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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:
22 April 2009 to 23 September 2010
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Cross-reference
Reason / purpose for cross-reference:
reference to other study

Data source

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

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.7 (Repeated Dose (28 Days) Toxicity (Oral))
Qualifier:
according to guideline
Guideline:
other: Japanese Guideline for Screening Toxicity Testing of Chemicals: Testing Methods for New Substances, enacted July 13, 1974, amended December 5, 1986
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Dodecamethylpentasiloxane
EC Number:
205-492-2
EC Name:
Dodecamethylpentasiloxane
Cas Number:
141-63-9
Molecular formula:
C12H36O4Si5
IUPAC Name:
2,2,4,4,6,6,8,8,10,10-decamethyl-3,5,7,9-tetraoxa-2,4,6,8,10-pentasilaundecane

Test animals

Species:
rat
Strain:
other: Hsd:Sprague Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Harlan Laboratories, B.V.
- Age at study initiation: ~8 weeks
- Weight at study initiation: 236 to 272 g (males), 183 to 220 g (females)
- Fasting period before study: no data available
- Housing: groups of 5 in Makrolon type-4 cages
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3
- Humidity (%): 30 to 70
- Air changes (per hr): 10 to 15
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 22 April 2009 To: 27 May 2009 (satellite A) or 10 June 2009 (satellite B)

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Remarks:
dried and deacidified
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS: The formulations were prepared weekly. L5 was weighed into a glass beaker on a tared Mettler balance. Thereafter the remaining vehicle was added. The mixtures were stirred and stored at room temperature. Homogeneity of the test substance in the vehicle was maintained during the daily administration period using a magnetic stirrer.

VEHICLE
- Justification for use and choice of vehicle (if other than water): no data available
- Concentration in vehicle: 0, 5, 50, 200 mg/ml
- Amount of vehicle (if gavage): 5 ml/kg bw
- Lot/batch no. (if required): no data available
- Purity: no data available
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
After the experimental start, samples of the vehicle and three samples (top, middle and bottom) of about 2 g of each concentration were taken prior to dosing for analysis of homogeneity, concentration and stability. About 2 g of each concentration was also taken for analysis during week 3 after commencement of dosing. A GC method was used for analysis. Accurate use of dodecamethylpentasiloxane (L5) and the corn oil vehicle were indicated and the application formulations were found to be homogeneously prepared. Formulations were stable.
Duration of treatment / exposure:
28 days
Frequency of treatment:
daily
Doses / concentrationsopen allclose all
Dose / conc.:
25 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:
5 (with an additional 5 animals/sex given 0 or 1000 mg/kg bw for recovery phase - satellite B)
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: results of range-finding study
- Rationale for selecting satellite groups: to assess recovery
- Post-exposure recovery period in satellite groups: 14 days
Positive control:
No positive control group

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: mortality/viability: twice daily; general clinical observations: before commencement of administration, twice daily on days 1 to 3, once daily on days 4 to 28 (treatment period), once daily on days 1 to 14 (recovery period)

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: The animals were observed in their home cages, outside their home cages in a standard arena and in the hand. The observations were performed once before commencement of administration and once weekly (weeks 1 to 3) thereafter

BODY WEIGHT: Yes
- Time schedule for examinations: weekly (during acclimation, treatment and recovery periods, and before necropsy)

FOOD CONSUMPTION: Yes
- Recorded once during the acclimatisation period and weekly thereafter.
- 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: No

FOOD EFFICIENCY: No

WATER CONSUMPTION: No

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: after 4 weeks and at the end of the recovery period
- Anaesthetic used for blood collection: Yes (light isoflurane)
- Animals fasted: Yes (18 h)
- How many animals: all animals
- Parameters checked in table 1 were examined

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: after 4 weeks and at the end of the recovery period
- Animals fasted: Yes (18 h)
- How many animals: all animals
- Parameters checked in table 1 were examined

URINALYSIS: Yes
- Time schedule for collection of urine: after 4 weeks and at the end of the recovery period
- Metabolism cages used for collection of urine: Yes
- Animals fasted: Yes (18 h)
- Parameters checked in table 1 were examined

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: during week 4, relevant parameters from a modified Irwin screen test were evaluated in all animals
- Dose groups that were examined: all groups
- Battery of functions tested: sensory activity / motor activity / grip strength / other: behaviour

OTHER: vaginal smear for oestrus
- Taken on day 22 of treatment
Sacrifice and pathology:
Sacrifice was after 28 days for the treatment only group and after 6 weeks for the recovery group.
GROSS PATHOLOGY: Yes (see table 2)
HISTOPATHOLOGY: Yes (for a comprehensive range of tissues in high-dose and control groups, and for livers only in other dose groups) (see table 2)
Other examinations:
No data available
Statistics:
The following statistical methods were used to analyse the results from investigations of body weight, grip strength, locomotor activity, clinical laboratory data, organ weights and ratios, and macroscopic findings:
1) The Dunnett-test based on a pooled variance estimate was applied if the variables could be assumed to follow a normal distribution for the comparison of the treated groups and the control groups for each sex.
2) The Steel-test (many-one rank test) was applied instead of the Dunnett-test when the data could not be assumed to follow a normal distribution.
3) Fisher's exact-test.

