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Administrative data

Description of key information

The key carcinogenicity study (RCC, 2005) is a two-year inhalation combined chronic toxicity and carcinogenicity study in rats conducted to an EPA guideline and to GLP, in which the NOAEC for general toxicity was ≥160 ppm (≥2420 mg/m3; the highest dose tested). Local effects on the nasal cavity and adaptive increases in liver weights (with no microscopic findings) were observed. The NOAEC for carcinogenic effects was ≥160 ppm (≥2420 mg/m3; the highest dose tested).

Key value for chemical safety assessment

Carcinogenicity: via oral route

Endpoint conclusion
Endpoint conclusion:
no study available

Carcinogenicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
carcinogenicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
01.12.1999 to 09.06.2005
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
test procedure in accordance with national standard methods
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.4300 (Combined Chronic Toxicity / Carcinogenicity)
GLP compliance:
yes
Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories Inc.
- Age at study initiation: Six weeks
- Weight at study initiation: Males: 92-130 g; Females: 80-112 g.
- Fasting period before study: No, but animals not fed during exposure
- Housing: Groups of up to five animals of same sex in Makrolon type IV cages
- Diet (e.g. ad libitum): Ad libitum
- Water (e.g. ad libitum): Ad libitum
- Acclimation period: Ten days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22± 3
- Humidity (%): 40-70
- Air changes (per hr):10-15
- Photoperiod (hrs dark / hrs light): 12/12


IN-LIFE DATES: From: 14.12.1999 To: 09.06.2005
Route of administration:
inhalation: vapour
Type of inhalation exposure (if applicable):
whole body
Vehicle:
other: filtered air
Details on exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Sealed chambers used for group isolation. Constructed from stainless steel, with glass doors. The chamber contained nine stainless steel wire cage units with excreta pan below each cage unit.
- Method of holding animals in test chamber: wire cage
- Source and rate of air: Compressed air (40 l/min) was supplied into the glass flasks and allowed the liquid to equilibrate with the temperature of the warm walls of the container. The vapour produced then passed through a pipe and was then mixed and diluted with 380 l/min of the filtered air to the chamber inlet duct. It passed through an ULTRA filter JK-S-19/30 filter before entering the exposure chamber. The temperature of the D5 vapour in the round flask was approx. 30oC in Group 2 (10 ppm), 50oC in Group 3 (40 ppm) and 80oC in Group 4 (160 ppm).


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:
The concentration in each chamber of the dose groups was determined daily, approximately five times per hour of exposure. Concentrations were determined by GC analysis.
Duration of treatment / exposure:
Sub-group A: interim sacrifice after 6 months; 26 weeks.
Sub-group B: interim sacrifice after 1 year; 52 weeks.
Sub-group C: sacrifice after 2 years, 1 year of exposure and 1 year of recovery.
Sub-group D: oncogenicity phase; up to 106 weeks.
Frequency of treatment:
Daily, 6 hours/day, 5 days/week
Post exposure period:
One year in Subgroup C
Dose / conc.:
0.15 mg/L air (nominal)
Remarks:
10 ppm (nominal)
Dose / conc.:
0.6 mg/L air (nominal)
Remarks:
40 ppm (nominal)
Dose / conc.:
2.42 mg/L air (nominal)
Remarks:
160 ppm (nominal)
No. of animals per sex per dose:
Subgroup A: 6; subgroup B: 10; subgroup C: 20; subgroup D: 60.
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: The highest exposure concentration is the highest vapour concentration that can be repetitively and reliably generated in whole-body exposure chambers for a study of this duration.
- Rationale for animal assignment (if not random): Random
- Rationale for selecting satellite groups: to investigate reversibility of adverse effects
- Post-exposure recovery period in satellite groups: one year
Positive control:
None
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Daily, as soon as possible following each exposure.
- Cage side observations for clinical signs of toxicity: behaviour, body position, respiration, nasal and ocular changes.


DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Twice during acclimitisation, weekly during weeks 2 to 14, then once every two weeks thereafter until the end of the study.


BODY WEIGHT: Yes
- Time schedule for examinations: During acclimitisation on day 1, 6 and on the day before the first exposure. The once weekly for the first 14 weeks. Thereafter the animals were weighed every four weeks until termination. In sub-groups C and D animals were weighed at the start of the week of terminal sacrifice. Animals were always weighed prior to daily exposure.


FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No


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:
- Dose groups that were examined: All animals in sub-group B, C and D before the start of exposure, and all surviving animals in control and highest dose groups of sub-group B, the last 10 animals/sex of sub-group C, and the first 10 animals/sex of sub-group D in control and highest dose groups prior to necropsy.


HAEMATOLOGY: Yes
- Time schedule for collection of blood: 3, 6, and 12 months of exposure
- Anaesthetic used for blood collection: Yes (ether)
- Animals fasted: Yes
- How many animals: First ten animals/sex/group from sub-group C
- Parameters checked in table 1 were examined.


CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: 3, 6, and 12 months of exposure
- Animals fasted: Yes
- How many animals: First ten animals/sex/group from sub-group C
- Parameters checked in table 1 were examined.


URINALYSIS: Yes
- Time schedule for collection of urine: 3, 6, and 12 months of exposure
- Metabolism cages used for collection of urine: Yes
- Animals fasted: Yes
- Parameters checked in table were examined.


NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes (see table 2)
HISTOPATHOLOGY: Yes (see table 2)

All animals that survived until sacrifice as well as all moribund animals were sacrificed. All macroscopic abnormalities were described and reported. All gross masses and clinically observed growths were confirmed at necropsy.

Subgroup A (6 month sacrifice): A portion of the liver was collected from all animals. A partial necropsy was performed on all animals in this group. Blood from cardiac puncture, peri-renal fat, abdominal fat and brown fat were also collected for determination of D5 concentration.
Subgroup B (sacrificed after one year): A portion of the liver was collected from all animals. Organ to body weight and organ to brain weight ratios were calculated. A complete necropsy was performed on all animals that died, were euthanised moribund or sacrificed at scheduled necropsy.
Subgroup C and D (sacrificed after 24 months): Organ to body weight and organ to brain weight ratios were calculated. A complete necropsy was performed on all animals that died, were euthanised moribund or sacrificed at scheduled necropsy.

Microscopic examinations were performed on control and highest dose group from sub-groups B, C and D. The lungs, liver, kidneys, nasal cavities and gross lesions and tissue masses were examined from all animals in groups 1, 2, 3 and 4 of sub-groups B, C and D.
Other examinations:
None
Statistics:
Analysis was two-tailed for significance levels of 5% and 1%. Generally, means are presented with standard deviations. Analysis of body weight, as well as organ weights and clinical pathology were analysed by a one way analysis of variance followed by comparison of control group to each treated group y Dunnett's test. The Steel test was applied instead of Dunnett's test if the data could not be assumed to follow a normal distribution. Fisher's Exact test was used to test for statistical significances between groups for the macroscopic and ophthalmoscopic data. Statistical analysis of histopathology data were recorded.
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):
not examined
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):
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
effects observed, treatment-related
Details on results:
See Section 7.5.3 for results relating to non-neoplastic findings.

A number of neoplastic lesions were diagnosed. Except for the uterus, the type, incidence and organ distribution of these neoplastic lesions were considered to be similar in both treated and control rats. The same was true for the number of primary neoplasms, the number of rats with primary neoplasms, the number of rats with more than one primary neoplasm, the number of rats with metastases, and the number of benign and malignant neoplasms per dose group and sex.

