2,6-xylidine appears as a liquid. Toxic by ingestion, inhalation and skin absorption. Slightly soluble in water. Used in pharmaceuticals, as dye intermediates and organic syntheses.
There were species differences in the hepatotoxicities induced by the isomers of xylidine. ... 2,6-Xylidine did not produce hepatic lesions in the rat but was a potent inducer of fatty degeneration in the liver of dogs. ... For 2,6-xylidine, the major metabolite in both rats and dogs was 4-hydroxy-2,6-dimethylaniline.
The major urinary metabolite of 2,6-xylidine in rats was 4-hydroxy-2,6-dimethylaniline, and 3-methy-2-aminobenzoic acid was a minor metabolite. ... In human liver slices, 2,6-xilidine was a metabolite of lidocaine.
来源:Hazardous Substances Data Bank (HSDB)
代谢
局麻药利多卡因（利多）和普鲁卡因（普利洛）被代谢成它们的组成芳香胺2,6-二甲苯胺（DMA，2,6-二甲苯胺）和2-甲基苯胺（MA，邻甲苯胺），分别在 rats. 利多和普利洛形成DNA加合物的能力在大鼠雄性F344大鼠的主要芳香胺靶组织中与等摩尔剂量的DMA和MA进行了比较，使用(32)P -后标记分析。直接将假定的DNA反应代谢物N-羟基-DMA和N-羟基-MA与分离的DNA反应产生参考加合物。大鼠通过口服灌胃给与0.5 mmol / kg b.wt的每种测试物质或载体一次或每天一次，持续7天。在重复给予普利洛或利多后，在肝脏和鼻粘膜中检测到DNA加合物。在利多和DMA重复给药的大鼠中仅检测到尿路上皮DNA加合物。DMA或MA给药组在单次和多剂量组中均显示加合物，除了单次DMA肝脏和尿路上皮样本，低于检测水平。在任何白细胞的样品中均未检测到DNA加合物。在利多和普利洛-DNA加合物检测到的色谱与DMA或MA给药的大鼠中形成的相对应，或相应N-羟基衍生物与DNA的化学反应。因此，利多和普利洛可以通过它们的芳香胺代谢物在大鼠中产生DNA加合物，尽管水平低于相等摩尔量的它们的胺代谢物。
The local anesthetics lidocaine (lido) and prilocaine (prilo) are metabolized to their constituent aromatic amines 2,6-dimethylaniline (DMA, 2,6-xylidine) and 2-methylaniline (MA, o-toluidine), respectively, which are both tumorigenic in rats. The capacity of lido and prilo to form DNA adducts was assessed in major target tissues for aromatic amines in male F344 rats in comparison to equimolar doses of DMA and MA using the (32)P-postlabeling assay. Direct reaction of putative DNA-reactive metabolites N-hydroxy-DMA and N-hydroxy-MA with isolated DNA yielded reference adducts. Rats were dosed by p.o. gavage with 0.5 mmol/kg b.wt. of each test substance or the vehicle either once or daily for 7 days. After repeat administrations of either prilo or lido, DNA adducts were detected in the liver and nasal mucosa. Urinary bladder DNA adducts were detected only in lido and DMA repeat dosed rats. Groups dosed with DMA or MA showed adducts in both single- and multiple-dose groups, except for the single-dose DMA liver and urinary bladder samples, which were below the level of detection. No DNA adducts were detected in any of the white blood cell samples under either dosing regimen. The lido- and prilo-DNA adducts detected were chromatographically indistinguishable from those formed either in DMA- or MA-dosed rats, respectively, or by chemical reaction of the corresponding N-hydroxy derivatives with DNA. Thus, lido and prilo can generate DNA adducts in rats via their aromatic amine metabolites, although at lower levels than equal molar quantities of their amine metabolites.
To cast light on whether the carcinogenic risk of 2,6-dimethylaniline (DMA), a metabolite of xylazine, may increase by ingestion of edible tissues from domestic animals treated with xylazine, the following studies of xylazine and DMA were performed. In Experiment I, male F344 rats received a single oral administration of 150 mg/kg of xylazine hydrochloride. Rats showed symptoms suggesting loss of sensation and pain immediately after the treatment. These signs had disappeared after 3 hr, but the animals died of hydrothorax and pulmonary edema by 9 hr. The plasma concentration of xylazine was 2.88 +/- 0.95 ug/mL at 15 min, and then decreased to 0.10 +/- 0.01 ug/mL at 6 hr. The plasma level of DMA remained at 0.03 to 0.04 ug/mL during the measurement period. In Experiment II, male F344 rats were fed a diet containing 1000 ppm of xylazine hydrochloride, regarded as the maximum tolerated dose, for 4 weeks. No clear clinical signs were evident and the plasma levels of xylazine and DMA were at the detection limit (0.02 ug/mL) or less, although follicular cell hypertrophy of the thyroid was observed in all the treated animals. In Experiment III, male F344 rats were fed a diet containing 3000 ppm or 300 ppm of DMA for 4 weeks. Histological changes, such as atrophy of Bowman's gland and irregular arrangement of olfactory epithelial cells, were only observed in the olfactory epithelium of the 3000 ppm group. The plasma levels of DMA were 0.20 to 0.36 ug/mL in the 3000 ppm group, but under the detection limit in the 300 ppm group. These results suggest that the probability of nasal carcinogenic effects of DNA on consumers via ingestion of edible tissues from food-producing animals treated with xylazine is extremely low, since DMA levels in the blood of rats subjected to continuous administration of high doses of xylazine remained under the detection limit.
