Dodecamethylcyclohexasiloxane

Repeated dose toxicity: oral

Administrative data

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

from 2005-04-26 to 2005-10-24

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference 1

Reference Type:

study report

Title:

Unnamed

Year:

2005

Report date:

2005

Reference 2

Reference Type:

other: letter

Title:

Re: TSCA Section 8(e) Notification of Substance Risk: Dodecamethylcyclohexasiloxane.

Author:

SEHSC

Year:

2009

Bibliographic source:

Letter from SEHSC

Report date:

2009

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)

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Dodecamethylcyclohexasiloxane

EC Number:

208-762-8

EC Name:

Dodecamethylcyclohexasiloxane

Cas Number:

540-97-6

Molecular formula:

C12H36O6Si6

IUPAC Name:

dodecamethylcyclohexasiloxane

Test animals

Species:

rat

Strain:

other: Crl:CD

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Labs, Raleigh, NC, USA
- Age at study initiation: 9 wk
- Weight at study initiation: 173-254 (f); 285-386 (m)
- Housing: 1/suspended wire mesh cage
- Diet: standard diet ad libitum
- Water: drinking water ad libitum
- Acclimation period:

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 67.7-72.5 deg F (approximately 20 degrees celsius)
- Humidity (%): 35-59
- Air changes (per hr): 15.6
- Photoperiod (hrs dark / hrs light): 12 h/12 h

IN-LIFE DATES: From 2005-05-12 for 28 or 29 days in the toxicity portion of this study.

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on oral exposure:

PREPARATION OF DOSING SOLUTIONS:

Prepared for the whole study. Analysed (GC) 4 times to ensure homogeneity, stability and concentration.

VEHICLE
Corn oil
- Lot/batch no.: 015K0115

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

GC analysis on 4 occasions to ensure homogeneity, stability and concentration.

Duration of treatment / exposure:

males 28d
toxicity females 29d
reproductive females 46d

Frequency of treatment:

daily, 7 days/wk

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

100 mg/kg bw/day (actual dose received)

Doses / concentrations 2

Dose / conc.:

330 mg/kg bw/day (actual dose received)

Doses / concentrations 3

Dose / conc.:

1 000 mg/kg bw/day (actual dose received)

No. of animals per sex per dose:

10 males
10 toxicity and 10 reproductive females

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale:
- Rationale for animal assignment (if not random): weight stratified randomization
- Rationale for selecting satellite groups: none
- Post-exposure recovery period in satellite groups: none

Positive control:

none

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: at sacrifice
- Anaesthetic used for blood collection: Yes (isoflurane)
- Animals fasted: yes
- How many animals: all toxicity groups

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at sacrifice
- Animals fasted: Yes / No / No data
- How many animals: all toxicity groups

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: FOB at start and completion
- Dose groups that were examined: males and toxicity group females
- Battery of functions tested: cage-side observations, hand-held observations, open field observations, categorical observations, hind and forelimb grip strength, landing foot splay, motor activity.

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
all toxicity groups
HISTOPATHOLOGY: Yes
Microscopic examination of a relatively large range of tissues of all control and hi-dose group animals, and the lungs and thyroid of both sexes and liver of females at the low and mid doses.
ORGAN WEIGHTS
weights of a relatively large range of organs determined

Other examinations:

Examination for reproductive parameters (reported in the relevant IUCLID section).

Statistics:

ANOVA (analysis of variance): body weights, organ weight, haematology, clinical chemistry etc
ANCOVA (analysis of covariance): FOB
Cochran-Armitage: microscopic findings

Results and discussion

Results of examinations

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

effects observed, treatment-related

Description (incidence and severity):

Prothrombin time prolonged in males at >=300 mg/kg bw/day with no clinical indication of clotting abnormalities.

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

not examined

Behaviour (functional findings):

no effects observed

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

Increased absolute and/or relative liver weight in both sexes at all doses (>=100 mg/kg bw/day; statistically significant), with a modest dose-relation in females. It was said that only the relative liver weight in high-dose females exceeded historical control values.

Relative absolute and/or adrenal weights in females were increased at all doses (>=100 mg/kg bw/day; statistically significant) without any dose relationship.

Kidney weights were increased in both sexes at all doses, but only for the low and mid dose groups was the change statistically significant. There was no dose relationship.

Gross pathological findings:

effects observed, non-treatment-related

Description (incidence and severity):

Microscopic examination identified a dose related increase in periportal lipidosis in the liver of females (controls: 4/10 minimal severity; treated groups 100, 330, 1000 mg/kg bw/day: 10/10, 10/10, 9/10 minimal to moderate severity). There was no other evidence of hepatotoxicity and the report considers this effect to be of “minimal toxicologic significance”. A subsequent re-evaluation of these data (TSCA 8(e), 2009) note that in the light of a dose-response in liver weight in females in the presence of hepatic histopathological changes in this sex, “it cannot be ruled out that the findings may be test article related”. In the context of this view, the LOAEL would be 100 mg/kg bw/day (in females).

Lung effects were considered an artefact due to the treatment route (further justification not given in study report, but presumably due to accidental dosing into the trachea).

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

Microscopic examination identified a dose related increase in periportal lipidosis in the liver of females (controls: 4/10 minimal severity; treated groups 100, 330, 1000 mg/kg bw/day: 10/10, 10/10, 9/10 minimal to moderate severity). There was no other evidence of hepatotoxicity and the report considers this effect to be of “minimal toxicologic significance”. A subsequent re-evaluation of these data (TSCA 8(e), 2009) note that in the light of a dose-response in liver weight in females in the presence of hepatic histopathological changes in this sex, “it cannot be ruled out that the findings may be test article related”. In the context of this view, the LOAEL would be 100 mg/kg bw/day (in females).

Lung effects were considered an artefact due to the treatment route (further justification not given in study report, but presumably due to accidental dosing into the trachea).

The incidence of animals with follicular cell hypertrophy in the thyroid appeared possibly related to treatment (incidence in groups 0, 100, 330, 1000 mg/kg bw/day: 0, 5, 2, 6 in males and 1, 2, 1, 5 in females). Severity was not affected by dose in either sex. This effect was considered to be secondary and adaptive, and typical of a xenobiotic which induces hepatic microsomal enzymes with increased degradation of thyroxin and triiodothyronine as a side effect.

Histopathological findings: neoplastic:

no effects observed

Other effects:

not examined

Effect levels

Key result

Dose descriptor:

NOAEL

Effect level:

>= 1 000 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

female

Basis for effect level:

other: No adverse effect observed.

Target system / organ toxicity

Critical effects observed:

no

Applicant's summary and conclusion

Conclusions:

In the oral combined repeated dose toxicity study with the reproduction/developmental toxicity screening test with dodecamethylcyclohexasiloxane (D6), conducted according to OECD Test Guideline 422 and in compliance with GLP (Dow Corning Corporation, 2005), the NOAEL for systemic toxicity was concluded to be at least 1000 mg/kg bw/day, the highest dose tested. The observed liver effects (increased absolute and/or relative liver weight in all treated groups and periportal lipidosis at all doses in females) were described as “of minimal toxicologic significance” and the thyroid effects (follicular cell hypertrophy, incidence possibly treatment-related in both sexes) were referred to as secondary and adaptive to the liver changes.