Uterus: A number of neoplastic findings were noted in the uterus. Except for endometrial adenocarcinoma, these findings did not distinguish exposed rats from controls. In sub-group C (1 year of exposure/1 year recovery) endometrial adenocarcinomas were noted in one rat of Group 1, one rat of Group 2 and two rats of Group 4. In sub-group D (2 years of exposure) endometrial adenocarcinomas were noted in one rat of Group 2 and five rats of Group 4, while none of these neoplasms was noted in Group 3 in either of these sub-groups.
In addition, endometrial adenoma was noted in one rat of Group 2 after 2 years of exposure (sub-group D). Adenomatous polyps were noted in one rat of each of groups 1 and 3 after 2 years of exposure (sub-group D), and in one rat of Group 4 after 1 year of exposure and 1 year of recovery (sub-group C).
In conclusion, the increased incidence of endometrial adenocarcimomas in the uterus of high dose rats after 2 years of exposure might be treatment-related, since there were no such neoplasms in the control rats of sub-group D. However, the relationship to exposure is unclear since these neoplasms occur occasionally also in control rats.
Relevance of carcinogenic effects / potential:
Due to the complexities surrounding the relevance of the observed uterine tumours to humans, a summary report has been prepared by the Silicone Industry that summarises current understanding of the scientific basis for disregarding these tumours when considering risk characterisation for humans. The summary is attached to the endpoint summary for carcinogenicity, and the conclusion from this summary was "that the tumorigenic effect of D5 in female rats exposed to very high concentrations for two years is related to a rodent- specific imbalance in the normal hormonal milieu that occurs in aging female Fischer 344 rats. These imbalances are common in rodents and are of no relevance to humans".
Key result
Dose descriptor:
NOAEC
Effect level:
>= 160 ppm
Sex:
male
Basis for effect level:
other: No toxicologically relevant adverse effects at any concentration tested. Excluding local effects in nasal cavity.
Remarks on result:
other:
Remarks:
Effect type: other: General toxicity and carcinogenicity (migrated information)
Key result
Dose descriptor:
NOAEC
Effect level:
>= 160 ppm
Based on:
test mat.
Sex:
female
Basis for effect level:
other: Based on uterine tumours following 24 months exposure to 160 ppm being not relevant to humans.
Remarks on result:
other: Effect type: carcinogenicity (migrated information)
Critical effects observed:
no
Conclusions:
In a two-year inhalation combined chronic toxicity and carcinogenicity study in rats conducted to an EPA guideline and to GLP (reliability score 1) the NOAEC for general toxicity was ≥160 ppm (2420 mg/m3; the highest dose tested). Local effects on the nasal cavity and adaptive increases in liver weights (with no microscopic findings) in females were observed at 160 ppm. The NOAEC for carcinogenic effects was 160 ppm (2420 mg/m3).
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEC
2 420 mg/m³
Study duration:
chronic
Species:
rat

Carcinogenicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Justification for classification or non-classification

On the basis of the current understanding of the data on the carcinogenic mechanism of action, D5 is not classified for carcinogenicity according to Regulation (EC) No. 1272/2008.

Additional information

The key inhalation chronic toxicity study (RCC Ltd, 2005) was conducted to EPA OPPTS 870.4300 (combined chronic toxicity/carcinogenicity), which is equivalent to OECD Test Guideline 453. Fischer 344 rats were exposed, whole body, to D5 vapour at nominal concentrations of 10, 40 or 160 ppm (150, 600 and 2420 mg/m3).The highest possible vapour concentration generated without appreciable aerosol or condensation was observed to be 160 ppm Exposures were 6 hours/day, 5 days/week. The animals were divided into 4 subgroups. Sub-group A (6 animals) was sacrificed after 6 months of treatment; subgroup B (10 animals) was sacrificed after 1 year; subgroup C (20 animals) was treated with D5 for 1 year and then allowed to recover for 1 year after which they were sacrificed; subgroup D (60 animals) was sacrificed after 2 years of treatment. The only systemic effect was increased liver weight without related histopathological findings; however, these were considered to be adaptive changes and are therefore not of toxicological relevance. The statistically significantly increased incidence of hyaline inclusions in the nasal respiratory/olfactory epithelium was noted in male and/or female rats of group 4 (160 ppm) sacrificed after 6, 12 and 24 months and are considered to represent a non-specific exposure-related effect. An increased incidence of hyaline inclusions was noted also in high dose males after the recovery period. It was not clear from this study whether or not this increase was related to the exposure. Histomorphologic changes in the nasal cavity were consistent with chronic inhalation of some mildly irritant chemicals but are also commonly observed in ageing rats. Since there were no other changes associated with a response to an irritant, such as an inflammatory cell infiltration or degenerative changes to the epithelium, the finding was considered to be non-specific and of low toxicological importance. The NOAEC for general systemic effects was ≥160 ppm (≥2420 mg/m3) and the NOAEC for local effects based on respiratory tract irritation was 40 ppm (600 mg/m3).

