Registration Dossier

Administrative data

Description of key information

In the key 28-day repeated dose oral toxicity study, conducted according to OECD Test Guideline 407 and in compliance with GLP (Dow Corning Corporation, 2010), 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. A systemic NOAEL of >=1000 mg/kg bw/day was concluded.

 

There are no repeated dose inhalation toxicity data for the registered substance, dodecamethylpentasiloxane (CAS 141-63-9), so data for the related substance, decamethyltetrasiloxane (CAS 141-62-8), have been used to assess the repeated dose inhalation toxicity of dodecamethylpentasiloxane (CAS 141-63-9). 

In a 90-day repeated dose inhalation toxicity study, conducted according to OECD Test Guideline 413 and in compliance with GLP (Dow Corning Corporation, 2010b) inhalation of decamethyltetrasiloxane at concentrations of 70 and 400 ppm were well tolerated and the concluded NOAEL for systemic toxicity in male and female rats was at least 400 ppm.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
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
Reason / purpose for cross-reference:
reference to other study
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
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)
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
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
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.
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.
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
Critical effects observed:
no
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.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subacute
Species:
rat

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
01.06.2009 to 17.09.2010
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day Study)
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories
- Age at study initiation: 9 weeks minimum
- Weight at study initiation: Males: 233.4-271.4 g; Females: 183.6-217.7 g.
- Fasting period before study: No
- Housing: Individually housed in suspended wire-mesh cages.
- Diet (e.g. ad libitum): Ad libitum (except during exposure, FOB or motor activity assessments.
- Water (e.g. ad libitum): Ad libitum (except during exposure, FOB or motor activity assessments.
- Acclimation period: Five days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20.5-23.2
- Humidity (%): 30-70
- Air changes (per hr): At least 10
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 17.06.2009 To: 30.03.2010
Route of administration:
inhalation: vapour
Type of inhalation exposure:
whole body
Vehicle:
clean air
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Exposures were conducted in 1000 litre stainless steel and glass TSE-system style inhalation chambers. The animal cage position assignment within each chamber was rotated daily. Generation of test substance vapour was performed using heated stainless steel J-tubes containing a column of stainless steel beads. The test substance was metered from reservoirs into J0 tubes using a Fluid Metering Incorporation pump and Harvard model syringe pumps. Compressed air flowed through the J-tube directed to the inlet port at the top of the exposure chamber. Just prior to entering the exposure chamber, the carrier/vapour mixture was combined with chamber supply (dilution) air where is was diluted to the target chamber concentration as it entered the exposure chamber.
- Method of conditioning air: Conditioned building air passed through HEPA and activated charcoal filters before delivery to the chamber. Moisture was added as necessary to maintain relative humidity within the required range.
- Temperature, humidity, pressure in air chamber: 22 ±3oC, 50 ±20% (no information on pressure)
- Air change rate: 12-15 chamber air changes per hour
- Treatment of exhaust air: No data

TEST ATMOSPHERE
- Brief description of analytical method used: Gas chromatography
- Samples taken from breathing zone: yes
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Homogeneity of the vapour concentration within the exposure chamber was evaluated prior to experimental start. A minimum of five locations were evaluated and compared to a reference location. Homogeneity of the vapour concentration was considered acceptable if all locations were within 10% of the reference location. Chamber atmosphere was analysed using a gas chromatography equipped with a flame ionisation detector to determine the actual chamber concentration of the test substance. Exposure concentration was evaluated at least once every 60 min.
Duration of treatment / exposure:
90 days
Frequency of treatment:
Daily (seven days/week)
Dose / conc.:
70 ppm
Remarks:
target
Dose / conc.:
400 ppm
Remarks:
target
No. of animals per sex per dose:
Ten
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: Exposure concentrations were selected based on the 28-day whole-body vapour inhalation study.
- Rationale for selecting satellite groups: To investigate the reversibility of any observed effects after 28 day recovery period.
- Post-exposure recovery period in satellite groups: Control and 400 ppm groups.
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: All animals were observed at least twice daily in their cages for mortality, morbidity and moribundity. General clinical observations were made at least once per day, beginning on the first day of exposure. Findings were noted for individual animals.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: All animals received a detailed physical examination once before the first exposure and weekly thereafter. The observations were made outside the home cage in a standard arena.

