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A LD50 value for acute oral toxicity was reported to be 1134 mg of submisssion substance per kg bw in male and female rats. An acute dermal LD50 was found to be > 2000 mg/kg bw in rats. As no mortality was observed when testing for acute inhalation toxicity using the highest technically feasible dose of 3870 mg/m³ the resulting LD50 was > 3870 mg/m³. After single exposure to o-Anisidin formation of relevant amounts of methaemoglobin was observed in a variety of species.

Key value for chemical safety assessment

Additional information

Male and female Wistar rats were subjected to test acute oral toxicity according to a standard acute method (OECD TG 401). The test material was administered by gavage at different doses. Animals showed a range of clinical signs and lethality (combined with visible changes in necropsy) was observed during the 14 days observation period, leading to a LD50 of 1890 mg/kg bw (corresponding to 1134 mg/kg bw submission substance only; male and female rats combined). This finding was supported by another study in which an oral LD50 of 1505 mg/kg bw was found for female rats.

Single dermal application (according to OECD TG 402) of test material o-anisidine at the limit dose did not cause lethality in male and female Wistar rats thus resulting in a LD 50 > 2000 mg/kg bw.

Acute inhalation toxicity of the test item has been investigated in male and female Wistar rats according to a standard acute method (OECD TG 403). They were exposed to 2.17 or 3.87 mg test substance per liter air for 4 h (maximal applicable dose). All animals survived the 14 days observation period. Clinical signs were: impairment of movement, respiration and refelxes, as well as blood nasal discharge and cyanosis. No macroscopic visible changes were observed at necropsy at the end of the observation period, resulting in a LC50 value of > 3.87 mg/L for the inhalation of aerosol.

According to the RAR o-anisidine induces methaemoglobin formation, similar to aromatic amines.

For example, in male CBA mice or male Alpk:APfSD rats, the single oral application via gavage of 690 or 690 and 1,380 mg o-anisidine/kg bw respectively with a sampling time ranging from 3 to 48 h resulted in significantly elevated methaemoglobin levels (mice: up to 4.8% versus 0.66% in controls; rats: up to 15.4% versus 1.1% in controls). In cats, a single i.v. injection of 7.7 mg o-anisidine/kg bw with a sampling time ranging from 1 to 5 h resulted in significantly elevated methaemoglobin levels (up to 11.5% versus 1.1% in controls). Another study with single intraperitoneal application of 100 mg o-Anisidin per kg bw into cats revealed drastic changes in the blood count (Heinz body formation; methaemoglobin formation (up to 11.9% versus 0% in controls); increased leucoyte; reduced lymphocyte count) and is fatal within 7 h. No lethality was seen at 10 mg/kg bw.

In conclusion LD50 values of studies referring to acute toxicity are in the range from >10 and <=100 mg/kg (cat, intraperitoneal) to 1134 mg/kg bw and > 2000 mg/kg bw (rat, dermal). For acute inhalation toxicity an LD50 of >3.87 mg/L was derived.

 

Available data presented in this IUCLID support the conclusion that MetHb formation is a relevant mode of action which might affect the assessment of human relevance of these results. With respect to MetHb forming substances rats are known to react with lower sensitivity and cats with higher sensitivity than humans. Based on that and considering the LD50 and LC50 values found the human acute toxicity dose is estimated to be higher than 100 and lower than 1134 mg/kg bw..

Justification for classification or non-classification

o-anisidine is classified in Annex VI to Regulation (EC) No 1272/2008 related to acute toxicity as follows: Acute Tox. 3 *, H301, H311, H331 and T; R23/24/25.

LD50 estimates of >100 and <1134 meet criteria for classification as cat 3 or 4 and R 25 or R22 (oral) according to DIRECTIVE 67/548/EEC or REGULATION (EC) No 1272/2008. Since MetHb formation in humans is suspected and since systemic availability for all three exposure routs is not unlikely these data comply with the current classified in Annex VI when following the precautionary principle.

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