The incidence of endometrial adenocarcinoma in subgroup D was 0, 1, 0, and 5 for female rats in the 0, 10, 40, and 160 ppm exposure groups, respectively. One female rat in the 0 and one female in the 40-ppm exposure groups, respectively, were diagnosed with endometrial adenomatous polyps. The combined tumour incidence for female rats in subgroup D was, therefore, 1, 2, 1, and 5 in the 0, 10, 40, and 160 ppm exposure groups, respectively. These data suggest an apparent increase in uterine endometrial adenocarcinomas at a D5 exposure concentration of 160 ppm for two years. There was no evidence of carcinogenic effects in male animals.

Discussion on Carcinogenicity of D5

 

In the two-year chronic vapour inhalation study with D5 in F344 rats, there were no toxicologically relevant changes in body weight, appearance, or behaviour suggestive of systemic toxicity (RCC, 2005). A reversible increase in liver weight has been reported following D5 vapour inhalation exposure of rats in sub-chronic toxicity studies (Burns-Naas et al., 1998a, 1998b; McKim et al., 1999). Hepatocellular hyperplasia and centrilobular hypertrophy were demonstrated after the first week of vapour inhalation exposure of female F344 rats to D5 but these effects proved transient in that they were not present after 2 or 4 weeks of exposure (Jean, 2005).

 

D5 has also been shown to be a functional ligand for CAR and PXR in an in vitro reporter gene assay (Jean et al., 2006; Dow Corning Corporation, 2005a, 2005b) and, consistent with this property, to induce hepatic CYP 2B1/2 and CYP3A1 in vivo (McKim et al., 1999; Zhang et al., 2000). In total these effects likely represent an adaptive response purposed with increasing hepatic metabolic capacity in an effort to metabolise and remove D5. The phenobarbital-like liver effect of D5 pointed to a potential for chronic exposure to yield liver tumours in the rodent study (Jean, 2016). However, exposure to D5 vapour for 6, 12, and 24 months was without notable effects on liver weight or histomorphology. There were no preneoplastic or neoplastic changes in the liver of D5 exposed rats at any of the time points. Such an outcome provides strong support for the assertion that the hepatic responses observed in the shorter-term studies were representative of adaptive responses.

 

There was a modest response to D5 vapour exposure within the upper respiratory tract. Hyaline inclusions, though present in the control group and demonstrating an increased incidence with age, occurred at a higher incidence in the 160 ppm exposure levels at each of the time points including the recovery group animals. Hyaline inclusions (also referred to as eosinophilic globules, eosinophilic droplets, and epithelial hyalinosis) in the nasal cavities are characterized as an “accumulation of brightly eosinophilic cytoplasmic inclusions in sustentacular cells of olfactory epithelium, respiratory epithelial cells, and epithelial cells of the nasal seromucous glands” (Renne et al., 2009), are believed to be proteinaceous in nature. The inclusions are commonly observed in laboratory animal studies involving inhalation exposure; however, they are not exclusive to this exposure route. The mechanism(s) involved in their emergence and persistence is not understood. Though they are often observed following inhalation exposure to noxious substances causing various degrees of nasal tissue injury, it is yet uncertain if they represent a non-specific adaptive response, a specific response to tissue injury, or an adverse effect in and of itself. The clear lack of nasal tissue injury (degeneration, necrosis, inflammatory infiltrate, dysplasia, and/or neoplasia) following repeated inhalation exposure to D5 vapour for 6-24 months suggests that their emergence in response to D5 represents an adaptive response.

 

D5 exposure was associated with a modest and borderline but statistically significant increased incidence of uterine endometrial adenocarcinoma in F344 rats at 160 ppm, the highest exposure level (Young and Morfeld, 2015). There was no effect on uterine weight or increased incidence of precursor lesions such as focal glandular hyperplasia. It has been reported that the incidence of spontaneous uterine adenocarcinoma in the F344 rat increases substantially with increasing age, especially ages beyond 24 months (Nyska et al., 1994). The incidence of spontaneous adenocarcinoma in the rat appears to vary markedly among strain and sub-strain and appears to reflect exposure to ovarian estrogens without sufficient anti-proliferative exposure to progesterone (Nagaoka et al., 1990).

