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Description of key information

The key repeated dose toxicity study was a 90-day inhalation study conducted in male and female rats, largely according to OECD 413 and with GLP compliance. The study identified a NOAEC value of 150 ppm (1.4 mg/l) in male and female rats. Overt toxicity and body weight effects were evident at 601 ppm (5.5 mg/l) which was identified as the LOAEC.

Key value for chemical safety assessment

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEC
1 365 mg/m³
Study duration:
subchronic
Species:
rat

Additional information

A number of repeated-dose inhalation exposure studies and two repeated-dose oral toxicity studies were conducted with D3. The oral studies, although not conducted according to an OECD guideline, were designed to investigate whether D3 increases liver weight similar to other oligomeric cyclosiloxanes. Test article-related increases in liver weights were seen in the male rats as low as 100 mg/kg-bw/day and in female rats at dose levels of 400 mg/kg-bw/day and above in the 14 -day study. In the 28 -day study, which was performed at a single dose level of 1500 mg/kg/day, increased liver weights were observed in both males and females.

In a combined repeated-dose/reproductive/developmental toxicity study conducted according to OECD TG 422 (DCC, 2002), Sprague-Dawley rats were exposed to D3 vapor via inhalation at 100, 500 or 2500 ppm (approximately 0.61, 4.5 or 22.8 mg/L) for up to 29 days for 6 hrs/day, 7 days/week. Decreased body weight gains and food consumption, increased liver weights and incidence of centrilobular hepatocellular hypertrophy (both sexes), increased kidney weights and decreased seminal vesicle weight (with an increased incidence of atrophy) in males were seen at 2500 ppm (22.8 mg/L). Males showed protein droplet nephropathy with markedly increased incidence at 500 and 2500 ppm (4.5 and 22.8 mg/L). Decreased serum glucose was observed at 500 ppm (4.5 mg/L) and above. Serum cholesterol was increased in females at the highest concentration. The LOAEC was considered to be 0.61 mg/L (100 ppm) (the lowest dose tested) based on kidney findings in males. However, this finding is specific to male rats and is not relevant for human health hazard assessment.

Sprague-Dawley rats (5/sex/dose at 0.084 and 0.945 mg/L; 10/sex/dose at 9.041 mg/L) were exposed to D3 aerosols via nose-only inhalation for 6 hrs/day, 7 days/week for 4 weeks (LPT, 1992). Mortality was noted in males and females at 9.041 mg/L. Symptoms prior to death were dyspnea, ataxia, reduced reflexes and piloerection. Hemorrhagic encrustation of the nose was seen at 0.945 mg/L and above. Slight inflammatory changes were seen in the nasal cavity at the highest concentration. Microscopically, aggregation of macrophages and perivascular round cell infiltration was seen in the lungs of high exposure animals. These changes are consistent with respiratory tract irritation. Complete recovery for the local effects was not achieved during the 4-week recovery period. The NOAEC for local effects was considered to be 0.084 mg/L. A NOAEC for systemic toxicity was considered to be 0.945 mg/L based on the mortality and clinical signs. Complete recovery was not seen for the local effects following the recovery period of 4 weeks. The NOAEC for local effects was considered to be 0.084 mg/L with a LOAEC of 0.945 mg/L.

In a 90-day whole body vapour inhalation study D3 (DCC, 2001), conducted largely according to the current guideline OECD 413, Fisher 344 rats were exposed to nominal concentrations of 0, 15, 150, 600 and 2500 ppm (measured concentrations: 0, 14.9, 187, 601, 2519 ppm) for 6 hrs/day, 7 days/week for 13 weeks. Overt toxicity, including body weight and clinical observations were evident at 601 ppm (5.5 mg/l) which was identified as the LOAEC. The test substance induced effects at all doses but up to 150 ppm these were considered transitory, adaptive/metabolic, not clearly adverse or giving no evidence of organ toxicity. The NOAEC was therefore determined to be 150 ppm (1.4 mg/l) in male and female F344 rats.

The 90-day study was selected as the key study on the basis that it is the study of longest duration and was assigned Reliability 1.

Justification for classification or non-classification

On the basis of a 90-day inhalatory LOAEL of 5.5 mg/l, D3 is not classified for specific target organ toxicity according to EC Regulation 1272/2008.