Registration Dossier

Administrative data

Description of key information

Based on the results of the key OECD 422 study, the NOAEC for 2,4,6,8-tetramethylcyclotetrasiloxane for systemic toxicity following inhaled administration in male and female rats is 100 ppm.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
50 mg/kg bw/day
Study duration:
subacute
Species:
rat

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEC
984 mg/m³
Study duration:
subacute
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 14-day range finder inhalation study, RCC Han rats (5 animals/sex/concentration) were exposed to

2, 4, 6, 8 -Tetramethylcyclotetrasiloxane at concentrations of 0, 100, 1000 and 4000 ppm for 14 consecutive days. There were no statistically significant differences in body weights and % of body weight gain. None of the macroscopic findings in males and females were statistically significant when compared to control values. One male animal in the high dose group was killed in extremis and there was one female spontaneous death in the high dose group. There were no statistically significant differences in absolute organ weights for males. The liver weight/body weight ratio (14% increased) and the kidney weight/brain weight ratios (18%) were statistically increased in males of the high dose group. In females, liver weight was statistically increased (33%) in the high dose group. Also in females, the liver weight/ body weight (37%) and liver weight/brain weight ratios were statistically increased (31%).

In the key 28-day inhalation study (Harlan, 2012) conducted to OECD 422 and to GLP, inhalation of 2, 4, 6, 8-Tetramethylcyclotetrasiloxane was not tolerated at the high dose concentration of 3000 ppm and resulted in the early death of three females and one male. After reduction of the high-dose level to 2000 ppm, two further females and a male were found dead.

Clinical laboratory investigations, necropsy and histopathology results all indicate that the urinary tract was a target organ for 2,4,6,8-tetramethylcyclotetrasiloxane. During macroscopic and microscopic examinations, stones/granular deposits in the urinary tract, injury, inflammation and dilation of urethra, urinary bladder, ureter or kidney were found in males and females which died before scheduled termination but also in most of the survivors at the dose level of 3000/2000 ppm and some males and females at the dose level of 1000 ppm. Changes in the urinary tract were still observed in both sexes at the high-dose level after the recovery period. In addition, in males and some females at the dose level of 3000/2000 ppm, higher kidney/body weight ratio was noted and increased blood concentration of urea was recorded in some males at the high-dose level. Uremia was considered to be a direct cause of the pre-term deaths or, alternatively, to cause heart failure and consequent deaths of males and females at the high-dose level. Impairment of the urinary tract observed in males and females at the dose levels of 3000/2000 and 1000 ppm was considered to be adverse.

In addition, the thyroid gland was also considered to be a target organ for the test item-related toxicity. Amorphous material in the colloid of the thyroid gland were observed in males of all treatment groups with dose dependency in its severity and incidence and was considered to have been caused by a metabolic change in the thyroid gland although this was considered not to be adverse.

Treatment with 2,4,6,8-tetramethylcyclotetrasiloxane also resulted in reductions in food consumption in males at all dose levels and in females at the dose level of 3000/2000 ppm and body weight gains and body weights at 3000/2000 ppm in both sexes.

Based on the results of this study the NOAEC for 2,4,6,8-tetramethylcyclotetrasiloxane for systemic toxicity following inhaled administration in male and female rats is 100 ppm.

There are no repeat dose toxicity studies for 2,4,6,8-tetramethylcyclotetrasiloxane for the oral or dermal route of exposure.

A 28 day repeat dose study is available for the read-across substance trimethoxy(methyl)silane. This substance hydrolyses rapidly to methylsilanetriol, which is also the proposed final hydrolysis product of 2,4,6,8-tetramethylcyclotetrasiloxane. This study is used as the starting point for the calculation of an oral DNEL for consumers. The hydrolysis product is relevant as exposure is via the environment, where hydrolysis would have occurred. A 90 day repeat dose study via the inhalation route is proposed by the Registrants.

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
A 28 day repeat dose study is available for the read-across substance trimethoxy(methyl)silane. This substance hydrolyses rapidly to methylsilanetriol, which is also the proposed final hydrolysis product of 2,4,6,8-tetramethylcyclotetrasiloxane. This study is used as the starting point for the calculation of an oral DNEL for consumers. The hydrolysis product is relevant as exposure is via the environment, where hydrolysis would have occurred.

Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:
The selected study is the only available repeated dose inhalation study for the registered substance. It was conducted in accordance with an appropriate OECD test guideline and in compliance with GLP.

Justification for selection of repeated dose toxicity inhalation - local effects endpoint:
The selected study is the only available repeated dose inhalation study for the registered substance. It was conducted in accordance with an appropriate OECD test guideline and in compliance with GLP.

Repeated dose toxicity: via oral route - systemic effects (target organ) cardiovascular / hematological: thymus; digestive: duodenum; digestive: jejunum; digestive: liver; glandular: adrenal gland; glandular: thyroids

Repeated dose toxicity: inhalation - systemic effects (target organ) urogenital: kidneys; urogenital: urinary bladder; urogenital: other

Justification for classification or non-classification

Based on the available inhalation data 2,4,6,8-tetramethylcyclotetrasiloxane is not classified for adverse effects following repeated inhaled exposures according to Regulation (EC) No 1272/2008.