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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
two-generation reproductive toxicity
Remarks:
based on test type (migrated information)
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Guideline study under GLP conditions.

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1994

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 416 (Two-Generation Reproduction Toxicity Study)
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
other: solid
Details on test material:
purity 99%

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Age at study initiation: (P) males 8 weeks; females 11 weeks
- Housing: one male and one female for mating, then individual
- Diet ad libitum
- Water ad libitum
- Acclimation period: 1 week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21
- Humidity (%): 60
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12 / 12

IN-LIFE DATES: From: To:

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
olive oil
Details on exposure:
P: males received the test substance for 77 days females for 14 days prior to mating, Then the animals received the tstsubstance upt and including the pups(F2) of the F1 generation
Details on mating procedure:
Start of mating procedure: Day 78 (p-generation); Day 204 (F1 generation).
End of mating procedure was 14 days (p-generation, respectively 30 days later (F1 generation).
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
After administration of the test substance for 77 days (male animals), 14 days (female animals) all animals were mated monogamic within the individual dosegroups and the administration of test substance was continued.
After the succeeded birth the dams were treated with the test material until the 21. day of life of the pups.
24 of these pups per sex and group remained in the experiment and were treated with the test substance until the elimination out of the experiment. After approx. 80 days the monogamic mating procedure was executed within this F1 generation to produce F2 generation.
Frequency of treatment:
daily
Details on study schedule:
see: table in ´Any other materials and methods´.
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 30, 90, 270 mg/kg/day, 7days/week
Basis:

No. of animals per sex per dose:
24 rats/dose/sex
Control animals:
yes
Details on study design:
After administration of the test substance for 77 days (male animals), 14 days (female animals) all animals were mated monogamic within the individual dosegroups and the administration of test substance was continued.
After the succeeded birth the dams were treated with the test material until the 21. day of life of the pups.
24 of these pups per sex and group remained in the experiment and were treated with the test substance until the elimination out of the experiment. After approx. 80 days the monogamic mating procedure was executed within this F1 generation to produce F2 generation.
Positive control:
no

Examinations

Parental animals: Observations and examinations:
for clinical signs and mortality , behavior during mating and birth of the litter, body weight development, food consumption
Litter observations:
number of pups per litter, gender, body weight, survival, and changes during early development such as eyes, and ears. from day 21 e.g. reflexes , orientation
Postmortem examinations (parental animals):
sacrifice of all animals, investigationmacroscopically and microscopically of reproductive organs,liver, spleen, kidneys including organ weight determination, and macroscopically all organs with obvious changes
Postmortem examinations (offspring):
only macrospcopical investigation if found dead in cage
all offsprings all organs which demonstated macroscopically changes
Statistics:
arithmetic mean, variance analysis followed by Schffe-test, H-test of Kruskal and Wallis or U-test accorcing to Wilcoxon, Mann and Whitney,Chi-square test
Reproductive indices:
Fertility index, Gestation index
Offspring viability indices:
survival index (day 4), lactation index (day 21)

Results and discussion

Results: P0 (first parental generation)

Details on results (P0)

no mortality in P-generation, sacrifice of 4 moribund animals in F1 of 270 mg-group and 1 in 30 mg-group of F1
P-Generation body weight comparable to controls; F1 (high dose group reduced body weight development compared to controls
P-and F1-generation : no effects of test substance on Fertility Index and Gestation Index
Pathology:
P-generation:high dose and F1-generation high dose and mid dose:
males: increased relative and absolute weights of liver and kidneys, decreased spleen weights, histopathological changes in kidney but not in livers

Effect levels (P0)

open allclose all
Dose descriptor:
other: NOAEL (fertility)
Effect level:
270 mg/kg bw/day (actual dose received)
Sex:
male/female
Basis for effect level:
other: The NOAEL for fertility was estimated to be 270 mg/kg/day;
Remarks on result:
other: Generation: P and F1 (migrated information)
Dose descriptor:
other: NOAEL (general toxicity)
Effect level:
90 mg/kg bw/day (actual dose received)
Sex:
male/female
Basis for effect level:
other: the NOAEL of the P and F1 parents was found to be 90 mg/kg/day based on kidney changes at the highest test dose;
Remarks on result:
other: Generation: P and F1 (migrated information)
Dose descriptor:
other: NOAEL (offspring)
Effect level:
30 mg/kg bw/day (actual dose received)
Sex:
male/female
Basis for effect level:
other: at 90 mg/kg/day toxicity in pups were seen associated with slight behavioral changes in pups from 90 mg/kg/day: the NOAL for these developmental effects is estimated at 30 mg/kg/day.
Remarks on result:
other: Generation: F1 and F2 (migrated information)

Results: F1 generation

Details on results (F1)

In the mid and the high dose groups :
reduced number of live pups at birth, increased number of pups deceased between days of lactation 1 to 4 and 5 to 21, reduced mean body weight of pups, retarded erection of ears and retarded of eye opening, reduced percentage of pups with positive draw-up test, dry and squamous skin and ring tails in pups followed by loss of the tail

Overall reproductive toxicity

Reproductive effects observed:
not specified

Any other information on results incl. tables

The NOAEL for fertility was estimated to be 270 mg/kg/day; the NOAEL of the F0 and F1 parents was found to be 90 mg/kg/day; at 90 mg/kg/day toxicity in pups were seen associated with slight behavioral changes in pups from 90 mg/kg/day: the NOAEL for these developmental effects is estimated at 30 mg/kg/day.

Applicant's summary and conclusion

Executive summary:

p-Dichlorobenzene, dissolved in olive oil, was administered orally to two generations of rats to detect possible effects of the test substance on reproduction (OECD guideline 416 and GLP). The doses used for the three test substance groups were 30, 90 and 270 mg/kg bw/day. Olive oil was applied to one group of male and female rats that served as control group. Dose volume was 1 ml per kg body weight for all groups.

In both generations the test substance had no effects on: time between beginning of mating and evidence of copulation,

time of gestation, fertility index, gestation index, percentage of dams with only dead pups, total number of pups at birth,

percentage of pups with positive ear reflex, graspring reflex and orientation reaction, absolute and relative weights of

female kidneys, spleens and livers.

In the mid and/or high dose groups the test substance had an effect on number of live pups at birth (reduced), number of pups deceased between days of lactation 1 to 4 and 5 to 21 (increased), mean body weight of pups (reduced), erection of ears

and opening of eyes (retarded), percentage of pups with positive draw up test (reduced), alterations of the skin (dry,

squamous) and ring tails in pups, absolute and relative organ weights of adult males (livers and kidneys: increased;

spleens: reduced).damages to the kidneys in mild-and high-dose groups of both generations are also probably test

substance related.

At the low dose of 30 mg test substance per kg body weight no effects of the test substance were detected on fertility parameters of rats; the next higher dose of 90 mg/kg already caused massive damage in pups.

The NOAEL for fertility was estimated to be 270 mg/kg/day; the NOAEL of the F0 and F1 parents was found to be 90 mg/kg/day; at 90 mg/kg/day toxicity in pups were seen associated with slight behavioral changes in pups from 90 mg/kg/day: the NOAEL for these developmental effects is estimated at 30 mg/kg/day.

Overall, the NOAEL for fertility was estimated to be 270 mg/kg bw/day, the NOAEL(genral toxicity) for P and F1 parents was found to be 90 mg/kg bw/dayand the NOAELis estimated at 30 mg/kg bw.