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EC number: 205-491-7 | CAS number: 141-62-8
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.
Table 1 Hepatic findings at terminal sacrifice
*: 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
*: p<0.01 by One-sided Exact Fischer Test
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.
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.
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