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Description of key information

14 d, rabbit, gavage: NOAEL: 780 mg/kg bw/ day (BASF AG 1968)
14 d, cat, gavage: NOAEL: 780 mg/kg bw/ day (BASF AG 1968)
6 wks, rat, feeding study: NOEAL: ca. 800 mg/kg bw/day (American Cyanamide Co., 1954)
Actually, there is no information available.
Actually, there is no information available.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Dose descriptor:
160 mg/kg bw/day

Additional information

The National Toxicology Program (NTP) initiated 2-week, and 13-week studies of 2,6-xylidine by gavage in F344/N rats. The U.S. Environmental Protection Agency (EPA) sponsored short-term gavage studies and 10-week range-finding feed studies in Charles River CD rats (a Sprague Dawley-derived strain).



Subacute oral toxicity

In the available studies on subacute toxicity the hepatotoxic effect of 2,6-xylidine is described. There are no indications of a nephrotoxic effect at these exposure times. The comparative studies with the 2,4-, 2,5- and 2,6-isomers show clear differences with regard to the toxic effect of the isomers mentioned above, depending on the species. In rats, 2,4-xylidine is more toxic than 2,5- or 2,6-xylidine, while in dogs the toxic effect of 2,6-xylidine is predominant (Hardy et al. and Short et al.).

Hardy (1986) examined the toxic effect of 2,6-xylidine, administered orally to rats and dogs, after a test duration of ten days. The daily dose was 262.5 mg/kg in the tests with rats. In rats 2,6-xylidine showed no difference to the control group for the clinical or pathological parameters. However, interaction of 2,6-xylidine and phenobarbital caused significant weight reduction with respect to the controls, with and without co-application, and also led to partial liver necroses in 3 out of 15 animals. Co-application of methylcholanthrene had no effects, apart from slight lipidosis of the hepatocytes. Proadifen showed toxic effects, such as diarrhoea, weight reduction and fatty degeneration of the liver cells. These effects were not intensified through 2,6-xylidine.

In dogs, daily administration of 25 mg/kg 2,6-xylidine by gavage for 10 days led to vomiting, as with 2,4-xylidine, weight reduction (no information on significance), but macroscopically to pale and enlarged livers in all dogs, and signs of icterus in 1 out of 5 dogs. The histopathological finding for all dogs was fatty degeneration of the centrilobular hepatocytes (Hardy, 1986).

In rats, 2,6-xylidine caused no clinical or histopathological effects during the test period, following a daily dose of 157.5 mg/kg for 20 days (Short et al., 1983), apart from piloerection; weight gain also corresponded to that of the controls. The only significant effect here was haemosiderosis in the spleen after 20 days application.

The toxic effects of 2,6-xylidine in a subacute test with F344 rats and B6C3F1 mice, have been described by Montgomery et al. (1982). The animals (5 female and 5 male per group) were given 0, 80, 160, 310, 620 or 1250 mg/kg 2,6-xylidine in corn oil once daily by gavage for 12 days. From 620 mg/kg onward all of the mice, except 1 female mouse (620 mg/kg), had died before the end of the test. However, the remaining mice showed no significant difference to the control group with regard to weight gain, haematology, clinical chemistry and urine analysis, with the exception of polychromasia in the male mice at 310 mg/kg. In rats the survival rate at 620 mg/kg was 3 out of 5 (male) and 4 out of 5 (female). None of the rats survived 1250 mg/kg up to the end of the test. Weight gain was reduced from 310 mg/kg (male) and 620 mg/kg (female) onward respectively (no information on significance). Haematology showed leukocytosis and nucleated erythrocytes in the male rats from 310 mg/kg onward and anisocytosis, polychromasia and poikilocytosis in the male and female rats from 310 mg/kg onward. The findings of clinical chemistry and urine analysis were normal. Histopathological evaluation and determination of the organ weights were not carried out. The NOEL was 160 mg/kg/day for both species.


