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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
screening for reproductive / developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2010
Report date:
2010

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Version / remarks:
1996
Deviations:
no
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Dimethoxydimethylsilane
EC Number:
214-189-4
EC Name:
Dimethoxydimethylsilane
Cas Number:
1112-39-6
Molecular formula:
C4H12O2Si
IUPAC Name:
dimethoxydimethylsilane

Test animals

Species:
rat
Strain:
other: Crl: CD® (SD) IGS BR VAF/Plus®
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Raleigh, NC 27610
- Age at study initiation: 9 weeks at experimental start
- Weight at study initiation: 192 to 239 g at experimental start (Females). 283 to 341 g at experimental start (Males)
- Housing: Animals were individually housed in suspended wire-mesh cages elevated above faecal pans containing Bed-O’ Cobs® litter, during quarantine/ acclimation and during the in-life phase of the study. Animals were given Nylabones® and Cozee Pads for environmental enrichment while in standard housing. Environmental enrichment was removed from the toxicity group male and female animals the afternoon/evening prior to necropsy.
- Diet: Lab diet 5002, Certified Rodent Diet (PMI Nutrition International) was provided ad libitum during the quarantine/acclimation period and throughout the study. Food was removed the afternoon/evening prior to necropsy of toxicology animals
- Water: Municipal water, further purified by reverse osmosis was available ad libitum via automatic watering system.
- Acclimation period: 5 days.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20.5 -21.7
- Humidity (%): 53-59
- Air changes (per hr): 14.3
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 20-10-2008 To: 30-07-2009.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: Each dosing solution was prepared individually. Dosing solutions were prepared by adding the appropriate amount of the test article to a tare container and adding the appropriate amount of corn oil to yield the desired dose level. Dosing solutions were administered by oral gavage with a 100 mm, 15 gauge (1.8 mm), plastic feeding tube and syringe. The test article was administered at a dose volume of 4 ml/kg bw and was calculated from the most recent body weight.


VEHICLE
- Justification for use and choice of vehicle (if other than water): Based upon the physical and chemical properties of the test article, dried and deacidified corn oil was considered to be the most appropriate vehicle for oral administration.
- Lot/batch no. (if required): 058K0070
Details on mating procedure:
- M/F ratio per cage: 1:1
- Length of cohabitation: Study day 15 up to Study day 28
- Proof of pregnancy: Females rats were evaluated daily for evidence of copulation, by confirming the presence of either vaginal plug or sperm in vaginal smear referred to as day 0 of pregnancy.
- After successful mating each pregnant female was caged (how): Day 0 of gestation was defined as the day evidence of copulation was observed, at which time the female was individually caged.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Dosing solution analysis was performed by a GC/FID method to verify concentration, stability, and homogeneity of the test article in carrier. Concentration verification was conducted for the initial and third dose preparations.
Duration of treatment / exposure:
Male rats were administered the test substance for 29 consecutive days including a two-week pre-mating phase, while female rats were administered the test substance up to 51 days in total. Female rats were exposed for a two-week pre-mating phase, a 1-14 day mating phase, and through day post-partum, up to 51 days in total.
Frequency of treatment:
Daily
Details on study schedule:
Not reported
Doses / concentrationsopen allclose all
Dose / conc.:
50 mg/kg bw/day (actual dose received)
Dose / conc.:
250 mg/kg bw/day (actual dose received)
Dose / conc.:
1 000 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
10
Control animals:
yes, concurrent vehicle

Examinations

Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: Yes

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule:Clinical observations were performed daily immediately following exposure.

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

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes


Oestrous cyclicity (parental animals):
Not reported
Sperm parameters (parental animals):
Parameters examined in [P] male parental generations:
[testis weight, epididymis weight, sperm morphology, ]
Litter observations:

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

GROSS EXAMINATION OF DEAD PUPS:
[yes, for external and internal abnormalities; possible cause of death was determined for pups born or found dead.]
Postmortem examinations (parental animals):
SACRIFICE
- Male animals: All surviving animals [After a minimum of 28 days on study]
- Maternal animals: All surviving animals were euthanised by CO2 inhalation on post-partum day 4.

