Carcinogenic Activity

National Toxicology Program Studies

Coumarin: http://ntp-server.niehs.nih.gov/htdocs/LT-studies/tr422.html

CONCLUSIONS
Under the conditions of these 2-year gavage studies there was some evidence of carcinogenic activity of coumarin in male F344/N rats based on increased incidences of renal tubule adenomas. There was equivocal evidence of carcinogenic activity of coumarin in female F344/N rats based on a marginally increased incidence of renal tubule adenomas. There was some evidence of carcinogenic activity of coumarin in male B6C3F1 mice based on the increased incidence of alveolar/bronchiolar adenomas. There was clear evidence of carcinogenic activity of coumarin in female B6C3F1 mice based on increased incidences of alveolar/bronchiolar adenomas, alveolar/bronchiolar carcinomas, and hepatocellular adenomas. The marginally increased incidences of squamous cell papillomas of the forestomach in male and female mice receiving 50 mg/kg may have been related to coumarin administration.

The administration of coumarin to rats was also associated with an increased severity of nephropathy in the kidney and of bile duct hyperplasia in the liver, increased incidences of ulcers of the forestomach, and necrosis, fibrosis, and cytologic alteration of the liver. Administration of coumarin to mice was also associated with centrilobular hypertrophy, syncytial alteration, and eosinophilic focus in the liver.

Methyleugenol: http://ntp-server.niehs.nih.gov/htdocs/LT-studies/tr491.html

CONCLUSIONS

Under the conditions of these 2-year gavage studies, there was clear evidence of carcinogenic activity of methyleugenol in male and female F344/N rats based on the increased incidences of liver neoplasms and neuroendocrine tumors of the glandular stomach in male and female rats and the increased incidences of kidney neoplasms, malignant mesothelioma, mammary gland fibroadenoma, and subcutaneous fibroma and fibroma or fibrosarcoma (combined) in male rats. A marginal increase in the incidence of squamous cell neoplasms of the forestomach may have been related to methyleugenol administration in female rats. There was clear evidence of carcinogenic activity of methyleugenol in male and female B6C3F1 mice based on the increased incidences of liver neoplasms. Neuroendocrine tumors of the glandular stomach in male mice were also considered related to methyleugenol administration. In male and female rats and mice, methyleugenol administration caused significant increases in nonneoplastic lesions of the liver and glandular stomach.

Safrole:

http://ntpserver.niehs.nih.gov/htdocs/CHEM_H&S/NTP_Chem9/Radian94-59-7.html

Review: IARC Cancer Review: Animal Sufficient Evidence IARC possible human carcinogen (Group 2B) [610] Status: EPA Carcinogen Assessment Group [610] NTP anticipated human carcinogen [610]

Toxicity and carcinogenicity studies of musk xylol were examined in B6C3F1 mice. The LD50 of the chemical was considered to be more than 4000 mg/kg. In the acute toxicity and 14-day repeated-dose oral toxicity studies, tremor was observed in some animals given high doses of the chemical. In the 17-week repeated-dose oral toxicity study, musk xylol was given at dietary dose levels of 0.0375, 0.6%. During the experimental period, almost all mice given 0.3% or more died. There was no difference in the body-weight gain between the treated groups given 0.15% or less and the control group. Histologically, enlargement and irregularity of hepatocyte were found in both sexes given 0.15% or more. Based on the results, the chemical was given at dietary levels of 0 (control), 0.075 or 0.15% for 80 weeks in the carcinogenicity study.

Overall tumor incidences in all treated groups of both sexes were significantly higher than those in the respective controls. Combined malignant and benign liver cell tumors increased clearly in both sexes and a significant positive trend for the occurrence of hepatocellular carcinomas was noted in males. Incidences of lung and Harderian gland tumors and lymphomas in treated groups were also slightly higher than those in controls. In addition, incidences and total numbers of malignant tumors increased significantly in treated groups of both sexes, although no dose-relation was evident. The results demonstrated that musk xylol is carcinogenic in B6C3F1 mice of both sexes when given at dose-levels of 0.075 or 0.15% in the diet for 80 weeks.

Abstract
Among the nitro musks, musk ketone (MK) as a synthetic compound with a typical musk odor is widely used in cosmetics. In the European Community the total amount used in fragrances has been reported to be 110 tons/a. Additionally, relevant amounts of MK are used in Indian joss sticks. As a result of its inherently low biodegradability MK has been detected in the aquatic environment (surface water, sediments, edible fish). Moreover, it has been shown that MK concentrates in human fatty tissue and breast milk, indicating that humans are constantly exposed. Several studies provided convincing evidence of lack of a genotoxic potential for MK. However, MK was identified as a strong inducer of phase I enzymes in rodents and a cogenotoxicant in vitro in human derived cells in rather low doses, suggesting that exposure to MK might increase the susceptibility to health hazards caused by carcinogens in humans.

In the body of the article, this is also stated: " Besides oral and dermal absorption another route of NMs (nitromusks) uptake has to be taken into account: the inhalation by using NM containing containing colognes or fragrance mist (sprays). Moreover, in regard to a NM burden of newborns a possible transplacentary exposure has to be evaluated."