 

The tumours in D5-exposed animals were advanced, raising the possibility that precursor lesions were obliterated by the spreading tumours. Klaunig et al., (2016) demonstrated that the endometrial adenocarcinoma findings are most likely consistent with an increase in the time in estrus (due to cycle alteration) during the first year of treatment, with development of endometrial adenocarcinoma and progression over the second year of treatment (Group D) or recovery (Group C). Although there was no reported increase in focal glandular hyperplasia following D5 exposure for 24 months, at least one tumour in the 160 ppm D5 treated group was reported to have glandular hyperplasia associated with the tumour. Possible explanations for the lack of associated precursor lesions include focal precursor lesions that were lost as a consequence of sectioning or onset of low-grade adenocarcinoma months prior to the development of persistent diestrus/pseudopregnancy, a state during which precursor lesions may have regressed. The latter explanation is supported by the observation from studies in aging F344 rats (Dekant and Klaunig, 2015) that D5 treatment was associated with an increase in estrogen exposure during the first few months of treatment but not thereafter. Another possibility is that presence of focal glandular hyperplasia as a precursor lesion is lost as the tumours have progressed to such an advanced stage that the tumour is now the predominant lesion. The adenocarcinomas by this time may have achieved hormone independence, preventing their regression in response to progesterone dominance.

 

D5 has been evaluated in a number of studies that cover a wide range of biological and toxicological end points. D5 is without significant estrogenic/androgenic/progestogenic potential, and it has not demonstrated mutagenic or genotoxic potential. Therefore, direct effects on the endometrium by D5 or a genotoxic mechanism of endometrial carcinogenesis appear unlikely modes of action to explain the observed increase in endometrial adenocarcinoma.

 

In summary, the respiratory tract effects seen in the chronic inhalation study with D5 can be considered as a non-specific response of the respiratory tract to repeated inhalation exposures to a mildly irritating agent.

 

The liver weight increases observed in several toxicity studies with D5 of shorter duration, but not in the two-year chronic study at termination, were not accompanied by histological changes in the liver. These observations suggest that the liver weight increases represent adaptive responses and are not adverse.

 

Mechanistic studies confirm that D5 is a weak “phenobarbital-like” inducer of cytochromes P450 in the rat. The “phenobarbital-like” enzyme induction pattern explains the small changes in liver weights seen in the inhalation studies.

 

D5 inhalation caused a small, but (borderline) statistically significant increase in the incidence of uterine adenocarcinoma in F344 rats at the highest exposure concentration of 160 ppm. General descriptive toxicity testing (acute, sub-acute and sub-chronic) performed prior to the conduct of the chronic study provided no indication that the uterus was a potential target organ. This included a demonstrated lack of mutagenicity/genotoxicity. The target organ and tumour type specificity (adenocarcinoma is a common spontaneous tumour in the aged F344 rat) may suggest the effect is associated with a treatment related alteration in pituitary control of the estrous cycle (Klaunig et al., 2015).

 

Recently, several additional studies (Klaunig et al., 2015; Dekant and Klaunig, 2015; Klaunig et al., 2016) have been performed to further investigate the mode of action by which endometrial adenocarcinomas may be produced by D5. In summary, taken as a whole, the mode of action data of D5 indicates that it is acting possibly via a dopamine receptor agonist-like mechanism to alter the pituitary control of the estrous cycle. Like dopamine receptor agonists, pharmacology studies show that D5 decreases pituitary lactotroph release of prolactin in vitro and decreases circulating prolactin levels in vivo in specific animal models designed to optimize the release of prolactin, an effect that can be competed for by a dopamine receptor agonist. Further studies in vitro confirmed the effect but suggest it may be an effect on one or more downstream components of the dopamine signal transduction pathway. Studies in aged animals show that the effects of D5 on estrous cyclicity are consistent with a dopamine-like effect and further suggest that D5 might be accelerating the aging of the reproductive endocrine axis in this strain of rat. These results are consistent with a mode of action for uterine endometrial adenocarcinoma tumorigenesis that is not relevant for humans.

 

References:

Burns-Naas, L.A., Mast, R.W., Klykken, P.C., McCay, J.A., White, K.L., Mann, P.C., Naas, D.J., 1998a. Toxicology and humoral immunity assessment of decamethylcyclopenta-siloxane (D5) following a 1-Month whole body inhalation exposure in fischer 344 rats. Toxicol. Sci. 43, 28e38.

