Carcinogenicity of N1-[tris(hydroxymethyl)]methyl-4-nitro-o-phenylenediamine fed to mated and non-mated Sprague-Dawley rats.
N1(-)[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.
Dressler
W E
WE
Clairol Research Laboratories, Stamford, CT 06922, USA.
Re
T E
TE
Ackerman
L J
LJ
Corbett
J F
JF
D000014:Abnormalities, Drug-Induced / Q000209:etiology; D000230:Adenocarcinoma / Q000139:chemically induced* / Q000556:secondary; D000818:Animals; D001774:Blood Chemical Analysis; D015197:Carcinogenicity Tests; D002273:Carcinogens / Q000633:toxicity*; D002294:Carcinoma, Squamous Cell / Q000139:chemically induced; D004032:Diet; D004305:Dose-Response Relationship, Drug; D005260:Female; D005317:Fetal Growth Retardation / Q000139:chemically induced; D008175:Lung Neoplasms / Q000139:chemically induced / Q000556:secondary*; D008297:Male; D015674:Mammary Neoplasms, Animal / Q000139:chemically induced* / Q000473:pathology; D015162:Micronucleus Tests; D009929:Organ Size / Q000187:drug effects; D010655:Phenylenediamines / Q000633:toxicity*; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D012098:Reproduction / Q000187:drug effects; D012626:Sebaceous Gland Neoplasms / Q000139:chemically induced
D002273:Carcinogens; D010655:Phenylenediamines; C095610:N1-(tris(hydroxymethyl))methyl-4-nitro-1,2-phenylenediamine