Registration Dossier

Administrative data

Description of key information

In a key 28-day oral gavage study conducted to OECD 407 and to GLP (Dow Corning Corporation, 2010a) the NOAEL for L4 was 25 mg/kg bw/day based on significantly elevated mean absolute liver weights, mean liver-to-body weight ratios and mean liver-to-brain weight ratios in males and females treated with 250 mg/kg bw/day and 1000 mg/kg bw/day (p<0.05 or p<0.01) and brown pigment accumulation which was considered to be an adverse finding, due to secondary periportal chronic inflammation and bile duct proliferation

In the key 90-day inhalation study (Dow Corning Corporation, 2010b) conducted to OECD 413 and to GLP, inhalation of L4 at concentrations of 70 and 400 ppm did not result in any effects attributable to treatment. The NOAEC was therefore considered to be at least 400 ppm, the highest concentration tested.

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:
18.03.2009 to 03.08.2010
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity in Rodents)
Qualifier:
according to
Guideline:
EU Method B.7 (Repeated Dose (28 Days) Toxicity (Oral))
Qualifier:
according to
Guideline:
other: Japanese Guidelines 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:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Harlan Laboratories, B.V.
- Age at study initiation: Approximately seven weeks.
- Weight at study initiation: Males: 222-239 g; Females: 163-188 g.
- Fasting period before study: No data
- Housing: Groups of five in Makrolon type-4 cages.
- Diet (e.g. ad libitum): Ad libitum
- Water (e.g. ad libitum): Ad libitum
- Acclimation period: Eight days

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

IN-LIFE DATES: From: 19.03.2009 To: 07.05.2009
Route of administration:
oral: gavage
Vehicle:
corn oil
Remarks:
dried and deacidified
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS: Formulations were prepared weekly. Decamethyltetrasiloxane (L4) was weighed into a glass beaker on a balance. Thereafter the remaining vehicle was added. The mixtures were stirred using a magnetic stirrer and stored at room temperature. Homogeneity of the test substance in the vehicle was maintained during the daily administration period using a magnetic stirrer.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
After experimental start, samples of the control group as well as three samples of about 2g of each concentration were taken prior to dosing for analysis of homogeneity, concentration and stability. Samples of about 2g of each concentration were taken during week 3 after commencement of dosing to confirm homogeneity and concentration. Analysis was determined by gas chromatography coupled to a flame ionisation detector and quantified with the area under the peak.
Duration of treatment / exposure:
28 days
Frequency of treatment:
Daily (seven days/week)
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:
Five (additional five animals in control and 1000 mg/kg bw/day groups)
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: Based on dose range-finding study.
- Rationale for selecting satellite groups: To investigate reversibility of any adverse effects observed.
- Post-exposure recovery period in satellite groups: yes, 14 days.
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Observations for viability and mortality were recorded twice daily. The animals were observed for clinical signs once before commencement of administration as well as twice daily on days 1 to 3, once daily on days 4 to 28 (treatment period), and once daily during 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. These observations were performed once before commencement of administration and once weekly (weeks 1 to 3) thereafter.

BODY WEIGHT: Yes
- Time schedule for examinations: Body weights were recorded weekly during the acclimatization, treatment and recovery periods and before necropsy.

FOOD CONSUMPTION: Food consumption was recorded once during the acclimatization period and weekly thereafter.

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 AND COMPOUND INTAKE (if drinking water study): No

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: After 4 weeks in main and recovery groups. After 6 weeks in recovery group.
- Anaesthetic used for blood collection: Yes, isoflurane.
- Animals fasted: Yes, for 18 hours
- How many animals: All animals
- Parameters checked in table No.1 were examined.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: After 4 weeks in main and recovery groups. After 6 weeks in recovery group.
- Animals fasted: Yes
- How many animals: All animals
- Parameters checked in table No.1 were examined.

URINALYSIS: Yes
- Time schedule for collection of urine: During 18 hours fasting period.
- Metabolism cages used for collection of urine: Yes
- Animals fasted: Yes
- Parameters checked in table No.1 were examined.

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: The animals were observed in their home cages, outside their home cages in a standard arena and in the hand. These observations were performed once before commencement of administration and once weekly (weeks 1 to 3) thereafter.
- Dose groups that were examined: All
- Battery of functions tested: appearance, behaviour, respiration, reflexes, motor activity.