BODY WEIGHT: Yes
- Time schedule for examinations: Individual body weights were determined beginning with randomisation into test groups, on the first day of exposure, at least weekly thereafter and the day of euthanasia.

FOOD CONSUMPTION:
- Individual food consumption was recorded at least weekly.

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: Yes
- Time schedule for examinations: Before initiation of exposure and near the end of exposure period. No examination at the end of the recovery period as no effects were found at the end of the treatment period.
- Dose groups that were examined: Control and treated groups (except recovery groups).

HAEMATOLOGY: Yes
- Time schedule for collection of blood: Prior to scheduled sacrifice.
- Anaesthetic used for blood collection: Yes (isoflurane)
- Animals fasted: Yes
- How many animals: All animals
- Parameters checked in table 1 were examined.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: Prior to scheduled sacrifice.
- Animals fasted: Yes
- How many animals: All animals
- Parameters checked in table 1 were examined.

Urinalysis: Yes
- Time schedule for collection of urine: 12-24 hours prior to necropsy
- Metabolism cages used for collection of urine: Yes
- Animals fasted: Yes
- Parameters checked in table 1 were examined.

NEUROBEHAVIOURAL EXAMINATION: Yes, FOB and motor activity evaluations were performed.
- Time schedule for examinations: Prior to exposure and during the last week of exposure.
- Dose groups that were examined: Control and treated animals (except recovery group).
- Battery of functions tested: cage-side obs, hand-held obs, open field obs, categorical obs, measurements/counts, motor activity.
Sacrifice and pathology:
GROSS PATHOLOGY: Yes (see table 2). All animals were subjected to a complete gross necropsy which included examination of the external surface and all orifices of the body, the cranial, thoracic and abdominal cavities and their contents.
HISTOPATHOLOGY: Yes (see table 2). Selected tissues and organs required for histopathological examination from all animals were taken and preserved. Selected organs were also weighed. Histopathology was not performed on the recovery groups as no effects were observed at the end of the treatment period.
Statistics:
Mean body weight values and body weight changes, mean food consumption values, mean organ weight and organ weight to body weight ratios, Functional Observational Battery (FOB) data and motor activity, mean haematology and clinical chemistry values, urinalysis values and histopathology data were evaluated. Data analysis was carried out in the Provantis v8.2 system for body weight ratios, food consumption, hematology, clinical chemistry and prothrombin times. These data were analysed using ANOVA. If data did not satisfy the requirements of normality of the residuals (Wilks-Shapiro) and homogeneity of variance (Bartlett's) a log of rank transformation was performed. If the ANOVA was significant (p<0.05), pair-wise comparisons of the exposed groups to control were made using Dunnett's test. Clinical signs data were analysed using Mixed Modelling repeated measures. FOB data were analysed using a combination of ANCOVA with baseline evaluations used as the covariate and repeated measures ANOVA. Categorical FOB data were analysed using the Joncheere-Terpsta test. Clinical pathology data were analysed with Provantis v8.2 and SAS v9.1.3. Statistically significant probabilities were reported for p values of <0.05 and <0.01.
Clinical signs:
no effects observed
Description (incidence and severity):
There were no statistically significant clinical observations noted between control and treated groups.
Mortality:
no mortality observed
Description (incidence):
Two animals in the control group were subjected to unscheduled necropsies on Days 72 and 77. These animals had similar gross findings including enlarged spleen and liver, small thymus and exorbital lacrimal glands. These animals also had a few specific individual findings and both had lymphosarcoma. There were no other deaths.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
There were no statistically significant differences between controls and treatment groups in the mean body weights on any of the three groups: males and females in the main groups and the recovery groups. There were no statistically significant differences between controls and the treatment groups in mean body weight gains for any interval for males and females in the main groups. There was a statistically significant increase (57%) and decrease (34%) in body weight gain compared to control values for the recovery group males during week 2 and 4 of study, respectively. Weight gain for the recovery group females was statistically increased, from controls on week 6, 10 and 17, respectively.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
There were no statistically significant differences between controls and treatment groups in weekly mean food consumption for males in the main groups. There was a statistically significant difference in weekly mean food consumption during the first week of study for the recovery group male group. The only statistically significant results in the main group females was a difference in weekly mean food consumption for the 70 ppm main group females during the fourth week of the study. There were no statistically significant difference between control and treated groups for the recovery group females.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
no effects observed
Description (incidence and severity):
No adverse effects
Haematological findings:
no effects observed
Description (incidence and severity):
There were no statistically significant differences in the main study for male rats. However, there were statistically significant decreases (p<0.05) in recovery Group 3 for red blood cells and monocytes. This was a decrease of 3.3% for red blood cells and 25.4% and 29.5%, respectively, for the monocytes (percent and absolute). The mean values for these parameters, as well as individual values, were within the historical range.

