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Toxicological information

Repeated dose toxicity: oral

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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

Referenceopen allclose all

Reference Type:
study report
Title:
Unnamed
Year:
2005
Report Date:
2005
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:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent

Test animals

Species:
rat
Strain:
other: Crl:CD
Sex:
male/female
Details on test animals 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 homogenieity, 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 homogeniety, stability and concentration.
Duration of treatment / exposure:
males 28d
toxicity females 29d
reproductive females 46d
Frequency of treatment:
daily, 7 days/wk
Doses / concentrationsopen allclose all
Dose / conc.:
100 mg/kg bw/day (actual dose received)
Dose / conc.:
330 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 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 observatons, categorical observations, hind and forelimb grip strength, landing foot splay, motor activity.
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
all toxicity grops
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
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not examined
Behaviour (functional findings):
no effects observed
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
no effects observed
Details on results:
CLINICAL SIGNS AND MORTALITY
No observed effect.

BODY WEIGHT AND WEIGHT GAIN
No observed adverse effect.

FOOD EFFICIENCY
Not examined

OPHTHALMOSCOPIC EXAMINATION
Not examined

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

CLINICAL CHEMISTRY
No biologically or toxicological significant effects on clinical chemistry findings.

NEUROBEHAVIOUR
No observed adverse effects

ORGAN WEIGHTS
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 PATHOLOGY
There were no treatment-related gross findings at any dose.

HISTOPATHOLOGY: NON-NEOPLASTIC
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 significant”. 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.

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:
Based on the results of this repeated dose study, the NOAEL (No Observed Adverse Effect Level) for Dodecamethylcyclohexasiloxane in the rat via the oral route was determined to be 1000 mg/kg/day (highest dose tested) for systemic toxicity.
Executive summary:

A well reported oral combined repeated dose/reproductive and developmental toxicity study in the rat, conducted according to the current guideline and in accordance with GLP, found liver effects in females at all doses that were judged to be “of minimal toxicologic significance”.