Carcinogenicity of N1-[Tris(hydroxymethyl)]methyl-4-nitro- o-phenylenediamine fed to mated and non-mated Sprague—Dawley rats

• Published in: Food and chemical toxicology 1995-08, Vol.33 (8), p.681,687-685,693
• Main Authors: Dressler, W.E., Re, T.E., Ackerman, L.J., Corbett, J.F.
• Format: Article
• Language: English
• Subjects: Abnormalities, Drug-Induced - etiology; Adenocarcinoma - chemically induced; Adenocarcinoma - secondary; Animals; Biological and medical sciences; Blood Chemical Analysis; Carcinogenicity Tests; Carcinogens - toxicity; Carcinoma, Squamous Cell - chemically induced; Diet; Domestic and cosmetic products toxicology; Dose-Response Relationship, Drug; Female; Fetal Growth Retardation - chemically induced; Lung Neoplasms - chemically induced; Lung Neoplasms - secondary; Male; Mammary Neoplasms, Animal - chemically induced; Mammary Neoplasms, Animal - pathology; Medical sciences; Micronucleus Tests; Organ Size - drug effects; Phenylenediamines - toxicity; Pregnancy; Rats; Rats, Sprague-Dawley; Reproduction - drug effects; Sebaceous Gland Neoplasms - chemically induced; Toxicology
• ISSN: 0278-6915; 1873-6351
• DOI: 10.1016/0278-6915(95)00032-W

N 1-[tris(hydroxymethyl)]methyl-4-nitro- o-phenylenediamine was fed in the diet to groups of 30 male and 55 female Sprague-Dawley rats at levels of 0.2, 0.6 and 2.0% for up to 6 months. One mid-dose and two high-dose females developed palpable mammary masses that were subsequently diagnosed as mammary adenocarcinomas at a 13-wk interim kill involving 10 rats/sex/group. After 14 wk, 25 females per group with no apparent masses were mated in a reproduction/teratology study. Mammary tumours developed in a dose-related fashion both in the pregnant rats and in the remaining 20 females/group that continued on treatment for 6 months. On gestation day 20 (wk 17–18) the final incidences of mammary adenocarcinomas in the low-, mid- and high-dose mated dose groups were 20, 60 and 84%, respectively, while the corresponding incidences in the non-mated females at 6 months were 5, 40 and 85%. Most mammary tumours were encapsulated but, at 6 months, lung metastases were noted in four rats, and four females also had Zymbal's gland tumours. Non-neoplastic changes in male and female rats considered to be related to treatment included increases in thyroid follicular cell size accompanied by an accumulation of golden-brown pigment, multifocal hepatic necrosis with non-suppurative inflammation, and renal tubular pigmentation. Increases in foetal variations in the mid- and high-dose groups were considered to be related non-specifically to retarded growth. Malformations observed in the high-dose group were found primarily in single foetuses and were not considered to be treatment related. Although the mean numbers of micronucleated polychromatic erythrocytes in bone marrow obtained from high-dose treated females after 13 wk slightly exceeded historical negative control values, the data were not considered indicative of a genotoxic effect because of the absence of either a dose relationship or a substantive increase in the frequency of micronucleated cells.