Registration Dossier

Diss Factsheets

Toxicological information

Toxicity to reproduction

Currently viewing:

Administrative data

Endpoint:
two-generation reproductive toxicity
Remarks:
based on test type (migrated information)
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1995-1997
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: taken from EU RAR

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
2004

Materials and methods

Test guideline
Qualifier:
no guideline available
Principles of method if other than guideline:
n/A
GLP compliance:
not specified
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Dibutyl phthalate
EC Number:
201-557-4
EC Name:
Dibutyl phthalate
Cas Number:
84-74-2
Molecular formula:
C16H22O4
IUPAC Name:
dibutyl phthalate
Test material form:
not specified
Details on test material:
no data

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
m 20/ f 20

Administration / exposure

Route of administration:
oral: feed
Vehicle:
not specified
Details on exposure:
0, 0.1, 0.5 and 1.0% in diet (0, 52, 256 and 509 mg/kg bw of DBP for males and 0, 80, 385 and 794 mg/kg bw DBP for females)
Details on mating procedure:
112-day cohabitation period
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
no data
Duration of treatment / exposure:
exposure of F0 and F1 generations: 119 days total - 7 days premating, 112 days mating
Frequency of treatment:
n/A
Details on study schedule:
Doses of 0, 0.1, 0.5 and 1.0% in diet were administered to groups of 20 m and 20 f animals for a 7-day premating period after which the
animals were grouped as mating pairs and treated during a 112-day cohabitation period. Then the pairs were separated and exposed during which period any final litters were delivered and kept for at least 21 days. Thereafter treatment of F1 animals was initiated at the same concentration as their parents. At the end of the continuous breeding period also a 7-day crossover mating trial was performed with Fo animals of control and 1% groups, then production of the F2 generation mating was done.
Doses / concentrations
Remarks:
Doses / Concentrations:
doses of 0, 0.1, 0.5 and 1.0% in diet (0, 52, 256 and 509 mg/kg bw for males and 0, 80, 385 and 794 mg/kg bw for females
Basis:
nominal in diet
No. of animals per sex per dose:
20
Control animals:
yes, plain diet
Details on study design:
Doses of 0, 0.1, 0.5 and 1.0% in diet were administered to groups of 20 m and 20 f animals for a 7-day premating period after which the
animals were grouped as mating pairs and treated during a 112-day cohabitation period. A control group of 40 m and 40 f rats received the basal
diet.
After a 112 days cohabitation period, the pairs were separated and exposed during which period any final litters were delivered and kept for at least 21 days. Thereafter treatment of F1 animals was initiated at the same concentration as their parents. At the end of the continuous breeding period also a 7-day crossover mating trial was performed with Fo animals of control and 1% groups, then production of the F2 generation mating was done.

Examinations

Parental animals: Observations and examinations:
all dose levels: growth, body weight, mating, pregnancy, fertility indices
Oestrous cyclicity (parental animals):
examined, no details available
Sperm parameters (parental animals):
sperm concentration and motility, % abnormal sperm or testicular spermatid head count
Litter observations:
number of live pups, weights of pups
Postmortem examinations (parental animals):
organ weights
Postmortem examinations (offspring):
organ weights, organ histopathology
Statistics:
no data available
Reproductive indices:
mating, pregnancy and fertility indices,
Offspring viability indices:
no data available

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
not specified
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Fo females at 1.0% showed decreased body wts
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Fo females at 1.0% showed decreased body wts
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
not specified
Other effects:
not specified

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
no effects observed
Reproductive function: sperm measures:
no effects observed
Reproductive performance:
no effects observed

Details on results (P0)

During the continuous breeding phase 1.0% in the diet caused a reduction in growth of Fo females. The total
number of live pups/litter was statistically significantly decreased at all dose-levels with a dose-relationship. Live pup wts were significantly
decreased at 0.5 and 1.0% in the diet. In the crossover mating trial, designed to determine the affected sex, no effect upon mating, pregnancy
or fertility indices were seen. Fo females at 1.0% showed decreased body wts and increased rel. liver and kidney wts. Fo males at 1.0% revealed increased rel. liver-, kidney-, and right cauda epididymis wts. Sperm parameters (sperm concentration and motility, % abnormal sperm or testicular spermatid head count), estrous cyclicity, and estrous cycle were not affected. The weight of pups from treated females (1.0% in the diet) was statistically significantly decreased.

Effect levels (P0)

Dose descriptor:
NOAEL
Effect level:
385 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: maternal toxicity

Results: F1 generation

General toxicity (F1)

Clinical signs:
not specified
Mortality / viability:
not specified
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
decreased at all dose levels
Sexual maturation:
not specified
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
Felames: lower absolute organ weight (right ovary, liver, kidneys), Males: lower relative weights of reproductive organs and higher relative liver and kidney wts.
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
pididymides absent or poorly developed, testicular atrophy, non-descendent testes,
Histopathological findings:
effects observed, treatment-related
Description (incidence and severity):
degeneration of seminiferous tubules, testicular interstitial cell hyperplasia, vesiculitis with inspissated secretion

Details on results (F1)

Live pup wts were significantly decreased at 0.5 and 1.0% in the diet. F1 males at 0.5% showed significantly increased kidney weights. The weight of
pups from treated females (1.0% in the diet) was statistically significantly decreased.
Pregnancy and fertility indices for F1 parents were statistically significantly lower at 1.0% in the diet. Live F2 pup wts were statistically significantly
lower at all dose-levels (also after adjustment for litter size). Female F1 parents at 1.0% showed statistically significantly lower body wts and absolute organ wts (right ovary, liver, kidneys). In male F1 parents at 1.0% body wt. and rel. wts of all reproductive organs were lower
while rel. liver and kidney wts were statistically significantly increased. Epididymal sperm count and testicular spermatid head count were statistically
significantly decreased at 1.0%. Epididymides were absent or poorly developed in 12/20 F1 males at 1.0% and in 1/20 F1 males
at both lower dosage levels. In 4/20 males at 1.0% and 1/20 at 0.5% in diet testicular atrophy was seen. Testes of 3/20 males at 1.0% were not
descended into the scrotal sacs; 4/20 males at this dose-level had poorly developed seminal vesicles and 4/20 had an underdeveloped prepuce
or penis. Histopathology showed degeneration of seminiferous tubules in 8/10 F1 males at 1.0% and in 3/10 at 0.5% DBP in the diet. 7/10 F1 males at 1.0% revealed testicular interstitial cell hyperplasia. Histopathology of seminal vesicles revealed in 1/10 F1 males at 1.0% vesiculitis
with inspissated secretion. There was no indication of an effect on estrous cyclicity or duration of the estrous cycles in F1 females at all dose-levels.

Effect levels (F1)

Dose descriptor:
LOAEL
Generation:
F1
Effect level:
52 mg/kg bw/day
Based on:
test mat.
Sex:
male
Basis for effect level:
other: embryotoxicity

Overall reproductive toxicity

Reproductive effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
In this study DBP appeared to be a reproductive toxicant in rats exposed both as adults and during development. The effects on the 2nd generation were greater than on the first generation. The lowest dose-level in this study, 0.1% in the diet (52 mg/kg bw for males; 80 mg/kg bw for females) is a LOAEL for embryotoxicity. The NOAEL for maternal toxicity is 0.5% in the diet (385 mg/kg bw).