IDENTIFICATION AND USE: 2,6-Xylidine (2,6-DBA) is a yellow liquid. 2,6-DBA is an intermediate in manufacturing pesticides, dyes, antioxidants, pharmaceuticals, resins, fragrances, and other products. HUMAN EXPOSURE AND TOXICITY: Based on a Shanghai Bladder Cancer Study, which enrolled 581 incident bladder cancer cases and 604 population controls, hemoglobin adducts of 2,6-DBA were significantly and independently associated with increased bladder cancer risk among lifelong nonsmokers in Shanghai, China. The findings of that study in China, combined with with previous data in Los Angeles, California, strongly implicate arylamines as potential causal agents of human bladder cancer. ANIMAL STUDIES: 2,6-DBA was not a skin sensitizer at concentrations of 0, 5, 10 or 25% w/v in a mouse local lymphnode assay. Three rabbits were exposed to 0.1 mL 2,6-DBA; eyes were not washed out. The animals were observed for 8 days. Slight corneal opacity, iritis and chemosis were completely reversible within 8 days. Moderate conjunctivae redness was not fully reversible in 2/3 animals within 8 days. However, a clear trend over time for decreasing effect strength was observable, and in 1/3 animals the redness was completely reversible. Rats were exposed for 7 hours to a vapor saturated atmosphere (0.75 mg/L). 0/12 animals died after the 7 hour exposure. Salivation, apathy, closed eyes and slight secretion of the nose were reversible within one day. In male and female rats given 400-700 mg/kg by gavage daily for four weeks, however, decreased weight gain, lowered hemoglobin values and liver enlargement were observed, with increases in the levels of microsomal glucuronyltransferase in males and females and of aniline hydroxylase in females. Chronic dosing of male and female beagle dogs with oral doses of 50 mg/kg body weight 2,6-DBA for four weeks resulted in decreased body weight, hyperbilirubinemia, hypoproteinemia and, in contrast to rats, marked fatty degenerative changes in the liver. 2,6-DBA produced only weak positive genotoxicity results with Salmonella typhimurium strains TA97, TA98, TA100, TA1535, and TA1537. The oral administration of up to 350 mg/kg of 2,6-DBA did not result in the induction of micronuclei in bone marrow of male mice either at 24, 48 or 72 hours after dosing. In Chinese hamster ovary (CHO) cells, 2,6-DBA produced chromosomal aberrations and sister chromatid exchanges. In 2-year feed studies, 2,6-DBA was clearly carcinogenic for male and female rats, causing significant increases in the incidences of adenomas and carcinomas of the nasal cavity. A rhabdomyosarcoma, a rare tumor of the nasal cavity, was observed in dosed rats of each sex. In addition, the increased incidences of subcutaneous fibromas and fibrosarcomas in male and female rats and the increased incidence of neoplastic nodules of the liver in female rats may have been related to the administration of 2,6-DBA.
来源:Hazardous Substances Data Bank (HSDB)
毒理性
毒性总结
处理 AS52 细胞使用 N-OH-2,6-二甲基苯胺（2,6-DMA）和 2,6-DMAP 导致细胞内产生反应性氧种（ROS）。当使用 N-OH-2,6-DMA 和 2,6-DMAP 处理 AS52 细胞时，观察到剂量依赖性的 DNA 链断裂。对这些结果进行比较评估表明，主要的致突变作用机制可能是通过细胞内结合的氨基酚/醌亚胺结构进行氧化还原循环产生 ROS，而不是通过形成共价 DNA 加合物。这些考虑并没有排除单环硝基亚离子形成 DNA 加合物的可能性，因为已经确定 2,6-DMA 衍生的自由硝基亚离子可以在水相条件下形成。（A15447）
Treatment of AS52 cells with N-OH-2,6-dimethylaniline (2,6-DMA) and 2,6-DMAP led to intracellular production of reactive oxygen species (ROS). DNA strand breaks were observed in a dose-dependent manner in AS52 cells when treated with each of the N-OH-2,6-DMA and 2,6-DMAP. Comparative evaluation of the results indicates that the principal mechanism of mutagenic action is likely to be through redox cycling of intracellularly bound aminophenol/quinone imine structures to generate ROS rather than through formation of covalent DNA adducts. These considerations do not rule out DNA adduct formation by monocyclic nitrenium ions because it has been established that the free nitrenium ion derived from 2,6-DMA can form under aqueous conditions. (A15447)
Evaluation: There is inadequate evidence in humans for the carcinogenicity of 2,6-dimethylaniline. There is sufficient evidence in experimental animals for the carcinogenicity of 2,6-dimethylaniline. Overall evaluation: 2,6-dimethylaniline is possibly carcinogenic to humans (Group 2B).
