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Toxicological information

Repeated dose toxicity: dermal

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Administrative data

Endpoint:
short-term repeated dose toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
08.11.1991 to 12.12.1991
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
comparable to guideline study
Cross-reference
Reason / purpose:
reference to other study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1993
Report Date:
1993

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 410 (Repeated Dose Dermal Toxicity: 21/28-Day Study)
Deviations:
yes
Remarks:
No urinalysis
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories, Portage, MI
- Age at study initiation: Approximately 8 weeks
- Weight at study initiation: Males: 229-262 g; Females: 206-241 g
- Fasting period before study: No
- Housing: Individually in standard stainless steel wire cages
- Diet (e.g. ad libitum): Ad libitum
- Water (e.g. ad libitum): Ad libitum
- Acclimation period: Seven days


ENVIRONMENTAL CONDITIONS
- Temperature (°F): 68-73
- Humidity (%): 30-70
- Air changes (per hr): No data
- Photoperiod (hrs dark / hrs light): 12/12


IN-LIFE DATES: From: 13.11.1991 To: 12.12.1991

Administration / exposure

Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Details on exposure:
TEST SITE
- Area of exposure: Dorsal
- % coverage: 10 %
- Type of wrap if used: Plastic wrap and cloth bandage
- Time intervals for shavings or clipplings: as needed


REMOVAL OF TEST SUBSTANCE
- Washing (if done): yes, with a wet gauze
- Time after start of exposure: Six hours


TEST MATERIAL
- Amount(s) applied (volume or weight with unit):
- Concentration (if solution):
- Constant volume or concentration used: yes/no
- For solids, paste formed: yes/no

USE OF RESTRAINERS FOR PREVENTING INGESTION: no, not required with wrap used.
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
28 Days
Frequency of treatment:
6 hours per day, 5 days per week for a period of 28 days
Doses / concentrationsopen allclose all
Dose / conc.:
100 mg/kg bw/day
Dose / conc.:
500 mg/kg bw/day
Dose / conc.:
1 000 mg/kg bw/day
No. of animals per sex per dose:
Ten
Control animals:
other: yes, wrapped without test substance
Details on study design:
- Dose selection rationale: No data
- Rationale for animal assignment (if not random): Random
- Rationale for selecting satellite groups: No satellite groups
- Post-exposure recovery period in satellite groups: No post-exposure period
Positive control:
None

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Twice daily on weekdays for general appearance, behavioral abnormalities, signs of toxicity and mortality.

DETAILED CLINICAL OBSERVATIONS: No


DERMAL IRRITATION: Yes


BODY WEIGHT: Yes
- Time schedule for examinations: On the initial day of the study, weekly during the study period and just prior to necropsy.


FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No data. Food consumption was measured weekly throughout the study period.


FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No


WATER CONSUMPTION: No


OPHTHALMOSCOPIC EXAMINATION: No


HAEMATOLOGY: Yes
- Time schedule for collection of blood: At study termination
- Anaesthetic used for blood collection: Yes (ketamine HCl)
- Animals fasted: Yes, for 16 hours
- How many animals: All
- Parameters checked in table No.1 were examined.


CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: At termination of the study
- Animals fasted: Yes, for 16 hours
- How many animals: All
- Parameters checked in table No.1 were examined.


URINALYSIS: No


NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
See Table 2. Organs examined at necropsy (macroscopic and microscopic):  At the end of dosing a complete necropsy was performed on all animals. The liver, kidneys, adrenals brain, spleen, ovaries and testes were examined and weighed. A complete set of organs/tissues were collected and retained in 10% buffered formalin. All tissues from the control and high dose groups were processed and examined microscopically. 
Other examinations:
None reported.
Statistics:
Statistical Methods:  Data was evaluated by two-sided Welch Trend Test.  All follow-up tests were one-sided and in the same direction as the overall trend.  P<0.05 was used as a critical level of significance.

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Dermal irritation:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
not examined
Details on results:
CLINICAL SIGNS AND MORTALITY: No deaths, overt signs of toxicity or changes in any of the control or treated animals. 

BODY WEIGHT AND WEIGHT GAIN: A slight but statistically significant decrease in body weight gains was observed in the high dose males during the last week of the study.

FOOD CONSUMPTION: A slight but statistically significant decrease in food consumption was observed in the high dose males during the last week of the study.

HAEMATOLOGY: No adverse changes occurred.

CLINICAL CHEMISTRY: No adverse changes occurred.

ORGAN WEIGHTS: A statistically significant decrease in liver and kidney weights were noted in the high dose males when expressed as organ to brain weight ratio.

GROSS PATHOLOGY: No adverse findings.

HISTOPATHOLOGY: Histopathology of organs and tissues for control and high dose group animals revealed no effects attributable to test material treatment. 

Effect levels

open allclose all
Dose descriptor:
NOAEL
Remarks:
relevant to human
Effect level:
>= 1 000 mg/kg bw/day
Sex:
male/female
Basis for effect level:
other: No adverse effects relevant to humans.
Dose descriptor:
NOAEL
Remarks:
rats
Effect level:
>= 1 000 mg/kg bw/day
Sex:
male/female
Basis for effect level:
other: No adverse effects.

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
In a 28-day repeated dose dermal toxicity study in rats, conducted using a protocol similar to OECD 410, and to GLP, the NOEL for hexamethyldisiloxane was considered to be 500 mg/kg/day, based on reduced kidney and liver weights in males. There were no such effects in females. Overall, the NOAEL was considered to be ≥1000 mg/kg bw/day for human relevant effects. The effects on kidney and liver weights were not accompanied by histopathological findings and were not observed in females, therefore are not considered adverse.