Burns-Naas, L.A., Mast, R.W., Meeks, R.G., Mann, P.C., Thevenaz, P., 1998b. Inhalation toxicology of decamethylcyclopentasiloxane (D5) following a 3-month noseonly exposure in fischer 344 rats. Toxicol. Sci. 43, 230e243.

Dekant, W., Klaunig, J.E., Toxicology of decamenthylcyclopentasiloxane (D5), 2016.Regul Toxicol Pharmacol. 2016 Feb;74 Suppl:S67-76. doi: 10.1016/j.yrtph.2015.06.011. Epub 2015 Jun 22.

Dow Corning Corporation, 2005a. Non-regulated Study: Assessment of Cyclic Siloxane Activation of the Constitutive Androstane Receptor Study. Report Number: 2005-I0000-55386.

Dow Corning Corporation, 2005b. Non-regulated Study: Assessment of Cyclic Siloxanes in anin VitroPregnane X Receptor (PXR) Reporter Gene Assay Study. Report Number: 2005-I0000-55384.

Jean A, Plotzke K.P., Anthony R. Scialli, A.R., 2016. Chronic toxicity and oncogenicity of decamethylcyclopentasiloxane in the Fischer 344 Rat. Regulatory Toxicology and Pharmacology 74 (2016) S57eS66.

Jean, P.A., Arthurton, J.A., You, L., Plotzke, K.P., 2006. Activation of pregnane x receptor (PXR) and constitutive androstane receptor (CAR) by octamethylcyclotetrasiloxane (D4) and decamethylcyclopentasiloxane (D5).VitroToxicol. 90 (1). ABS#1827.

Jean, P.A., 2005. Non-regulated Study: Effects of Decamethylcyclopentasiloxane (D5) on Cell Proliferation in the Liver of Female Fischer 344 Rats: a 28-day Inhalation Study Report on D5 Hypertrophy/hyperplasia. USEPA-OPPT, TSCA Document Processing Center, Washington, D.C., Document Control Number: FYI-0305e01491A.

Klaunig, J.E., Dekant, W., Plotzke, K., Scialli, A.R., Biological relevance of decamethylcyclopentasiloxane (D5): analysis of the potential mode of action of decamethylcyclopentasiloxane induced uterine tumorigenicity, 2015.

McKim Jr., J.M., Choudhuri, S., Wilga, P.C., Madan, A., Burns-Naas, L.A., Gallavan, R.H., Mast, R.W., Naas, D.J., Parkinson, A., Meeks, R.G., 1999. Induction of hepatic metabolizing enzymes in female fischer-344 rats following repeated inhalation exposure to decamethylcyclpentasiloxane (D5). Toxicol. Sci. 50, 10e19.

Nagaoka, T., Onodera, H., Matsushima, Y., Todate, A., Shibutani, M., Ogasawara, H., Maekawa, A., 1990. Spontaneous uterine adenocarcinomas in aged rats and their relation to endocrine imbalance. J. Cancer Res. Clin. Oncol. 116 (6), 623e628.

Nyska, A., Klein, T., Scolnik, M., Waner, T., Klein, B., 1994. Unusually high incidence of spontaneous endometrial adenocarcinoma in aged virgin Fischer rats. Exp. Toxicol. Pathol. 46, 7e9.

Renne, R., Brix, A., Harkema, J., Herbert, R., Kittel, B., Lewis, D., March, T., Nagano, K., Pino, M., Rittinghausen, S., Rosenbruch, M., Tellier, P., Wohrmann, T., 2009. Proliferative and nonproliferative lesions of the rat and mouse respiratory tract. Toxicol. Pathol. 37 (7), 5Se73S.

Young, L.J., Morfeld, P., Statistical considerations for a chronic toxicity study: exposure to decamethylcyclopentasiloxane (D5) and incidence of endometrial adenocarcinomas in a 2-Year inhalation study with fischer rats, 2015.

Zhang, J., Falany, J.L., Xie, X., Falany, C.N., 2000. Induction of rat hepatic drug metabolizing enzymes by dimethylcyclosiloxanes. Chemico-Biological Interact. 124, 133e147.