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

HISTOPATHOLOGY / ORGAN WEIGHTS
Tissues and organ taken for histopathological examination:
Adrenal, Brain (including cerebrum, cerebellum and pons), Cecum, Colon, Duodenum, Epididymis, Heart, Ileum, Jejunum, Kidneys, Liver, Lungs, Lymph nodes, Ovaries, Prostate, Sciatic nerve, Seminal vesicles, Spinal cord, Spleen, Sternum with bone marrow, Stomach, Testes, Thymus, Thyroid, Trachea, Urinary bladder and Uterus (horns and cervix).
The following organs were weighed:
Adrenal, Brain (including cerebrum, cerebellum and pons), Epididymis, Heart, Kidneys, Liver, Seminal vesicles, Spleen, Testes, Thymus,and Uterus (horns and cervix).
Postmortem examinations (offspring):
Not applicable
Statistics:

For reproductive endpoints that involve occurrence up to birth (corpora lutea counts, total implants, post-implantation losses, day’s gestation) and for the total number of pups in the litter and total live pups in the litter, an ANOVA was done. If a statistically significant difference across treatment groups was seem pair-wise comparisons are made between the control group and the treated groups using Dunnett’s tests. For the remaining endpoints an ANOVA with the treatment and total litter size as independent variables was done. For all these analyses total litter size is defined as the total number of pups, both alive and dead. If the treatment was a significant variable in the analysis, then pair-wise comparisons were made between the control and each treated group using Dunnett’s test and adjusting for the litter sizes.

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
effects observed, treatment-related
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
Histopathological findings: non-neoplastic:
no effects observed
Other effects:
not specified

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
not specified
Reproductive function: sperm measures:
effects observed, treatment-related
Reproductive performance:
effects observed, treatment-related

Details on results (P0)

CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS)
All but one animal survived to their scheduled necropsy. For the males at 1000 mg/kg bw/day, significant abnormal observations (p<0.01) were noted and included soiling of the chin and urogenital area. Abdominal, chin, muzzle and urogenital soiling were significant abnormal observations (p<0.01) in the reproductive group females at 1000 mg/kg bw/day.

BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS)
There were no statistically significant differences between controls and treatment groups in the mean body weights on any of the test groups.
There were no differences in the average daily food consumption between controls and the males groups for any of the measured time periods. In the reproductive group females, at 1000 mg/kg bw/day, there was a significant decrease (35%) in food consumption from control s during the intervals post-partum days 0-4.


REPRODUCTIVE FUNCTION: SPERM MEASURES (PARENTAL ANIMALS)
In the testes there was moderate to marked seminiferous tubule degeneration observed in all 1000 mg/kg bw/day male rats that was characterised by degeneration of spermatocytes. A downstream effect was observed in the epididymides of the same rats. This is an adverse finding.

REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS)
In the reproductive group females, there was no statistically significant difference across treatment groups for corpora lutea and total implants. However, there was statistically significant difference at 1000 mg/kg bw/day for post-implantation losses, days of gestation, total pups and total live pups with the 1000 mg/kg bw/day groups having significantly more post-implantation losses, a longer gestation period, fewer pups in the litter and fewer live pups in the litter than were seen in the control.

ORGAN WEIGHTS (PARENTAL ANIMALS)
The increased liver weights in males and females at 1000 mg/kg bw/day correlated with the histopathologic finding of panlobular hypertrophy and centrilobular hypertrophy in females at 250 mg/kg bw/day. In males, adrenal cortical atrophy was accompanied by a decrease in absolute and relative adrenal weights at 1000 mg/kg bw/day, seminiferous tubule degeneration was accompanied by a decrease in absolute and relative testes weights at 1000 mg/kg bw/day, epididymal effects were accompanied by a decrease in absolute and relative decreases in epididymal weights, and kidney nephropathy findings were accompanied by an increase in relative kidney weights.


