Use of this information is subject to copyright laws and may require the permission of the owner of the information, as described in the ECHA Legal Notice.
EC number: 944-528-8 | CAS number: -
Oral (OECD 422), rat: NOAEL = 40 mg/kg bw/day
The test substance was tested in a combined repeated dose oral toxicity study with the reproduction/developmental toxicity screening study according to OECD Guideline 422 and in compliance with GLP (2013). The dose levels for the main study were selected based on a previous dose range-finding toxicity study in Han Wistar rats using dose levels of 0, 50, 150 and 500 mg/kg bw/day (2012). Four groups of 5 males and 5 females were treated by gavage with the test substance once daily over a 14-day period. At 500 mg/kg bw/day, two females were found dead on Day 4 and one male and one female were found dead on Day 5. The remaining males and females at this dose level were sacrificed on Day 5 of the treatment period for ethical reasons. At 50 and 150 mg/kg bw/day, all males and females survived until the scheduled necropsy. At 500 mg/kg bw/day, mean food consumption and body weight gain were statistically significantly reduced in the males and females up to necropsy. At 150 mg/kg bw/day, mean food consumption in males was slightly but not statistically significantly reduced during the treatment period. No test substance-related macroscopical findings were observed in the males and females at any dose level. Based on these observations, dose levels of 10, 40 and 200 mg/kg bw/day were considered to be suitable for the main study. In the main study, 11 Han Wistar rats per sex and dose were treated via gavage with the test substance. The control group received the vehicle corn oil. Male animals were treated for at least 28 days, starting 2 weeks before the mating period and a maximum of 14 days during mating. Females were treated 2 weeks before mating and throughout gestation until the F1 generation reached Day 3 post partum. Since a low fertility was observed after the mating period further animals were added to the study. Six males and females each were added to control and 40 mg/kg bw/day dose group and 8 animals each to the 10 mg/kg bw/day dose group. It was noted at the end of the study that the automatic light cycle of 12 h on / 12 h off was not functional. Therefore, all animals were subjected to 24 h light.
In the main study, no mortality occurred during the study period that was considered to be related to treatment with the test substance. At all dose levels during the weekly clinical observations, there were incidences in males and females of delayed pupil reflex/absent iridic reflex, especially in the acclimatization period. This was considered to be a result of the lighting problem, to which the animals acclimatized. Incidences of salivation were observed in males and females at 200 mg/kg bw/day. Isolated incidences of swaying gait, decreased activity, increased activity, ruffled fur and Straub phenomenom were observed, which were considered to be incidental. Significant reduced food consumption (11.3%) was noted in males at 200 mg/kg bw/day. In females the mean food consumption was statistically significantly reduced up to Days 8 - 11 of the pre-pairing period (-14.5% over the whole of the pre-pairing period) at 200 mg/kg bw/day. It remained reduced during the gestation period and was statistically significantly reduced over the last 2 weeks. Over the whole of the gestation period, mean food consumption was -11.7% compared to the control group. Mean body weight was significantly reduced (5%) in males from Day 7 of the pre-pairing period until the end of the study at 200 mg/kg bw/day. In females mean body weight and body weight gain were statistically significantly reduced on Day 9 at 200 mg/kg bw/day during the pre-pairing period. However, the difference to the control group was only slight (2%). No treatment-related effects were noted in functional observations, haematology and biochemistry in males or females in any test substance group. At 200 mg/kg bw/day, absolute liver weight and body weight ratio were statistically significantly increased in males (12 and 20%, respectively). In addition, the absolute weight, body weight ratio and brain weight ratio of the liver (22, 28 and 21%, respectively) and kidneys (22, 26 and 20%, respectively) were statistically significantly increased in females at 200 mg/kg bw/day. However, no microscopical findings were found that correlated to changes in the liver and kidneys. In females at 200 mg/kg bw/day, the absolute weight, body weight ratio and brain weight ratio of the thymus were significantly decreased (45, 43 and 46%, respectively). This correlated with the reduced lymphocytes in the thymus, observed at microscopical examination. According to the authors the decreased lymphocytes in the thymus were most likely related to non-specific stress induced by their pregnant status, rather than a test substance related effect. Furthermore, histopathological examination revealed an increased incidence and severity of hyaline droplets in the renal tubular epithelium in males at 200 mg/kg bw/day which are considered to be specific to the male rat and do not represent a risk to humans.
In conclusion, adverse effects on systemic toxicity after repeated exposure were observed at 200 mg/kg bw/day. Therefore, a NOAEL of 40 mg/kg bw/day was derived for systemic toxicity in the OECD 422 study in male and female rats due to effects on food consumption and increased liver weights at 200 mg/kg bw/day.
Whitlow, S. (2012). [trade name]: 14-Day Dose Range-Finding Study in the Han Wistar Rat. Testing laboratory: Harlan Laboratories Ltd., Füllinsdorf, Switzerland. Report no.: D60384. Owner company: Symrise AG, Holzminden, Germany. Study number: 2012022. Report date: 2012-12-12.
Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint: The reliable GLP compliant OECD Guideline study was chosen.
The available data on repeated oral dose toxicity of the test substance do not meet the criteria for classification according to Regulation (EC) 1272/2008, and are therefore conclusive but not sufficient for classification.
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.
Welcome to the ECHA website. This site is not fully supported in Internet Explorer 7 (and earlier versions). Please upgrade your Internet Explorer to a newer version.
Close Do not show this message again