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Diss Factsheets

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:
2002-03-25 to 200211-07
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2002
Report date:
2002

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
other: OECD 422
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Hexamethylcyclotrisiloxane
EC Number:
208-765-4
EC Name:
Hexamethylcyclotrisiloxane
Cas Number:
541-05-9
Molecular formula:
C6H18O3Si3
IUPAC Name:
hexamethyl-1,3,5,2,4,6-trioxatrisilinane
Test material form:
other: white solid (no further information)

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Canada, 188 LaSalle, St. Constant, Canada
- Age at study initiation: >=8 wk
- Weight at study initiation: 187-238 g (f); 250-313 g (m)
- Housing: 1/suspended wire cage
- Diet: standard diet ad libitum
- Water: drinking water ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-25
- Humidity (%): 30-70
- Air changes (per hr): 10-15
- Photoperiod (hrs dark / hrs light): 12 h/12 h

IN-LIFE DATES: From: 2002-03-25 To: 2002-11-07

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: 450 l steel and glass Rochester-style inhalation chambers with stainless steel exposure caging.
- Method of holding animals in test chamber: individual stainless steel caged compartments
- Method of conditioning air: air passed through series of purification filters
- System of generating particulates/aerosols: TS placed in warming chamber (75 deg C). The liquid TS was then metered into a heated metal J-tube for vapourization.
- Air change rate: at 10 exchanges of chamber volume per h

TEST ATMOSPHERE
- Brief description of analytical method used: GC
- Samples taken from breathing zone: automatic sampling from chamber

Acclimatization for 3 h on 2 days
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Analysis of test atmosphere was conducted by gas chromatography with flame ionisation detection (GC/FID) and each chamber was evaluated at least once per hour during the exposure period. For each day of exposure the mean test atmosphere D3 concentration (actual) as determined from the GC/FID analysis, was compared with the theoretical concentration (nominal), derived from the estimated chamber air flow rate and test substance consumption, as a quality control measure to evaluate exposure system performance.
Details on mating procedure:
- M/F ratio per cage: 1:1
- Length of cohabitation: continuously until evidence of copulation
- Proof of pregnancy: vaginal plug or sperm in vaginal smear (day 0)
Duration of treatment / exposure:
Exposure period: 28 days for males and 46 days for females.
Premating exposure period (males): 2 weeks.
Premating exposure period (females): 2 weeks.
Mated femaes were exposed up to Day 19 of gestation.
Dams were not exposed during the lactation period.
Frequency of treatment:
6 hours/day; 7 days/week
Duration of test:
46 days
No. of animals per sex per dose:
10
Control animals:
other: yes, control group was exposed to filtered air
Details on study design:
- Dose selection rationale: based on the results of a previous 90-day inhalation study (DCC, 2001)

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily or twice daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: weekly

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes (see Table 1)
- Time schedule for collection of blood: at sacrifice
- Anaesthetic used for blood collection: Ketamine, HCL/Xylazine
- How many animals: all toxicity groups

CLINICAL CHEMISTRY: Yes (see Table 1)
- Time schedule for collection of blood: at sacrifice
- How many animals: all toxicity groups

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: prior to exposure and during wk 4
- Dose groups that were examined: all toxicity groups
- Battery of functions tested: FOB and motor activity examinations. These included: cage-side, hand-held, open field and categorical observations, rectal temperature, hindlimb/forelimb grip strength and landing foot splay. Motor activity was also determined using a Cage Rack Activity System.
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:
Examination for gross external malformations only.
Statistics:
Statistical methods: Bartlett's test and Kolmogorov-Smirnov test. Parametric data was tested using one-way Analysis of Variance (ANOVA) followed by Dunnett's Test (if significant); nonparametric data was tested by Kruskal-Wallis Test followed by Wilcoxon. Categorical data and histomorphology findings were evaluated with Fisher's
Exact Test. Statistically significant probabilities are reported at either the p<0.05 or p<0.01 levels.