GROSS PATHOLOGY (PARENTAL ANIMALS)
The ovaries appeared enlarged in one female/group administered ≥50 mg/kg bw/day. The seminal vesicles appeared small in 4 males administered 1000 mg/kg bw/day, and in one animal each at the 50 and 250 mg/kg bw/day dosage levels.

Testes:
There was moderate to marked seminiferous tubule degeneration observed in all 1000 mg/kg bw/day male rats, significant at p<0.01. Minimal seminiferous tubule degeneration was recorded for one male rat dosed at 250 mg/kg bw/day (not statistically significant). The finding was not observed in control rats or those administered 50 mg/kg bw/day. The finding was characterised by degeneration of spermatocytes that appeared to be arrested and dying while in meiotic division (to become spermatids) or degenerating at earlier spermatocytes stages. Because of cell death at the meiotic spermatocytes stage, meiotic spindles were observed much more commonly in the high-dose males than in controls.

Epididymides:
The beginning of the downstream effect of the spermatocyte degeneration in the testes was observed in the epididymides of all 1000 mg/kg bw/day male rats. A mild increase in immature spermatids was observed throughout the epididymides in 10/10 animals, significant at p<0.01 however they were especially common in the head portion. A minimal number of immature spermatids were observed in one 250 mg/kg bw/day male rat. Mild to moderate hypospermia, statistically significant at p<0.01, in 9/10 animals was also observed at the highest dosage, but it should be noted that this was largely confined to the head of the epididymides. Sperm numbers appeared to be near normal in the remainder of the epididymides.



Effect levels (P0)

Dose descriptor:
NOAEL
Effect level:
250 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: At 1000 mg/kg bw/day- in males: hepatic protoporphyrin accumulation, adrenal cortical atrophy, kidney protein droplet nephropathy, testicular seminiferous tubule degeneration with epididymides involvement and in females rats, periportal vacuolation

Target system / organ toxicity (P0)

Critical effects observed:
not specified

Results: F1 generation

General toxicity (F1)

Clinical signs:
no effects observed
Mortality / viability:
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
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)
The number of day 4 viable pups and the ratio of the number of viable pups to the total litter size was significantly different, with the 1000 mg/kg bw/day group having fewer viable pups by day 4 and a smaller viable/total ratio than did the control group. The percentage of post-natal loss was significantly different, with the 1000 mg/kg bw/day having a significantly higher loss than did the control group.

CLINICAL SIGNS (OFFSPRING)
No data

BODY WEIGHT (OFFSPRING)
The initial litter weight and average pup weight (defined using the live pup litter weight divided by the total number of live pups on day 0) were significantly different only for the 250 mg/kg bw/day group having a significantly increased litter weight and average pup weight compared to that in the control group after adjusting for litter size. The litter size was also a significant variable for these two endpoints with larger litters having litter weights but smaller average pup weights. For the final litter weight and average pup weights, there was also a significant difference, but it was the 1000 mg/kg bw/day group that was significantly different from the control group with both smaller overall litter weights and smaller average pup weight than in the control groups. There were no grossly external abnormalities observed in the pups.


Effect levels (F1)

Dose descriptor:
NOAEL
Generation:
F1
Effect level:
250 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: see 'Remark'

Target system / organ toxicity (F1)

Critical effects observed:
not specified

Overall reproductive toxicity

Reproductive effects observed:
not specified

Any other information on results incl. tables

Table 2. Summary of Mean Reproductive Parameters for Reproductive Group Female Rats.

 

 

Control (0 mg/kg bw/day)

50 mg/kg bw/day

250 mg/kg bw/day

1000 mg/kg bw/day

Litter Size

Corpora Lutea Counts

Mean

21

 

18

 

17

 

22

 

N/A

Std

5

 

5

 

3

 

5

 

 

N

10

 

8

 

10

 

8

 

 

Total Implants

Mean

15

 

16

 

14

 

13

 

N/A

Std

1.2

 

2.0

 

2.0

 

3.7

 

 

N

10

 

8

 

10

 

8

 

 

Post-Implantation Loss (%)

Mean

9.8

***

4.3

 

8.6

 