Functional Observation Battery (FOB): During week 4, relevant parameters from a modified Irwin screen test were evaluated in all animals.

Vaginal smear for estrus stage: A vaginal smear was taken from all females during the last week of treatment and the stage of estrus was evaluated.
Sacrifice and pathology:
Sacrifice after 4 weeks for the main group. Sacrifice after 6 weeks for the recovery group.

GROSS PATHOLOGY: Yes (see table 2)
HISTOPATHOLOGY: Yes (see table 2)
Statistics:
The following statistical methods were used to analyse body weight, grip strength, locomotor activity, clinical laboratory data, organ weights and ratios as well as macroscopic findings: 1) The Dunnett-test (many to one t-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
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:
no effects observed
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
no effects observed
Behaviour (functional findings):
no effects observed
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
not examined
Details on results:
CLINICAL SIGNS AND MORTALITY: There were no deaths and no general clinical signs associated with the test substance. In females, slight chromodacryorrhea was evident in one female during weeks 1, 2 and 3 of treatment.

BODY WEIGHT AND WEIGHT GAIN: No treatment-related changes in body weights or body weight gains were noted after the treatment period or at the end of the recovery period. Marginally higher body weight noted in males at 1000 mg/kg bw/day were not significantly higher than those of the controls and considered to be within the range of typical variation. On Day 8 of treatment, the mean body weight gain of the males treated with 1000 mg/kg bw/day was significantly elevated (p<0.05) when compared with the controls.
FOOD CONSUMPTION: No effects.

FOOD EFFICIENCY: No effects.

HAEMATOLOGY: After four weeks of treatment, no test substance-related differences were noted in males or females. At 1000 mg/kg bw/day, significantly lower hemoglobin and hematocrit were noted in males only. The respective platelet counts in males and females were significantly elevated when compared with the controls, yet remained distinctly lower than the mean platelet count of the historical control values. Therefore, these differences were considered to be incidental. The mean activated thromboplastin time in females was significantly lower when compared with controls, but this difference was not evident in males.

At 250 mg/kg bw/day, the red cell count, hemoglobin and hematocrit vlaues of males were all significantly lower than those of the controls, whereas females were unaffected. The red cell distribution width was significantly lower in males but this finding was not dose related and therefore considered to be unrelated to the test item. The mean absolute reticulocyte count was lower in females and in males but only in females did the difference attain statistical significance. The mean relative number of 'large unstained cells' was significantly lower in females when compared with controls.

At 25 mg/kg bw/day significant reductions in the men relative basophil and the mean absolute monocyte counts in males and females, respectively, were significantly lower when compared with their respective control values. These differences were not dose-related.

By the end of the two week recovery period, none of the minor differences noted in the 1000 mg/kg bw/day group were considered to be late effects of the treatment. In males and females, the mean cell volume was significantly lower than the respective controls. In females, the mean cell hemoglobin was also significantly reduced. There was a significant reduction in the mean number of high fluorescence reticulocytes of females but not in males.

CLINICAL CHEMISTRY: After four weeks of treatment, a number of statistically significant and toxicologically relevant changes were noted. Significantly elevated blood glucose levels were noted in males and females treated with 25 mg/kg bw/day (p<0.05), males treated with 250 mg/kg bw/day (p<0.01), and in males and females treated with 1000 mg/kg bw/day (both p<0.01). Significantly reduced mean total bilirubin levels were noted in both sexes at 25 mg/kg bw/day (p<0.05), both sexes at 250 mg/kg bw/day (p<0.01) and both sexes at 1000 mg/kg bw/day (p<0.01).

The mean urea level was significantly elevated in males treated with 1000 mg/kg bw/day (p<0.05). The mean cholesterol level was significantly elevated in females treated with 1000 mg/kg bw/day (p<0.01) when compared with controls. Males at this dose level were unaffected.

Aspartate aminotransferase activity was significantly lower in females at 25 mg/kg bw/day (p<0.01), both sexes at 250 mg/kg bw/day (p<0.05 in males and p<0.01 females), and in females at 1000 mg/kg bw/day (p<0.01) when compared with controls. Alkaline phosphatase activity was also significantly reduced in females at 250 mg/kg bw/day (p<0.05) and 1000 mg/kg bw/day (p<0.01).

