies, litter weights, postnatal mortality. Live pups were counted, sexed and the sex ratio calculated.


GROSS EXAMINATION OF DEAD PUPS: no, for external and internal abnormalities; possible cause of death was not determined for pups born or found dead.
Postmortem examinations (parental animals):
SACRIFICE
- Male animals: All surviving animals on Day 29 of exposure.
- Maternal animals: All surviving animals on postnatal day 4.


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


HISTOPATHOLOGY / ORGAN WEIGHTS: See Key study entry in Section 7.5.3.
Postmortem examinations (offspring):
SACRIFICE: Day 4 postpartum.


GROSS NECROPSY: Not conducted.


HISTOPATHOLOGY / ORGAN WEIGHTS: Not conducted.
Statistics:
All data analysis was conducted using SAS version 8.2. Statistically significant probabilities were reported for p-values of <0.05, 0.02 and 0.01.
Reproductive indices:
Mean gestation length, mean number of implantation sites, mean number of corpora lutea, mean mating and fertility indices.
Offspring viability indices:
Mean litter size, mean live litter size, mean litter weight, mean ratio live births/litter size.

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:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Other effects:
not examined

Reproductive function / performance (P0)

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

Details on results (P0)

CLINICAL SIGNS AND MORTALITY: there were no deaths or treatment-related clinical signs of toxicity.


BODY WEIGHT AND WEIGHT GAIN: statistically significant increase in body weigh gains observed during week four of toxicity group females. No other significant finding.


FOOD CONSUMPTION: No significant findings.


HAEMATOLOGY: In males, slight but statistically significant decreases in percent monocytes were noted in 1000 and 5000 ppm groups. However, the decrease was not considered to be of toxicological significance because the values were within the laboratory historical controls.


CLINICAL CHEMISTRY: In females there were statistically significant decreases in chloride levels in the 1000 and 5000 ppm exposure groups. The slight decreases were not considered treatment-related because they were within the range typical of this strain and age.


REPRODUCTIVE FUNCTION: ESTROUS CYCLE (PARENTAL ANIMALS): Not examined.


REPRODUCTIVE FUNCTION: SPERM MEASURES (PARENTAL ANIMALS): No adverse findings.


REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS): No adverse findings.


ORGAN WEIGHTS (PARENTAL ANIMALS): Slight but statistically significant increase in mean spleen weights was observed in the 5000 ppm group females. There was no correlation with histopathological changes.


GROSS PATHOLOGY (PARENTAL ANIMALS): No adverse findings.


HISTOPATHOLOGY (PARENTAL ANIMALS): The were no findings clearly attributable to treatment. There were some minor, adaptive changes in the liver.

Effect levels (P0)

Dose descriptor:
NOAEL
Effect level:
>= 5 000 ppm
Sex:
male/female

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:
not examined
Histopathological findings:
not examined

Details on results (F1)

VIABILITY (OFFSPRING): No adverse findings.


CLINICAL SIGNS (OFFSPRING): No clinical signs reported.


BODY WEIGHT (OFFSPRING): No affect on pup weights.

Effect levels (F1)

Dose descriptor:
NOAEL
Generation:
F1
Effect level:
>= 5 000 ppm
Sex:
male/female

Overall reproductive toxicity

Reproductive effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
In an inhalation OECD 422 study conducted to GLP (reliability score 1) the NOAELs for general systemic toxicity of the adult rats and reproductive toxicity were both at least 5000 ppm (the highest concentration tested) in rats.
Executive summary:

In an inhalation OECD 422 study conducted to GLP (reliability score 1) the NOAELs for general systemic toxicity of the adult rats and reproductive toxicity were both at least 5000 ppm (the highest concentration tested) in rats.