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Description (incidence and severity):
No treatment-related signs of toxicity (hair loss noted around the eyes of two females at 25 mg/kg bw/day and periocular scabbing noted in control and treated animals).
Mortality:
no mortality observed
Description (incidence):
All animals survived to scheduled necropsy.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
No treatment-related effects (mean body weight was not affected by the end of treatment, but was significantly elevated in treated males and females on day 8 of the recovery period).
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
no adverse effects.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Description (incidence and severity):
A number of statistically significant differences to the control parameters were noted in rats treated with 1000 mg/kg bw/day. However, these differences were either gender-specific, due to slightly high control values, or were not supported by concomitant changes in related parameters, and considered to be unrelated to the treatment.
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
The few differences noted in the clinical biochemistry parameters were considered to be unrelated to the treatment.
Urinalysis findings:
no effects observed
Description (incidence and severity):
After the end of the treatment period, the urinalysis parameters of the males and females were unaffected at all dose levels and no late effects were evident after the end of the recovery period.
Behaviour (functional findings):
no effects observed
Description (incidence and severity):
There were no treatment-related findings in the FOB. Minor transient differences in the mean locomotor activity in males at 1000 mg/kg bw/day were considered to be unrelated to the test substance. In males treated with 1000 mg/kg bw/day, the mean locomotor activity during 0-10 minutes was significantly increased when compared with the control males. Females were unaffected at this dose.
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
With the exception of the changes in the mean absolute and relative liver weights, none of the differences in organ weights or ratios were accompanied by microscopical changes and were therefore considered to be unrelated to treatment. The increased mean absolute and relative liver weights were considered to be related to metabolic adaptation, and were reflected in microscopic findings. These findings were not evident after the recovery period. Elevated liver weights, particularly in combination with hepatocellular hypertrophy, was considered reversible and considered to be an adaptive finding without adverse toxicological relevance.
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
No gross findings, considered to be exposure-related, were noted in this study.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Although the presence of higher mean levels of α-2u-globulin of the punctate staining pattern in the kidneys of male rats at 250 or 1000 mg/kg bw/day were considered to be possible treatment-related effects, the lack of a dose-response relationship or any morphological changes in the kidneys was considered to indicate that these changes were of no toxicological relevance. The toxicologically irrelevant elevation of α-2u-globulin protein in the kidneys of male rats is a well-known species- and gender-specific phenomenon and, in the absence of any correlating morphological changes, was not considered to be adverse. Hepatocellular hypertrophy was also evident in 1000 mg/kg bw/day animals. The hepatocellular hypertrophy, noted after the treatment period, is considered to be an adaptive process due to enzyme induction rather than a toxic effect, and was reversible after the end of the recovery period. Perilobular fatty change (at 0, 25, 250 and 1000 mg/kg bw/day with dose dependent occurrence and severity) noted after the end of the treatment period reverted to control levels after recovery, was not considered adverse.
Histopathological findings: neoplastic:
not examined
Other effects:
no effects observed
Description (incidence and severity):
The sampling and evaluation of the stage of estrus on day 22 of treatment did not indicate any abnormal distributions of diestrus, metestrus, proestrus or estrus.

Effect levels

Key result
Dose descriptor:
NOAEL
Effect level:
>= 1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no toxicologically-relevant treatment-related effects at any dose

Target system / organ toxicity

Critical effects observed:
no

Applicant's summary and conclusion

Conclusions:
In a GLP 28-day study performed according to OECD Test Guideline 407, no biologically significant, treatment-related effects were reported in rats given dodecamethylpentasiloxane (L5) by oral gavage at 25, 250 or 1000 mg/kg bw/day. An NOAEL of >=1000 mg/kg bw/day was derived.
Executive summary:

In a GLP study performed according to OECD Test Guideline 407, groups of five male and five female rats (with additional satellite groups of five males and five females given the top and the control dose) were treated with dodecamethylpentasiloxane (L5) via the oval (gavage) route for 28 days. Doses of 25, 250 or 1000 mg/kg bw/day were administered, with a concurrent control group treated with the vehicle alone (corn oil) at 5 ml/kg bw.

Over the course of the study, a range of parameters were investigated (mortality, clinical signs of toxicity, food consumption, body weight, behaviour). During week 4, a functional observation battery was carried out and grip strength and locomotor activity tests were performed. Necropsy was performed immediately after treatment at 28 days, or after a recovery period of 14 days (satellite groups), and macro- and microscopic analyses were performed. Blood and urine were taken for analysis immediately after treatment and after the recovery period.

Under the conditions of this study, no biologically-significant, treatment-related effects were observed at any dose.

An NOAEL of >=1000 mg/kg bw/day was derived.