LBX98

Carcinogenicity

Description of key information

7.7 Carcinogenicity:
SS - m/p cresol (male rat). NTP, 2007. KL.3
SS - m/p cresol (female mice). NTP, 2007. KL.3

Additional information

The following discussion below has been taken from the NTP technical report on Cresols. It however is important to note that due to the design of these studies NOAEL for either neoplastic or non-neoplastic findings could be determined. These dietary study designs resulted in effectively nutritional effects due to the high doses of test material given.

In 2007, US Health and Human Services published a Toxicity and Carcinogenicity Study in which only male rats or only female mice were fed m/p-cresol mixture over a period of two years without interim kill. Neither absolute/relative organ weights nor blood biochemistry data were reported. The report contains only histopathological data.

 

The NTP generated carcinogenicity data has been discussed below in light of the NTP technical Report on cresols (2008).

Rat study Male F344/N rats received in feed 0, 1500, 5000 and 15000 ppm daily for 105 weeks. Under the condition of these 2 -year studies, there was equivocal evidence of carcinogenic activity on m/p-cresol based on the 4/50 male rats with renal tubular adenomas. The incidence of these neoplasms was not significant but exceeded the historical control data of the laboratory (1/297[feed studies]). In NTP studies the kidney is the second most commonly affected site for chemically induced neoplasms in the male rat and these are most adenomas (NTP, 2006). In this study it could be speculated that the increased incidence of adenoma in the 15000 ppm group arose by mechanisms of action similar to that proposed for hydroquinone. Hydroquinone markedly increases the number of renal tubular cell adenomas when administered to F344/N male (but not female) rats at nephrotoxic doses. There is speculation that this is attributed to a minor metabolite 2,3,5 -tris(glutathione-S-yl)hydroquinone a potent toxic and redox-active species. The formation of benzoquinones from m and p-cresol and quinone methide from p-cresol is inferred from identification of specific glutathione conjugates formed in rat and human liver microsomal incubations. In rats, cresols are detoxicated primarily by conjugation to glucuronic acid of sulphate. It is likely that minor amounts of cresol-derived glutathione conjugates are also formedin vivo. However the potential for formation of quinone like reactive metabolites from cresols should be much lower than from hydroquinone itself. Therefore the potential non-neoplastic response in the kidney should be much weaker in cresol-exposed rats than in rats exposed to similar doses of hydroquinone. No increased incidences of other neoplasms were observed in any other tissues of cresol exposed rats. However due to the presence of renal tubule adenomas in the high exposure concentration group the evidence of carcinogenicity in rats in the NTP study was considered equivocal.

 

Mouse study Female B6C3F1 mice received in feed 0, 1000, 3000, 10000 ppm for 106-107 weeks. Under the conditions of these 2-year studies there was some evidence of carcinogenic activity of m/p-cresol mixture based on the increased incidence of forestomach squamous cell papillomas. However, there is no human counterpart for the rodent forestomach. Therefore, the forestomach squamous cell paplillomas are of minor significance for the human situation. In addition, due to the corrosive property of the test substance, chronic irritation is expected to be the mode of action.

 

Significantly increased incidences of respiratory epithelial hyperplasia of the nose were significantly increased in the 3000 and 10000 ppm groups. However cresols have been shown to be respiratory irritants in humans and animals following inhalation exposure. The non-neoplastic lesions were most likely due to inhalation exposure of the p-isomer volatising from the feed during consumption and not from direct systemic exposure following oral absorption. Such lesions are considered to be an adaptive response and are among those commonly observed in NTP inhalation studies of chemicals that are known irritants (NTP, 2000).

 

Under the conditions of these 2 year studies, there was equivocal evidence of carcinogenic activity of m/p cresol in male F344/N rats based on the marginally increased incidence of renal tubule adenoma. There was some evidence of carcinogenic activity of m/p cresol in female B6C3F1 mice based on the increased incidence of forestomach squamous cell papilloma.

 

Exposure to m/p cresol resulted in increased incidences of non-neoplastic lesions in the kidney (hyperplasia), nose (inflammatory, hyperplasia and metaplasia) and liver (eosinophilic focus) of rats. Increased incidences of non-neoplastic lesions were observed in the respiratory tract (hyperplasia in the nose and lung), thyroid gland (follicular degeneration) and liver (eosinophilic focus) of mice.

 

References:

National Toxicology Program (NTP, 2000). NTP Technical report on the toxicology and carcinogenesis studies of napthalene (CAS no. 91 -20 -3) in F344/N rats (inhalation studies). Technical report series No. 500. NIH publication No. 01 -4434. National Institutes of Health, Public Health Services, US Department of Health and Human Services, Research Triangle Park, NC.

National Toxicology Program (NTP, 2006). NTP Technical report on the toxicology and carcinogenesis studies of benzophenone (CAS no. 119 -61 -9) in F344/N rats and B6C3F1 mice (feed studies). Technical report series No. 533. NIH publication No. 06 -4469. National Institutes of Health, Public Health Services, US Department of Health and Human Services, Research Triangle Park, NC.

National Toxicology Program (NTP, 2008). NTP Technical report on the toxicology and carcinogenesis studies of cresols (CAS No. 1319 -77 -3) on male Fe44/N rats and female B6C3F1 mice (feed studies). Technical report series No. 550. NIH publication No. 08 -5891. National Institutes of Health, Public Health Services, US Department of Health and Human Services, Research Triangle Park, NC.