Magnusson et al. (1971) examined the hepato- and nephrotoxic effects on rats and dogs. In rats the effects after oral administration of 2,0, 100, 500 and 700 mg/kg/day 2,6-xylidine for 4 weeks are similar to those of 2,5-xylidine. In this case one male animal also died (4th - 5th test day), following the high dose. The liver weights were increased after the medium and highest doses in male and female rats. Histopathology showed focal liver necroses, however this was limited to one female and one male animal of the highest dose group. No nephrotoxic effect was observed with this isomer either, since both the urine analysis and histopathological findings were normal. The NOEL was thus 20 mg/kg/day. The absence of statistical calculations in this study must be criticized, however. in dogs, vomiting was observed after application from 10 mg/kg onward, and at 50 mg/kg poor general condition, weight reduction and reduced sulphobromophthalein clearance at the end of the test, and increased relative liver weights. The autopsy showed pale livers, even at 2 mg/kg. Histopathology showed slight steatosis of the liver cells here, at 10 mg/kg moderate and at 50 mg/kg severe steatosis (autopsy findings: yellowish liver). In both dogs with severe steatosis hypoproteinemia, hyperbilirubinemia and a generalised icterus were found (Magnusson et al.,


In the second study by Magnusson et al. (1979) with rats, the relative liver weights following oral administration of 400 and 500 mg/kg respectively for 4 weeks, were significantly increased. Morphometric analysis of the hepatocyte size showed significant differences to the control group in the centrilobular liver sections of the female and male rats. The enlargement of the hepatocytes was attributable to a proliferation of the smooth ER. The glycogen content was reduced (not quantified), and the activity of the aniline hydroxylase in the female rats was significantly increased.


In the NTP studies, compound-related deaths occurred in groups administered 0.62 g/kg or more. All animals receiving 1.25 g/kg died before the termination of the studies. Depression in mean body weight relative to that of the vehicle controls was greater than 10 % in male rats administered 0.31 g/kg or more and in female rats administered 0.62 g/kg. A generalized leukocytosis and an increase in the number of nucleated red blood cells were observed in male rats administered 0.31 or 0.62 g/kg. Slight anisocytosis, poikilocytosis, and polychromasia of the red blood cells occurred more frequently in dosed than in vehicle control animals. No significant differences clinical chemical and urinalysis parameters observed between dosed and vehicle control male rats.


Subchronic and chronic oral toxicity

In a subchronic study (NTP) with rats no death occurred. Mean body weight gains were over 10 % less in male and female rats receiving the highest (0.31 g/kg) dose and in female rats administered 0.04 and 0.16 g/kg than in controls. No noteworthy clinical signs were observed in any of the animals in these studies. Necropsy findings involved increased liver/bodyweight ratios for high dose males and females as well as increased liver weight to body weight ratios ( 0.16 g/kg males) and increased liver/ brain weight and kidney / brain weight ratios in females given 0.31 g/kg.


In the feeding study of Lindstrom et al. ( 1963) 2,6-xylidine led to a significant reduction in body weight gain in the male animals from 2500 ppm onward (125 mg/kg/day) after 26 weeks and in the females from 5000 ppm onward (250 mg/kg/day). With this isomer the significant increase in the relative organ weights of liver, spleen and kidneys after 26 weeks was limited to the two highest dosages, with the exception of the kidneys of the male rats (also at 2500 ppm). The relative weights of heart and testes were significantly increased in the male rats at the highest dose. The autopsy findings were normal for the liver. The kidneys showed scarring at 10,000 ppm (500 mg/kg/day) and histopathology also gave the same findings for the kidneys. No further histopathological differences to the control group were observed, apart from centrilobular enlarged and periportal smaller hepatocytes.

A study of the carcinogenicity of 2,6-xylidine was carried out (Montgomery et al., 1982) on behalf of the US Department of Health and Human Services with 56 male and 56 female Charles River CD rats per dosage group respectively. Parent animals and test animals were given 0, 0.3, 1 or 3 g 2,6-xylidine per kg feed in corn oil. This dosage corresponds to an intake of 0, 15, 50 and 150 mg/kg body weight per day, according to Lehmann (1954). The start of application was the 5th week of life for the parent animals, and application was ended on the 21st day post natum. On this day treatment was discontinued with the test animals and they were treated for a further 102 - 104 weeks with 2,6-xylidine in the above dosage via the feed. Clinical symptoms caused through the substance were not observed in any of the dose groups.

The weight gain was reduced, in the female rats from 1 g/kg onward, and in the male animals at 3 g/kg (no data on the significance). At 3 g/kg the survival rate of the male rats was highly significantly reduced, and at 1 g/kg significantly reduced.




Actually, there is no information available.



Actually, there is no information available.

Justification for classification or non-classification

Regarding the results of all studies in rats the subchronic NOAEL of 2,6-xylidine is 160 mg/kg bw/day due to the effects observed in haematological parameters and organ weights. In the chronic study the NOAEL was found to be 150 mg/kg bw/day for male and female animals. Based on the GHS and the EU criteria for classification and labelling there is currently no need for classification of effects due to repeated oral exposure to the test substance.


There are no indications given to classify 2,6-xylidine for its repeated dermal or inhalative toxicity.