To cast light on whether the carcinogenic risk of 2,6-dimethylaniline (DMA), a metabolite of xylazine, may increase by ingestion of edible tissues from domestic animals treated with xylazine, the following studies of xylazine and DMA were performed. In Experiment I, male F344 rats received a single oral administration of 150 mg/kg of xylazine hydrochloride. Rats showed symptoms suggesting loss of sensation and pain immediately after the treatment. These signs had disappeared after 3 hr, but the animals died of hydrothorax and pulmonary edema by 9 hr. The plasma concentration of xylazine was 2.88 +/- 0.95 ug/mL at 15 min, and then decreased to 0.10 +/- 0.01 ug/mL at 6 hr. The plasma level of DMA remained at 0.03 to 0.04 ug/mL during the measurement period. In Experiment II, male F344 rats were fed a diet containing 1000 ppm of xylazine hydrochloride, regarded as the maximum tolerated dose, for 4 weeks. No clear clinical signs were evident and the plasma levels of xylazine and DMA were at the detection limit (0.02 ug/mL) or less, although follicular cell hypertrophy of the thyroid was observed in all the treated animals. In Experiment III, male F344 rats were fed a diet containing 3000 ppm or 300 ppm of DMA for 4 weeks. Histological changes, such as atrophy of Bowman's gland and irregular arrangement of olfactory epithelial cells, were only observed in the olfactory epithelium of the 3000 ppm group. The plasma levels of DMA were 0.20 to 0.36 ug/mL in the 3000 ppm group, but under the detection limit in the 300 ppm group. These results suggest that the probability of nasal carcinogenic effects of DNA on consumers via ingestion of edible tissues from food-producing animals treated with xylazine is extremely low, since DMA levels in the blood of rats subjected to continuous administration of high doses of xylazine remained under the detection limit.
/MILK/ ... The potential transfer of 2,6-dimethylaniline (2,6-DMA) from mother to nursing infant via milk is of toxicological concern. Solid-phase microextraction with separation and detection using gas chromatography-mass spectrometry was optimized and used for the analysis of 2,6-DMA in milk. 2,6-DMA-d9 was synthesized and used for quantitation by the isotope ratio method. At a concentration of 5 ppb 2,6-DMA, the method detection limit was 0.20 ppb, and the relative standard deviation was 3.6%. Samples of milk were obtained from bovines administered lidocaine (2.9-3.9 mg/kg) during surgery. A breast milk sample was also obtained from a human donor who received 36 mg lidocaine during dental work. 2,6-DMA was present at levels ranging from 14.5 to 66.0 ppb in bovine milk and was detected at 1.6 ppb in the human milk sample. Our results demonstrate that 2,6-DMA, formed by the metabolism of lidocaine, is transferable to bovine and human milk.
/MILK/ Xylazine hydrochloride was administered i.m. at 0.35 mg/kg to 13 steers and 10 lactating dairy cows at Time 0. Ten minutes later, tolazoline hydrochloride was given i.v. at 4 mg/kg. Tissue and milk samples were analyzed using gas chromatography with nitrogen and phosphorous detection to determine concentrations of xylazine, 2,6-dimethylaniline (a toxic metabolite of xylazine), and tolazoline (at various intervals). Concentrations of xylazine and 2,6- dimethylaniline were below the limit of quantitation (10 microg/kg) by 72 hours in tissues and 12 hours in milk. The concentration of tolazoline was below 10 microg/kg by 96 hours in tissues and 48 hours in milk. ...
/MILK/ Lidocaine is a topical anesthetic drug used in dairy cows for laparotomy (caesarean section, abomasal displacement). Because there are no registered drugs for this indication, it can be applied under the so-called Cascade rules (off-label use), with the restriction that the off-label withdrawal periods of 7 days for milk and 28 days for meat are taken into account. In animals, lidocaine is rapidly metabolized into various metabolites, one being 2,6-dimethylaniline (DMA) which is reported to possess carcinogenic and mutagenic properties and detected also in milk. To investigate whether the off-label withdrawal periods are long enough to exclude the presence of lidocaine and DMA, and potential other metabolites, in edible products, a study was performed with eight dairy cows treated with lidocaine by injection in the abdominal muscles. At various time points blood samples, milk and urine were collected. Four animals were slaughtered 3.5 hr after treatment, the other four after 48.5 hr. The injection site, meat, liver and kidney were analyzed for levels of lidocaine, DMA, monoethylglycinexylidide (MEGX) and 3-OH-lidocaine. It was shown that DMA is an important metabolite in dairy cows and can be detected in both meat and milk. In addition, also MEGX, 3-OH-lidocaine and three other metabolites were
