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Description of key information

In the chosen key study according to OECD TG 407 and GLP, oral administration of 4-methylanisole in olive oil in Wistar rats for 28 days (5 days/week) led to adverse effects on the liver and clinical symptoms, being a consequence of the irritating potential of the test substance. Under the experimental conditions chosen a NOEL of 100 mg/kg bw/d was determined for males and females for repeated dose toxicity after oral administration of the test material for 28 days. 

Key value for chemical safety assessment

Additional information

In the chosen key study according to OECD TG 407 and GLP, 4-methylanisole in olive oil was administered at doses of 100, 300 and 1000 mg/kg bw/d to 5 Wistar rats per sex and dose for 4 weeks (5 days/week) by gavage (BASF21C0810/89101). For comparison, 5 male and 5 female rats served as a vehicle control and were dosed with olive oil. Animals receiving 1000 mg/kg bw/day 4-methylanisole showed clinical signs (salivation, ataxia, tremor, laboured respiration). Clinical chemistry revealed an increase in cholesterol in the females. Significantly increased mean absolute and relative liver weights, accompanied with a diffuse hypertrophy and single cell necrosis of hepatocytes in all male and female rats was observed. The observed decreases in mean absolute and relative spleen weights and decreases in mean relative thymus weight in male rats as well as increases in mean absolute and relative kidney weights in female rats lacked a histopathological correlate. In one male rat, a focal hyperplasia and hyperkeratosis of the mucosa of the forestomach was observed, being indicative for an irritating potential of the test substance. In the dose group of 300 mg/kg bw/d, some male and female animals showed salivation after gavage of the test substance and a decreased mean absolute spleen weights in male rats was observed, lacking a histopathological correlate. Animals receiving 100 mg/kg bw/d did not show any substance related changes.

The increase of the absolute and relative liver weights, together with slight hypertrophy of the hepatocytes and the occurrence of single cell necroses in both sexes at a dose of 1000 mg/kg bw/d represents an adverse and treatment related effect. However, changes in other organ weights were not considered to be treatment related, since no histopathologic correlate was present, no changes in the differential blood counts were observed and findings were not observed for both sexes. The observed clinical symptoms are considered a consequence of the irritating potential of the test substance and are thus only a local, but not a systemic toxic effect. This is confirmed by the fact, that in one male animal of the highest dose group hyperkeratosis and focal hyperplasia were seen in the forestomach. Under the experimental conditions chosen a NOEL of 100 mg/kg bw/d was determined for males and females for repeated dose toxicity after oral administration of the test material for 28 days.

 

Further studies are available as short summaries from secondary sources, which have not been chosen as key or supportive studies (see IUCLID Chapter 7.5.):

In a subacute oral study in rats similar to OECD TG 407, reported as short summary of results in a publication, 10 (male/female) Wistar rats were treated daily for 28 days with doses of 0, 40, 120 and 240 mg/kg bw/d via gavage (Brunsborg 1994). The only adverse effects reported were decreases in serum creatinine and urea in the mid and high dose group for both sexes and a decrease in the packed cell volume in the mid and high dose group for males. However, neither lowered total muscle mass, liver damage nor adverse effects on the kidneys were reported in this study, serving as explanation for the effects observed. Furthermore these findings were not confirmed in the given key study, even at a limit dose of 1000 mg/kg bw/d.

 

In a dermal subacute range finding study, reported as short summary in a database, 5 Sprague-Dawley rats per sex and group were treated topically (semiocclusive) with 4-methylanisole (0, 66, 190, 700, 1000 mg/kg/day) as neat material or in a 50% solution in diethylphtalate daily for 6 hours over a period of 14 days (Atkinson 1994).

Mortality, clinical signs, food and water intake, body weight and skin reactions were monitored and blood and urine samples were collected for urinalysis, hematology and clinical chemistry screens. At the end of the application period, necropsy was conducted, organ weights were determined and several tissues were examined histologically (not further specified). After application of the neat test material (i.e. 1000 mg/kg bw/d), all rats were reported to be sacrificed on day 9 due to severe irritation. No further adverse effects were reported. For the other dose groups, no treatment related findings were reported, besides irritation at the test site (not further specified).

Justification for classification or non-classification

The present data on repeated dose toxicity do not fulfill the criteria laid down in 67/548/EEC and CLP, and therefore, a non-classification is warranted.