Registration Dossier

Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2004-09-14 to 2005-02-21
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions

Data source

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

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
other: OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Deviations:
yes
Remarks:
There is a discrepancy about treatment duration of females between executive summary and treatment regime paragraph. Also, the pups were killed on postnatal day 4.
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
other: liquid

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories Inc., United States
- Age at study initiation: 7 weeks
- Weight at study initiation:
Females: 189.8 to 237.2 g
Males: 285.5 to 357.1 g
- Fasting period before study: none
- Housing: individually housed individually in suspended wire-mesh cages during quarantine and throughout the course of the study.
- Diet: Certified rodent diet, ad libitum
- Water: Municipal water, ad libitum
- Acclimation period: 6 days

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

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: Dosing solutions were prepared twice during the course of the study. Corn oil was the chosen vehicle. The test substance was weighed then enough vehicle was added to obtain the correct volume.

VEHICLE
- Justification for use and choice of vehicle (if other than water): Corn oil was the chosen vehicle in the 14-day range-finding study.
- Concentration in vehicle: no data
- Amount of vehicle (if gavage): no data
- Lot/batch no. (if required): 1st preparation 122K0131; 2nd preparation 103K0107
- Purity: As provided by the manufacturer
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Dosing solutions analysis were analysed by CG/FID to verify concentration, stability and homogeneity of the test substance in the vehicle. Prior to the experiment, a high dose solution was prepared and stability testing was performed on days 0, 14, 35 and 50. Following the second preparation of dose solutions, homogeneity analysis of the low and high dose solutions was conducted on day 0 and stability analysis of the low dose solution was conducted on days 0 and 50. Concentration verification was of the dose solutions was conducted on the day of the first preparation and prior to the end of dosing.
Details on mating procedure:
- M/F ratio per cage: A 1:1 mating ratio was used.
- Length of cohabitation: The female animals were housed continuously with the same male until evidence of mating occurred.
- Proof of pregnancy: presence of a vaginal plug and/or sperm in vaginal smear referred to as day 0 of pregnancy
- After successful mating each pregnant female was caged: individually
- Any other deviations from standard protocol: no
Duration of treatment / exposure:
Both males and females were treated with the test substance for 2 weeks prior to mating period and continued through the mating period. Males were treated for 92 days and females were treated up to and including postpartum day 3 according to treatment regime paragraph in the study report or up to gestation day 19 according to the execute summary in the study report.
Frequency of treatment:
Daily, 7 days a week
Duration of test:
Males: 92 days
Females: treated up to and including postpartum day 3 according to treatment regime paragraph in the study report or up to gestation day 19 according to the execute summary in the study report.
No. of animals per sex per dose:
10 males and 10 females per dose
Control animals:
yes, concurrent no treatment
Details on study design:
- Dose selection rationale: Dose levels were determined based on the results of a 14-day range-finding study. Doses were administered at a volume of 2 mL/kg of body weighed. The administered volumes were based on the weekly scheduled body weights.

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Prior to the start of treatment and during the 12th week of the study
- Cage side observations included: abnormal muscle movements, abnormal behaviour, posture and resistance to removal

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: General clinical observations were made once a day throughout the treatment period. All animals received detailed physical observations once before the start of the treatment and weekly thereafter.

BODY WEIGHT: Yes
- Time schedule for examinations: Individual body weights were determined prior to the treatment, on the first day of dosing, then weekly and on the day of necropsy. During gestation females were weighed on gestation days 0, 7, 14 and 20, within 24 hours after parturition, and on day 4 postpartum.

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day # Females were euthanized on postpartum day 4. Mated females that did not deliver were euthanized on gestation days 25 or 26.
- Organs examined: For pregnant females, the number of corpora lutea and the number of implantation sites were recorded. For the females that failed to produce litter the uteri were examined to determine possible reabsorbed implant sites.

OTHER:
FOOD CONSUMPTION: Yes
- Time schedule for examination: Individual male animals' food consumption was recorded on the first day of dosing, weekly thereafter until the day of necropsy with an exception of the two week mating period. Female animals' food consumption was recorded on days 1, 8, 15, and on gestation days 0, 7, 14 and 20, and on day 4 postpartum.
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of resorptions: Yes
Fetal examinations:
- External examinations: Yes: all per litter
- Soft tissue examinations: No
- Skeletal examinations: No
- Head examinations: Yes
Statistics:
- ANCOVA was used to analyse Reproductive Parameters.
- ANOVA was used to analyse litter size.
Indices:
The evaluated indices were: 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

Details on maternal toxic effects:
No treatment-related toxic effect was noted in female animals.

Effect levels (maternal animals)

Key result
Dose descriptor:
NOAEL
Effect level:
>= 1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: No adverse effects observed

Maternal abnormalities

Key result
Abnormalities:
no effects observed

Results (fetuses)

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

Details on embryotoxic / teratogenic effects:
No treatment-related toxic effect was noted in pups.

Effect levels (fetuses)

Key result
Dose descriptor:
NOAEL
Effect level:
>= 1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No adverse effects observed

Fetal abnormalities

Key result
Abnormalities:
no effects observed

Overall developmental toxicity

Key result
Developmental effects observed:
no

Any other information on results incl. tables

Table 1: Mean reproductive parameters for reproductive group female rats

 

 

Litter

Initial

Final

 

 

 

Days gestation

Male pups

Female pups

Males/females

Total pups

Day 4 viable pups

Viable/ total

Litter weight (g)

Average pup weight (g)

Litter weight (g)

Average pup weight (g)

Total implants

Corpora lutea

Group 1

 

Mean

22

8.4

7.9

1.1

16.3

15.4

0.9

108.9

6.7

160.5

10.5

17.0

22.6

N

7A

7

7

7

7

7

7

7

7

7

7

7

7

Group 2

 

Mean

21.9

7.0

8.1

0.9

15.1

14.7

1.0

95.6

6.3

150.2

10.3

16.6

21.3

N

9A

9

9

9

9

9

9

9

 

9

9

9

9

Group 3

 

Mean

21.7

6.1

9.6

0.7

15.7

15.3

1.0

99.9

6.4

152.7

10.0

16.4

18.0

N

7A

7

7

7

7

7

7

7

7

7

7

7

7

Group 4

 

Mean

21.8

6.9

8.8

0.9

15.7

15.1

1.0

98.9

6.3

147.2

9.8

16.6

20.9

N

9B

9

9

9

9

9

9

9

9

9

9

9

9

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

A: data of non-pregnant females with positive evidence of mating not included in calculations

B: data of female that failed to deliver not included in calculations

Table 2: Summary of reproductive performance for reproductive group female rats

 

Group 1 (control)

Group 2 (200 mg/kg bw/day)

Group 3 (500 mg/kg bw/day)

Group 4 (1000 mg/kg bw/day)

Females on study

10

10

10

10

Females that died during study

0

0

0

0

Females euthanized in extremis

0

0

0

0

Females allowed to deliver

10

10

10

10

Nongravid

3

1

3

0

Gravid

7

9

7

10

Females with evidence of copulation

10

10

10

10

Number which delivered

7

9

7

9

Number which did not deliver

3

1

3

1

Females with no evidence of copulation

0

0

0

0

Number which delivered

0

0

0

0

Number which did not deliver

0

0

0

0

Applicant's summary and conclusion

Conclusions:
In a Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test in rats for 1,3,5-trimethyl-1,1,3,5,5-pentaphenyltrisiloxane , the reported NOAEL value for maternal and developmental toxicity was >= 1000 mg/kg/day.