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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
27.10.2006 to 21.12.2007
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
comparable to guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2007
Report Date:
2007

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
other: OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Deviations:
yes
Remarks:
Only one concentration tested.
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Inc.
- Age at study initiation: 9 wks
- Weight at study initiation: (P) Males: 300.7-350 g; Females: 195.5-240 g
- Fasting period before study: No
- Housing: Individually housed in suspended wire-mesh cages. Except during mating, gestation and lactation periods. Mating: home cage of the male; Gestation: shoebox cages; Lactation: dams housed with litters.
- Diet (e.g. ad libitum): Ad libitum (except during inhalation exposure, FOB and motor activity assessments).
- Water (e.g. ad libitum): Ad libitum (except during inhalation exposure, FOB and motor activity assessments).
- Acclimation period: Five days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20.95-21.71
- Humidity (%): 31-69
- Air changes (per hr): 12.1
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 21.11.2006 To: 28.06.2007 (these are the dates given for the experimental period, specific dates for dosing not stated)

Administration / exposure

Route of administration:
inhalation: vapour
Type of inhalation exposure (if applicable):
whole body
Vehicle:
clean air
Details on exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: 1000 litre stainless steel and glass, TSE-system style, whole-body inhalation exposure chambers.
- Method of holding animals in test chamber: In cages
- Source and rate of air: Nash Air Compressor (rate not specified).
- Method of conditioning air: Series of filters to remove contaminants.
- Temperature, humidity, pressure in air chamber: Temp: 19-25oC, humidity 30-70% (no other information, but it was stated that conditions were maintained according to the protocol).
- Air change rate: 12-15 air changes per hour
- Treatment of exhaust air: No data

TEST ATMOSPHERE
- Brief description of analytical method used: Gas chromatography using a flame ionization detector.
- Samples taken from breathing zone: yes
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Gas chromatography using a flame ionization detector (mean measured chamber concentration was 388+30.9 ppm).
Details on mating procedure:
- M/F ratio per cage: 1:1
- Length of cohabitation: Continuous until evidence of copulation observed.
- Proof of pregnancy: vaginal plug or sperm in vaginal smear referred to as day 0 of pregnancy.
- After successful mating each pregnant female was caged (how): Shoebox cages.
Duration of treatment / exposure:
Males: 29 days
Toxicity group females: 28 days
Reproductive group females: 15 days prior to mating, through the mating period and up to day 19 of gestation (up to 41 days).
Frequency of treatment:
Daily (seven days/week)
Duration of test:
30 days
Doses / concentrations
Dose / conc.:
400 ppm
Remarks:
equivalent to 5.1 mg/l
No. of animals per sex per dose:
Ten
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: Based on results from previous study.

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: All animals were observed at least twice daily in their cages for mortality, morbidity and moribundity throughout the in-life phase of the study. General clinical observations were made at least once per day, beginning on the first day of treatment (except on days of detailed examinations). Clinical observations were also performed on all animals on the day of, but prior to, scheduled necropsy.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: All animals, once before the first exposure and weekly thereafter. Examinations included but were not limited to changes in skin, fur, eyes, mucous membranes, occurrence of secretions and excretions, and autonomic activity. Changes in gait, posture and response to handling as well as the presence of clonic or tonic movement, stereotypies, difficult or prolonged parturition or bizarre behaviour.

BODY WEIGHT: Yes
- Time schedule for examinations: Individual body weights were determined beginning with randomisation into test groups, on the first day of exposure, at least weekly thereafter, and the day of necropsy. During gestation, the females were weighed (at a minimum) on gestation days 0, 7, 14 and 20 within 24 hours after parturition, and day 4 postpartum.

FOOD CONSUMPTION: Individual animal food consumption was recorded at least weekly on an individual animal basis for the periods listed: Reproductive female rats: two week pre-mating period, gestation and postpartum (feeder weights were taken on days 1, 8, 15 and on gestation days 0, 7, 14, 20 and on day 0 and 4 postpartum).

WATER CONSUMPTION: No

OTHER: The duration of gestation was calculated from Day 0 gestation for each female. From Day 20 after evidence of mating, pregnant animals were checked at least three times daily for evidence of parturition.
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: No
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: No
- Number of late resorptions: No
Fetal examinations:
- External examinations: Yes all pups
- Soft tissue examinations: No
- Skeletal examinations: No
- Head examinations: No
Statistics:
All data analyses was conducted using SAS version 9.1.3. Statistically significant probabilities were reported for p-values of <0.05, <0.02 and <0.01.
Indices:
Gestation length, mean number of implantation sites, mean number of corpora lutea, mean mating and fertility indices. Mean litter size, mean live litter size, mean litter weight, mean ratio live births/litter size.

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:no effects

Effect levels (maternal animals)

Dose descriptor:
NOAEC
Effect level:
>= 400 ppm
Based on:
test mat.
Basis for effect level:
other: maternal toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Effect levels (fetuses)

Dose descriptor:
NOAEC
Effect level:
> 400 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no developmental effects observed

Overall developmental toxicity

Developmental effects observed:
no

Applicant's summary and conclusion

Conclusions:
In a combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test conducted using a protocol comparable to OECD 422 and to GLP (reliability score 2) the NOAEC for general and developmental toxicity was at least 400 ppm (the only concentration tested) according to the study report.