23.5

**

N/A

S td

5.9

 

7.7

 

10.2

 

14.3

 

 

N

10

 

8

 

10

 

8

 

 

Days Gestation

Mean

22

 

22

 

22

 

23

***

N/A

Std

1

 

1

 

1

 

1

 

 

N

10

 

8

 

10

 

8

 

 

Total Pups

Mean

13.7

***

16.0

 

13.0

 

10.3

***

N/A

Std

0.8

 

2.3

 

1.8

 

2.8

 

 

N

10

 

8

 

10

 

8

 

 

Total Live Pups Day 0

Mean

13.4

***

15.6

 

12.7

 

9.8

***

N/A

Std

0.8

 

2.8

 

1.7

 

2.7

 

 

N

10

 

8

 

10

 

8

 

 

Male pups

Mean

7

 

8

 

6

 

5

 

***

Std

2

 

3

 

2

 

3

 

 

N

10

 

8

 

10

 

8

 

 

Female pups

Mean

6

 

8

 

6

 

5

 

*

Std

1

 

2

 

2

 

2

 

 

N

10

 

8

 

10

 

8

 

 

Males/Females

Mean

1.4

 

1.1

 

1.2

 

1.2

 

 

Std

0.8

 

0.7

 

0.7

 

0.9

 

 

N

10

 

8

 

10

 

8

 

 

Day 4 Viable pups

Mean

13

***

15

 

13

 

7

***

***

Std

1

 

3

 

2

 

4

 

 

N

10

 

8

 

10

 

8

 

 

Viable/total

Mean

0.97

***

0.96

 

0.97

 

0.74

***

 

Std

0.04

 

0.04

 

0.05

 

0.31

 

 

N

10

 

8

 

10

 

8

 

 

Initial Litter Weight (g) [Live Pups only]

Mean

88

***

100.0

 

93.1

*

64.4

 

 

Std

7.4

 

13.8

 

11.8

 

14.1

 

 

N

10

 

8

 

10

 

8

 

 

Initial Average pup Weight (g) [Live Pups only]

Mean

6.6

***

6.5

 

7.4

***

6.8

 

***

Std

0.5

 

0.6

 

0.4

 

0.7

 

 

N

10

 

8

 

10

 

8

 

 

Final Litter weight (g)

Mean

145.5

***

160.6

 

142.0

 

72.9

***

***

Std

12.6

 

18.8

 

16.0

 

15.5

 

 

N

10

 

8

 

10

 

7

 

 

Final Average pup (g)

Mean

11.0

***

10.5

 

11.3

 

8.9

***

 

Std

0.9

 

1.0

 

1.0

 

1.3

 

 

N

10

 

8

 

10

 

7

 

 

Post-Natal Loss (%)

Mean

0.7

***

1.3

 

0.7

 

24.0

***

*

Std

2.3

 

3.7

 

2.3

 

32.6

 

 

N

10

 

8

 

10

 

8

 

 

Note: Asterisks next to the control indicates a significant treatment effects in the ANOVA, asterisks in the litter column indicates a significant litter effect in the ANOVA with p–values of *<0.05, ** <0.02 or *** <0.01 in the control column and significance in the litter sizes with p-values of *<0.05, **<0.02 or *** <0.01 in the litter significance column. N/A is the litter column indicates that the litter was not used as a covariate in the analysis of that endpoint.

% Post-Implantation Loss = ((# Implantations - # Live at First Litter Check) # Implantations)* 100

% Post-Natal Loss = ((#Live pups Day 0 - # Live pups Day 4) # live pups Day 0)* 100

Applicant's summary and conclusion

Conclusions:
The study was conducted according to OECD 422 test guideline, and in compliance with GLP for the registered substance. Based on observations at 1000 mg/kg bw/day (an increase in post-implantation loss, an increase in days of gestation, a decrease in live pups, a decrease in the total viable pups/total, a decrease in final litter weight, a decrease in final average pup weight and an increase in the % of post-natal loss), the NOAEL for reproductive toxicity is 250 mg/kg bw/day.