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EC number: 201-557-4
CAS number: 84-74-2
2 -Week Dose-Finding Phase
All rats survived to the end of the 2-week phase. The mean body weight
gain of males in the 20,000 ppm group was 10% less than that of control
males, and females exposed to 20,000 ppm lost weight. Feed consumption
by males exposed to 10,000 ppm or greater was decreased during Week 1.
Feed consumption by females decreased with increasing exposure
concentration during Week 1, and feed consumption by females exposed to
20,000 ppm was also decreased during Week 2. No clinical signs related
to dibutyl phthalate exposure were noted.
Continuous Breeding Phase One male and one female exposed to 5,000 ppm
died during the continuous breeding period; the male was killed due to
paralysis of undetermined etiology, and the female due to renal failure.
The mean body weight of females in the 10,000 ppm group was 11% lower
than that of the controls at 17 weeks (the end of the continuous
breeding period). Feed consumption by exposed animals was generally
similar to that by the controls.
All control and exposed pairs were fertile (Table E1). The average
number of litters per pair and cumulative days to litter for exposed
pairs were similar to those of the controls. The mean body weight of
dams in the 10,000 ppm group was significantly lower than that of the
controls at the delivery of each litter and throughout lactation of the
final litter; the mean body weights of dams in the 1,000 and 5,000 ppm
groups were also slightly lower than the mean body weight of control
dams during lactation, and the decreases were significant on Days 14 and
21 for dams in the 5,000 ppm group and on Day 21 for dams in the 1,000
ppm group (Table E1). The number of live pups per litter generall
decreased with increasing exposure concentration (Table E2). Male pup
weights in three of five litters in the 5,000 and 10,000 ppm groups and
female pup weights in all litters in the 10,000 ppm group were
significantly lower than those of control pups. Total and adjusted live
pup weights of all litters in the 10,000 ppm group and two litters in
the 5,000 ppm group were significantly lower than in the controls; two
other litters in the 5,000 ppm group also had lower adjusted live pup
weights than the controls. The average ratio of live male pups to live
pups was decreased in the first and third litters in the 10,000 ppm
group. No biologically significant clinical signs of toxicity were noted.
For the final litter of pups reared to weaning, the weights of male and
female pups from breeding pairs in the 10,000 ppm group were less than
those of control pups through postnatal Day 21 (Table E3). The number of
live pups per breeding pair and pup survival in exposed groups were
similar to those of the controls.
Crossover Mating Trial
During the crossover mating trial, one control female died due to
lymphoma and one female from the 10,000 ppm group died due to cardiac
failure. These deaths were not attributed to exposure to dibutyl
phthalate. There were no significant differences in mating, pregnancy,
or fertility indexes or number of days to litter between the groups
(Table E4). During the week of breeding, the mean body weight of females
exposed to 10,000 ppm was significantly less than that of control dams;
at delivery, the mean body weight of exposed dams remained slightly less
than that of the controls. No significant clinical signs of toxicity
Relative kidney and liver weights of exposed males and females and the
absolute liver weight of exposed males were significantly greater than
those of the controls (Table E5). The relative right cauda epididymal
weight of exposed males was also significantly increased. There were no
significant differences in spermatid or epididymal spermatozoal
measurements in exposed males or in estrous cycle lengths in exposed
females (Table E6). These trials suggest that fertility and
gametogenesis were unaffected in the F0 rats that received 10,000 ppm.
Offspring Assessment Phase
All F1 rats survived to the end of the offspring assessment phase. The
mean body weights of male and female F1 rats exposed to 10,000 ppm were
less than those of the controls at weaning (males, 15%; females, 7%) and
remained less throughout breeding; however, mean body weights of control
and exposed dams were similar at delivery (Table E7). During the week of
breeding, feed consumption by rats in the 10,000 ppm group was less than
that by the control group. Mating, pregnancy, and fertility indexes of
rats in the 10,000 ppm group were significantly decreased, and only a
single litter was produced by dams in this group. These data suggest
that adverse reproductive effects were present in both male and female
F1 rats receiving 10,000 ppm. Female (F2 ) pup weights, total live pup
weights, and adjusted live pup weights were decreased in all exposed
groups (Table E7), and the adjusted live male pup weight for litters in
the 5,000 ppm group was also decreased. There were no clinical signs of
toxicity in F1 rats or F2 rat pups.
At necropsy, the relative kidney weights of F1 males in the 5,000 and
10,000 ppm groups and the relative liver weight of males in the 10,000
ppm group were significantly increased (Table E8); absolute and relative
right epididymal, cauda epididymal, and testis weights, prostate gland
weights, and seminal vesicle weights were decreased in males exposed to
10,000 ppm. Absolute kidney, liver, and right ovary weights of females
in the 10,000 ppm group were decreased. Spermatid heads per testis and
per gram testis, spermatid count, and sperm concentration were
significantly decreased in F1 males (Table E9). Epididymides were absent
or poorly developed in 12 of 20 males in the 10,000 ppm group and in 1
of 20 males in each of the two lower exposure groups. The testes of four
males exposed to 10,000 ppm and one male exposed to 5,000 ppm were
atrophied. The testes of three males in the 10,000 ppm group were not
descended into the scrotal sacs; four males in this group had poorly
developed seminal vesicles and four had an underdeveloped prepuce or
penis. No significant differences in estrous cycle length or in the
percent of time spent in the various estrous stages were noted in
females, although an extended estrous cycle (primarily due to a longer
estrus) was suggested by the data (Table E9). These necropsy data also
suggest that the reproductive system was a target of dibutyl phthalate
toxicity in male and female F1 rats receiving 10,000 ppm. Delayed
maturation is suggested as well in male F1 rats receiving 5,000 ppm or
greater, based upon the testicular and accessory gland findings.
This study is part of a series of examinations performed by the National
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