Evaluation of the oral subchronic toxicity of AHTN (7-Acetyl-1,1,3,4,4,6-hexamethyl-1,2,3,4-tetrahydronaphthalene) in the rat.
7-Acetyl-1,1,3,4,4,6-hexamethyl-1,2,3,4-tetrahydronaphthalene (AHTN) is used as a fragrance material in a wide variety of consumer products. Because of its widespread exposure, a 90-day oral feeding study, with 4-week recovery periods for selected rats, was conducted. AHTN was added to the diet of rats at levels calculated to result in mean daily doses of 1.5, 5, 15 or 50 mg AHTN/kg body weight/day. On completion of the treatment period, 3 males and 3 females from each of the high dose groups and controls were maintained for a treatment free period of 4 weeks. There were no adverse effects revealed upon clinical examination or following extensive histopathological examinations. Histopathological examination of the prostate, seminal vesicles, mammary gland and testes of males and ovaries, mammary gland, uterus and vagina of females, undertaken on all animals in all test groups, revealed no evidence of hormonal effects of AHTN. A statistically significant decrease in body weight gain was observed in both sexes in the high dose group only. Statistically significant effects were observed in hematology and blood chemistry, although these effects were all within the range for historical controls and were not proportional to dose. A green to dark brown coloration in the livers and mesenteric lymph nodes was also seen in high dose animals. At the end of the treatment-free period, the color change was almost completely reversed; one high dose male still had green colored lymph nodes, but the liver appeared normal. A green coloration of the lacrimal glands in females, but not males, was also seen in 8/12, 4/15 and in 1 female given 50, 15 and 5 mg/kg body weight/day, respectively. This green color was still present in 2/3 of the high dose females after the treatment-free period. Microscopic examination of unstained sections of frozen livers under UV illumination did not reveal any fluorescence that might have been consistent with porphyrin accumulation. These findings were clearly related to administration of AHTN, but were not accompanied by any histopathological changes. In discolored livers, all fractions of liver homogenate were abnormally colored; the change was most prominent in the mitochondria. Some dissolved pigment was obtained by extraction of liver homogenates with DMSO/trichloroacetic acid mixtures, but its identity remains to be established. Further work on the mechanism of production of the abnormal color is in progress. Based on these results, the 90-day conservative no-observed-effect level (NOAEL) is 1.5 mg/kg body weight/day.
Api
Anne Marie
AM
Research Institute for Fragrance Materials, Inc., 50 Tice Boulevard, Woodcliff Lake, NJ 07677, USA. amapi@rifm.org
Smith
Robert L
RL
Pipino
Sandra
S
Marczylo
Timothy
T
De Matteis
Francesco
F
D000284:Administration, Oral; D000818:Animals; D001774:Blood Chemical Analysis; D004305:Dose-Response Relationship, Drug; D005260:Female; D006403:Hematologic Tests; D006728:Hormones / Q000097:blood; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008198:Lymph Nodes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D009281:Naphthalenes / Q000008:administration & dosage / Q000737:chemistry / Q000633:toxicity*; D019055:No-Observed-Adverse-Effect Level; D010053:Ovary / Q000187:drug effects / Q000473:pathology; D011897:Random Allocation; D051381:Rats; D011919:Rats, Inbred Strains; D012737:Sex Factors; D013737:Testis / Q000187:drug effects / Q000473:pathology; D013764:Tetrahydronaphthalenes; D018675:Toxicity Tests; D014599:Uterus / Q000187:drug effects / Q000473:pathology; D015430:Weight Gain / Q000187:drug effects
D006728:Hormones; D009281:Naphthalenes; D013764:Tetrahydronaphthalenes; C033116:acetyl methyl tetramethyl tetralin