Lactate dehydrogenase activity was significantly lower in males and females treated with 1000 mg/kg bw/day (both p<0.05). Lower creatine kinase levels were statistically significant in females treated with 25 mg/kg bw/day (p<0.05) and 1000 mg/kg bw/day (p<0.01). Reductions of these parameters are generally not associated with systemic toxicity.

Females treated with 1000 mg/kg bw/day also showed a dose-related, statistically significant increase in phospholipid levels (p<0.01) when compared with controls. Increased gamma glutamyltransferase activity was significantly elevated (p<0.01) in females treated with 1000 mg/kg bw/day, and as all but one female showed elevated values for this parameter, it was considered to be test substance-related.

There were also changes in electrolyte and transport proteins. At 1000 mg/kg bw/day, potassium and chloride were significantly elevated (both p<0.01) and phosphorus was reduced (p<0.01) in males. In females, sodium was significantly elevated (p<0.05) and phosphorus was reduced (p<0.01). The pattern of change in albumin and globulin levels were generally similar in both sexes. At 250 and 1000 mg/kg bw/day, albumin values were significantly reduced in males (p<0.01 at both dose levels) and females (p<0.05 and p<0.01, respectively). However, only the resulting changes in total proteins of females attained statistical significance (p<0.05 and p<0.01, respectively), and the resulting albumin/globulin ratios of both sexes were significantly reduced (p<0.01).

After the recovery period, phosphorus levels remained significantly lower (p<0.05) in males previously treated with 1000 mg/kg bw/day. In females, significantly reduced total bilirubin (p<0.05) and significantly reduced bile acids (p<0.05) were noted, although the latter difference was due to a markedly higher control value rather than a reduction in the value recorded in the females that were treated. The mean aspartate aminotransferase activity of the females was significantly reduced (p<0.05) when compared with the controls, and the calcium level was also significantly reduced (p<0.01) when compared with the controls. The different values were either unchanged after the end of the treatment period, due to outlying values or contrary to changes generally not associated with systemic toxicity.

URINALYSIS: No adverse findings.

ORGAN WEIGHTS: After four weeks treatment, test substance-related changes included significantly elevated mean absolute liver weights, mean liver-to-body weight ratios and mean liver-to-brain weight ratios in males and females treated with 250 mg/kg bw/day and 1000 mg/kg bw/day (p<0.05 or p<0.01). At 250 mg/kg bw/day, the differences in mean absolute liver weights were 32.3% and 32.8%, respectively, for males and females. At 1000 mg/kg bw/day, the differences were 23.3% and 60.7% for males and females, respectively.

Although these changes were considered to be largely adaptive in nature, they were not completely reversible after the recovery period in the remaining treated females. Significantly elevated mean absolute liver weights, mean liver-to-body weight ratios and mean liver-to-brain weight ratios (all p<0.01) persisted after two weeks recovery when compared with the controls.

After two weeks recovery, males had significantly elevated mean absolute and relative thyroid weights (all p<0.05) that were not evident after the treatment period. However, in the absence of microscopic findings these were considered not be late effects. In females, a significantly elevated mean kidney-to-brain weight ratio was noted that was not observed after the treatment period.

No difference in organ weights were noted at 25 mg/kg bw/day after the end of the treatment period or in the remaining animals after the recovery period.

GROSS PATHOLOGY: Treatment-related macroscopic findings included accentuated lobular pattern on the liver in both males and females treated with 250 and 1000 mg/kg bw/day at the end of the treatment period. All other findings were within the range of normal background lesions that may be recorded in animals of this strain and age.

HISTOPATHOLOGY: In the liver, minimal to slight brown pigment accumulation in the intrahepatic bile duct in males treated with 250 and 1000 mg/kg bw/day was observed. These pigments were brownish in haematoxylin and eosin stain and negative for bile pigment in the Hall stain. Bile duct proliferation as well as periportal chronic inflammation at minimal to slight severity was recorded in males treated with 1000 mg/kg bw/day.

Hepatocellular hypertrophy was recorded at minimal severity in three males treated with 1000 mg/kg bw/dat at the end of the treatment period. Incidence and severity of periportal fatty change in the liver was increased (the severity was dose-related, but not statistically significant) in females treated with 25, 250 and 1000 mg/kg bw/day.

In the thyroid, follicular cell hypertrophy at minimal severity was recorded in a single male treated with 1000 mg/kg bw/day.

The remaining findings were within the range of normal background lesions.

