We. Dressler et al., CARCINOGENICITY OF S(HYDROXYMETHYL)]METHYL-4-NITRO-O-PHENYLENEDIAMINEFED TO MATED AND NON-MATED SPRAGUE-DAWLEY RATS, Food and chemical toxicology, 33(8), 1995, pp. 681
s(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 fe
males developed palpable mammary masses that were subsequently diagnos
ed as mammary adenocarcinomas at a 13-wk interim kill involving 10 rat
s/sex/group. After 14 wk, 25 females per group with no apparent masses
were mated in a reproduction/teratology study. Mammary tumours develo
ped in a dose-related fashion both in the pregnant rats and in the rem
aining 20 females/group that continued on treatment for 6 months. On g
estation day 20 (wk 17-18) the final incidences of mammary adenocarcin
omas in the low-, mid- and high-dose mated dose groups were 20, 60 and
84%, respectively, while the corresponding incidences in the non-mate
d females at 6 months were 5, 40 and 85%. Most mammary tumours were en
capsulated but, at 6 months, lung metastases were noted in four rats,
and four females also had Zymbal's gland tumours. Non-neoplastic chang
es in male and female rats considered to be related to treatment inclu
ded increases in thyroid follicular cell size accompanied by an accumu
lation of golden-brown pigment, multifocal hepatic necrosis with non-s
uppurative 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 we
re not considered to be treatment related. Although the mean numbers o
f micronucleated polychromatic erythrocytes in bone marrow obtained fr
om 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.