Females in Group 2 of the main study had statistically significant decreases (p<0.05) for haemoglobin and haematocrit (4.1% and 4.7%, respectively). The mean values, as well as individual values, for haemoglobin and haematocrit were within the historical range. There were no statistical differences noted in the female recovery groups.

The statistically significant findings observed in males and females may be treatment-related; however, were not considered toxicologically significant since the values were within historical control ranges and there were no histomorphological correlates. There were no other significant differences noted in the other haematology parameters across groups for either sex.
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
Male rats in the main study Group 2 had statistically significant differences (p<0.05) noted for alanine aminotransferase and total bilirubin in Group 3. These were an increase of 22.5% for alanine aminotransferase and a decrease of 16.6% for total bilirubin as compared to the concurrent control group. There was a statistically significant decrease (p<0.05) in recovery Group 3 for albumin. This was a decrease of 5.7% compared to concurrent control. Although there were statistical differences the mean values, as well as individual values, were within the historical range for these parameters.

Statistically significant decreases were noted for female rats in the main study Groups 2 and 3 for aspartate aminotransferase and total bilirubin (p<0.05). These were decreases of 30% and 28.9% for aspartate aminotransferase and 15.7% and 14.4% for total bilirubin as compared to the concurrent control groups. There was a statistically significant decrease (p<0.05) in the recovery group 3 for creatinine, which was a decrease of 12.5% from concurrent controls. Although these were statistically different, the mean values were within the historical range for these parameters. There were individual values below the historical range for alanine aminotransferase in Groups 2 and 3, but individual values for total bilirubin and creatinine were within the historical range.

The statistically significant findings observed in males and females may be treatment-related; however, were not considered toxicologically significant since the values were within the historical control ranges and there were no histomorphological correlates. There were no other significant differences noted in the other clinical chemistry parameters across either sex.
Urinalysis findings:
no effects observed
Description (incidence and severity):
Urine from the male rats in the main Group 3 had a statistically significant decrease for volume (p<0.01) and statistically significant increases for specific gravity (p<0.01) and urobilinogen (p<0.05), but no differences noted in the recovery groups. In the categorical variables there was protein >=300 mg/dl noted in Groups 1, 2 and 3 of the main group (2, 4 and 6 animals, respectively) and in the recovery Groups 1 and 3 (4 and 5 animals), although not statistically significant. The decrease in urinary output and the increase of protein in the urine appear to be dose responsive. Since BUN and creatinine were similar to control values and there were no correlated histomorphological changes in the kidney, these findings may be considered treatment-related; however, not toxicologically significant.

Urine from the female rats in the main groups did not have statistically significant differences for the continuous variables, but a statistically significant difference (p<0.05) was noted in Group 3 of the recovery group for urobilinogen. In the categorical variables there was protein >=300 mg/dl noted one each in Groups 1 and 2 of the main group and one in recovery Group 3, although not statistically significant.
Behaviour (functional findings):
no effects observed
Description (incidence and severity):
There were no statistically significant or biologically relevant findings.
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
There were no statistically significant differences compared to controls noted for organ weights and organ weight to body weight ratios for males in the main groups and the recovery groups. There was a statistically significant differences noted for the liver weight to body weight ratio in females of 400 ppm main group compared to controls (7.9% increase). There was also a statistically significant increase in uterus weight, absolute and relative (67 and 60% increase, respectively) in females of the recovery group 400 ppm. These increases in organ weights may be treatment-related and were not considered adverse as there were no histopathological correlates.
Gross pathological findings:
no effects observed
Description (incidence and severity):
Only occasional findings were observed, which for the most part had no corresponding microscopic finding. Discolouration of the adrenal glands and white single discolouration of the pituitary gland were also noted; pituitary observations were limited to females from Groups 2 and 3. Most of the adrenal findings had no corresponding microscopic finding, although one Group 3 male with a small adrenal gland did have a minimal decrease of the cortex of the adrenal gland. With the exception of one of the pituitaries from the Group 2 female, wherein the corresponding microscopic finding was minimal focal hyperplasia, none of the pituitary gross observations had corresponding microscopic findings. Enlarged uterus in a Group 2 female was correlated microscopically with dilatation of the horns due to the estrus stage.