IMMUNOHISTOCHEMICAL STAINING: Findings in the kidney sections subjected to immunohistochemical staining for alpha-2u-globulin indicated a test substance-related accumulation of alpha-2u-globulin in male rats from the 1000 mg/kg bw/day group compared to rats from the concurrent control groups.

THYROID HORMONE ANALYSIS: In the absence of any morphological findings that would support a possible effect upon T3, T4 and TSH, these analyses were omitted.

FOB: There were no significant test substance-related changes.

LOCOMOTOR ACTIVITY: Slight increased values were noted during the early stages of the locomotor activity in males and females treated with 1000 mg/kg bw/day when compared with the controls, and was considered to be a slight test substance-related effect. Significant elevated mean locomotor activity was noted in males treated with 1000 mg/kg bw/day from 10-20 minutes (p<0.01), from 20-30 minutes (p<0.05) and from 0-60 minutes (p<0.01). The remaining measurement intervals of these males and the males treated with 25 mg/kg bw/day and 250 mg/kg bw/day compared favourably with those of the control males. The mean locomotor activity of the females treated with 1000 mg/kg bw/day was significantly elevated during 0-10 minutes (p<0.05), when compared with the control females.

VAGINAL SMEAR FOR ESTRUS STAGE: The number of estrus cycles did not show test substance-related differences.
Key result
Dose descriptor:
NOAEL
Effect level:
25 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
organ weights and organ / body weight ratios
other: brown pigment accumulation was considered to be an adverse finding, due to secondary periportal chronic inflammation and bile duct proliferation
Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
25 mg/kg bw/day (actual dose received)
System:
hepatobiliary
Organ:
bile duct
liver
Treatment related:
yes
Dose response relationship:
yes
Relevant for humans:
yes

Table 1 Hepatic findings at terminal sacrifice

Findings/incidence/mean severity grade  Group 1    (0 mg/kg bw/d)  Group 2    (25 mg/kg bw/d)  Group 3   (250 mg/kg bw/d)  Group 4   (1000 mg/kg bw/d)
   5 M  5 F  5 M  5 F  5 M  5 F  5 M  5 F
Brown pigment accumulation #  -  -  -  1/1.0  -  5/1.8*  -
 Bile duct proliferation #  -  -  -  -  -  -  5/1.4*  -
 Periportal chronic inflammation #  -  -  -  -  -  -  5/1.4*  -
 Hepatocellular hypertrophy #  -  -  -  -  -  -  3/1.0  -
 Fatty change: perilobular  -  3/1.0  -  5/1.2  5/1.8  1/1.0  5/2.8

*: p<0.01 by one-sided exact Fischer Test

#: p<0.01 by Armitage/Cochran Trend Test

Table 2 Hepatic findings at the end of the recovery period

 Findings/incidence/mean severity grade  Group 1     Group 4   
   5 M  5 F  5 M  5 F
Brown pigment accumulation  -  -  5/1.4*  -
 Bile duct proliferation  -  -  2/1.0  -
 Periportal chronic inflammation  -  -  5/1.2*  -
 Hepatocellular hypertrophy  -  -  -
 Fatty change: perilobular  -  2/1.0  -  4/1.5

*: p<0.01 by One-sided Exact Fischer Test

#: p<0.01 by Armitage/Cochran Trend Test

Conclusions:
In a 28-day oral gavage study conducted to OECD 407 and to GLP (reliability score 1) the NOAEL for decamethyltetrasiloxane was 25 mg/kg bw/day based on significantly elevated mean absolute liver weights, mean liver-to-body weight ratios and mean liver-to-brain weight ratios in males and females treated with 250 mg/kg bw/day and 1000 mg/kg bw/day (p<0.05 or p<0.01). In addition, brown pigment accumulation, observed after four weeks of treatment in five males at 1000 mg/kg bw/day and one male at 250 mg/kg bw/day, was considered to be an adverse finding, due to secondary periportal chronic inflammation and bile duct proliferation in five males at 1000 mg/kg bw/day. In females at 1000, 250 and 25 mg/kg bw/day, periportal fatty change was not accompanied by degeneration or inflammation and was considered to be non-adverse. After the recovery period, the severity of perilobular fatty change was reduced in the females previously treated at 1000 mg/kg bw/day.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
25 mg/kg bw/day
Study duration:
subacute
Species:
rat
System:
hepatobiliary
Organ:
liver

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:
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 and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Inc.
- 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 (%): 41-62
- 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 J0tubes 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 air changes of chamber volume 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.
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.
- 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 reveived 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 / No / No data
- 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 gorup).
- 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, FOB and motor activity, mean haematology and clinical chemistry values, urinalysis values and histopathology data were evaluated.
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:
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Behaviour (functional findings):
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
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: 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. There were no other deaths. There were no statistically significant clinical observations noted between control and treated groups.