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Observations recorded during the weekly detailed physical examinations were not different from those recorded during the daily clinical examinations. The clinical observations that were indicative of an adverse effect of the treatment were minimal and involved an increased incidence of anogenital staining and brown staining on the head. Anogenital staining was observed in 100% of reproductive group females in the 2500 ppm groups. A single occurrence was observed in one reproductive group female in the 100 ppm group. 100% of the reproductive group females in the 2500 ppm groups exhibited staining on the head at least once during the in-life phase of the study. There were no other clinical effects of toxicity.
Mortality:
no mortality observed
Description (incidence):
All adult animals survived to their scheduled necropsy.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Group mean body weight for 500 and 2500 ppm -exposed reproductive group females were consistently lower (≤ 8%) than the control group. However, the decreases were not statistically significant except for the 2500 ppm exposure group on gestation day 20 (8% lower relative to Control). Similarly, group mean body weight gain for the exposed reproductive group females in the 500 and 2500 ppm exposure groups were typically lower (S 30%), though not statistically significant, than controls prior to week 3 of gestation. Females in the 2500 ppm exposure group demonstrated a statistically significant 21% decrease in body weight gain at gestation week 3. These changes in body weight and body weight gain are consistent with those observed for the toxicity group females (pre-mating) and with the effects on litter size (gestation and post-partum periods).
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
There were no statistically significant differences in mean weekly food consumption values for the exposed reproductive group females relative to control. However, values were generally lower than control (2-12%). The one exception being a greater consumption of food (21%) during the parturition period (gestation day 20 - postpartum day 0/1) that likely represents differences in parturition (litter size and care).
Food efficiency:
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Description (incidence and severity):
Not examined for reproductive toxicity group females.
Clinical biochemistry findings:
not examined
Description (incidence and severity):
Not examined for reproductive toxicity group females.
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Description (incidence and severity):
Not examined for reproductive toxicity group females.
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
No treatment-related effects were noted on ovary and uterine weights for toxicity group females.
Gross pathological findings:
no effects observed
Description (incidence and severity):
No effects seen in female reproductive organs and tissues.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
No effects seen in female reproductive organs and tissues.
Histopathological findings: neoplastic:
not examined

Maternal developmental toxicity

Number of abortions:
no effects observed
Pre- and post-implantation loss:
effects observed, treatment-related
Description (incidence and severity):
Statistically significant decreases in the number of uterine implantation sites (33% decrease) when compared to the control in the 2500 ppm group.
Total litter losses by resorption:
no effects observed
Early or late resorptions:
no effects observed
Dead fetuses:
no effects observed
Description (incidence and severity):
There were no effects on pup viability.
Changes in pregnancy duration:
no effects observed
Description (incidence and severity):
There were no effects on gestation length.
Changes in number of pregnant:
effects observed, non-treatment-related
Description (incidence and severity):
All of the reproductive group females presented with positive evidence of mating on or before the seventh day of pairing and all but one of the reproductive group females became pregnant. The exception was a female from the 2500 ppm exposure D (Animal D0033). The uterus from this female was negative for implantation sites.
Other effects:
no effects observed
Description (incidence and severity):
There were no effects on number of corpora lutea.

Effect levels (maternal animals)

Key result
Dose descriptor:
NOAEC
Effect level:
500 ppm
Based on:
test mat.
Basis for effect level:
pre and post implantation loss

Maternal abnormalities

Abnormalities:
no effects observed

Results (fetuses)

Fetal body weight changes:
effects observed, treatment-related
Description (incidence and severity):
Statistically significant decreases were noted for litter size (number of pups per litter on PND 0 and 4) and litter weight (27% decreases relative to control on PND 0 and 4) at 2500 ppm.
Reduction in number of live offspring:
no effects observed
Changes in sex ratio:
no effects observed
Changes in litter size and weights:
effects observed, treatment-related
Description (incidence and severity):
Statistically significant decreases were noted for litter size (number of pups per litter on PND 0 and 4) and litter weight (27% decreases relative to control on PND 0 and 4) at 2500 ppm.
Changes in postnatal survival:
no effects observed
External malformations:
no effects observed
Skeletal malformations:
no effects observed
Visceral malformations:
no effects observed

Effect levels (fetuses)

Key result
Dose descriptor:
NOAEC
Effect level:
500 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
changes in litter size and weights

Fetal abnormalities

Abnormalities:
no effects observed

Overall developmental toxicity

Developmental effects observed:
yes
Lowest effective dose / conc.:
2 500 ppm
Treatment related:
yes
Relation to maternal toxicity:
not specified
Dose response relationship:
not specified
Relevant for humans:
not specified

Applicant's summary and conclusion

Conclusions:
In the combined repeated dose/reproductive and developmental inhalation toxicity screening test, conducted according to OECD Test Guideline 422 and in compliance with GLP, exposure to 2500 ppm (22.8 mg/L) of the test substance was associated with decreased implantation sites and litter size at 2500 ppm dose group. Therefore, the NOAEC for reproductive and developmental toxicity was concluded to be 500 ppm (4.55 mg/L).