Occasional other gross observations were noted but were considered sporadic and not indicative of a treatment-related effect.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
Neoplasms were observed in two of the Group 1 control males and in one of the Group 3 males. The benign subcutaneous fibroma in the Group 3 male was considered an incidental finding unrelated to test substance administration. No treatment-related findings were observed in evaluated tissues from Group 3 males and females at the terminal sacrifice, except for a statistically significant increased incidence of alveolar macrophages in the Group 3 females. Alveolar macrophages of minimal severity were observed in the lung of five of ten Group 3 females but not in control female lungs. This is a very common incidental finding; however, it was statistically significant and appears to be treatment-related in females, although not considered an adverse effect. Alveolar macrophages were observed in control and high dose males; however, not a statistically significant increase above control values.
Histopathological findings: neoplastic:
not examined
Key result
Dose descriptor:
NOAEC
Effect level:
>= 400 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No adverse treatment-related effects.
Critical effects observed:
no
Conclusions:
In a 90-day inhalation study conducted to OECD 413 and to GLP (reliability score 1) inhalation of decamethyltetrasiloxane at concentrations of 70 and 400 ppm were well tolerated. There were no clinical signs or treatment-related effects associated with exposure in the ophthalmologic endpoints, body weights, food consumption and rat neurobiological function. Certain changes in serum chemistry and haematology parameters, urinary volumes and organ weights (absolute and relative) may be treatment-related, but not toxicologically significant. The only treatment-related microscopic finding in Group 3 females was an increased incidence of alveolar macrophages, though not considered an adverse effect. Based on the results of this study the NOAEL for decamethyltetrasiloxane for systemic toxicity in male and female rats is at least 400 ppm.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
5 083 mg/m³
Study duration:
subchronic
Species:
rat

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

In the key repeated dose oral toxicity study, conducted according to OECD Test Guideline 407 and in compliance with GLP (Dow Corning Corporation, 2010), 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 the registered substance, dodecamethylpentasiloxane (L5) (CAS 141-63-9) 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 lever for any of the examined parameters. Therefore, the NOAEL for systemic toxicity was concluded to be >=1000 mg/kg bw/day.

A 7-day oral supporting study was available as a summary report, which concluded the same NOAEL as the key study (Dow Corning Corporation, 2009f).

There are no repeated dose inhalation toxicity data for the registered substance, dodecamethylpentasiloxane (CAS 141-63-9), so data for the related substance, decamethyltetrasiloxane (CAS 141-62-8), have been used to assess the repeated dose inhalation toxicity of dodecamethylpentasiloxane(CAS 141-63-9). 

In a 90-day repeated dose inhalation toxicity study, conducted according to OECD Test Guideline 413 and in compliance with GLP (Dow Corning Corporation, 2010b) inhalation of decamethyltetrasiloxane at concentrations of 70 and 400 ppm were well tolerated. There were no clinical signs or treatment-related effects associated with exposure in the ophthalmologic endpoints, body weights, food consumption and rat neurobiological function. Certain changes in serum chemistry and haematology parameters, urinary volumes and organ weights (absolute and relative) may be treatment-related, but not toxicologically significant. The only treatment-related microscopic finding in Group 3 females was an increased incidence of alveolar macrophages, though not considered an adverse effect. Based on the results of this study the NOAEL for decamethyltetrasiloxane for systemic toxicity in male and female rats is at least 400 ppm.

Justification for classification or non-classification

Based on the available data, dodecamethylpentasiloxane (L5) does not require classification for specific target organ toxicity following repeated dose exposures according to Regulation (EC) No 1272/2008.