title: Toxicity and blood concentrations of xylazine and its metabolite, 2,6-dimethylaniline, in rats after single or continuous oral administrations.
abstract: 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 micrograms/ml at 15 min, and then decreased to 0.10 +/- 0.01 microgram/ml at 6 hr. The plasma level of DMA remained at 0.03 to 0.04 microgram/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 microgram/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 microgram/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.
authors.affiliation: Division of Pathology, National Institute of Health Sciences, Tokyo, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Yasuhara
authors.forename: H
authors.initials: H
authors.lastname: Kobayashi
authors.forename: Y
authors.initials: Y
authors.lastname: Shimamura
authors.forename: T
authors.initials: T
authors.lastname: Koujitani
authors.forename: H
authors.initials: H
authors.lastname: Onodera
authors.forename: H
authors.initials: H
authors.lastname: Takagi
authors.forename: M
authors.initials: M
authors.lastname: Hirose
authors.forename: K
authors.initials: K
authors.lastname: Mitsumori
mesh_terms: D000284:Administration, Oral; D000814:Aniline Compounds / Q000008:administration & dosage / Q000097:blood* / Q000633:toxicity*; D000818:Animals; D004334:Drug Administration Schedule; D006984:Hypertrophy / Q000139:chemically induced / Q000473:pathology; D008297:Male; D020714:Maximum Tolerated Dose; D009296:Nasal Cavity / Q000187:drug effects / Q000473:pathology; D009831:Olfactory Mucosa / Q000187:drug effects / Q000473:pathology; D051381:Rats; D011916:Rats, Inbred F344; D013961:Thyroid Gland / Q000187:drug effects / Q000473:pathology; D014991:Xylazine / Q000008:administration & dosage / Q000097:blood* / Q000633:toxicity*
chemical_list: D000814:Aniline Compounds; D014991:Xylazine; C007766:2,6-xylidine