BODY WEIGHT AND WEIGHT GAIN: 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: 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.

OPHTHALMOSCOPIC EXAMINATION: No adverse effects.

CLINICAL CHEMISTRY: 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.

HAEMATOLOGY: 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.

URINALYSIS: 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.

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.

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.

NEUROBEHAVIOUR: There were no statistically significant or biologically relevant findings.

ORGAN WEIGHTS: 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 PATHOLOGY: 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.

HISTOPATHOLOGY: 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.
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

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:
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 and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Inc.
- 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 (%): 41-62
- 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 J0tubes 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 air changes of chamber volume 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.
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.
- 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 reveived 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 / No / No data
- 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 gorup).
- 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, FOB and motor activity, mean haematology and clinical chemistry values, urinalysis values and histopathology data were evaluated.
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:
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Behaviour (functional findings):
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
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: 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. There were no other deaths. There were no statistically significant clinical observations noted between control and treated groups.

BODY WEIGHT AND WEIGHT GAIN: 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: 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.

OPHTHALMOSCOPIC EXAMINATION: No adverse effects.

CLINICAL CHEMISTRY: 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.

HAEMATOLOGY: 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.

URINALYSIS: 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.

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.

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.

NEUROBEHAVIOUR: There were no statistically significant or biologically relevant findings.

ORGAN WEIGHTS: 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 PATHOLOGY: 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.

HISTOPATHOLOGY: 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.
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: 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

There is one reliable key oral study and three supporting oral repeated dose toxicity studies for L4. The supporting studies are all of reliability score 4 because they do not meet current guideline requirements for repeated dose toxicity testing. One of the studies was a 7-day range-finding study that did not show any effects. The other two studies were longer duration dietary studies for which the level of reporting was poor. No adverse effects were observed in the dietary studies, but it is not clear whether the bioavailability of the substance was compromised by insufficient dietary lipids, which are required for micellar solubilisation and subsequent absorption of this very lipophilic substance.

In a 28-day oral gavage study conducted to OECD 407 and to GLP (Dow Corning Corporation, 2010a) the NOAEL for L4 was 25 mg/kg bw/day in males and females based on significantly elevated mean absolute liver weights, mean liver-to-body weight ratios and mean liver-to-brain weight ratios in males and females treated with 250 mg/kg bw/day and 1000 mg/kg bw/day (p<0.05 or p<0.01). In addition, some hepatic brown pigment accumulation in the bile duct was observed after four weeks of treatment in five males at 1000 mg/kg bw/day and one male at 250 mg/kg bw/day. Under polarised light some pigment accumulations show birefringence, but this finding was not consistent in size or between animals. Pigment accumulation was considered to be an adverse finding due to the secondary periportal chronic inflammation and bile duct proliferation observed in five males at 1000 mg/kg bw/day. In females at 1000, 250 and 25 mg/kg bw/day, periportal fatty change was not accompanied by degeneration or inflammation and was considered to be non-adverse. After the recovery period, the severity of perilobular fatty change was reduced in the females previously treated at 1000 mg/kg bw/day.

There are three good quality inhalation studies. The longest duration study was selected as the key study. The results from the key study and the inhalation OECD 422 screening study suggest that L4 does not cause any toxicologically significant adverse effects via this route of exposure.

In a 90-day inhalation study (Dow Corning Corporation, 2010b) conducted to OECD 413 and to GLP, inhalation of L4 at concentrations of 70 and 400 ppm was 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 NOAEC for L4 for systemic toxicity in male and female rats is at least 400 ppm. In the rat uterotrophic assay (Dow Corning Corporation, 2006b) a very weak estrogenic response in the luminal epithelial cells only was noted.

There are no repeated dose toxicity studies for the dermal route of exposure.



Justification for classification or non-classification

Based on the available oral and inhalation data L4 does not require classification for adverse effects for repeat dose toxicity according to Regulation (EC) No 1272/2008.