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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: OECD guideline not defined.

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1985

Materials and methods

Principles of method if other than guideline:
Method: other: Teratogenicity
Groups of inseminated female rabbits were exposed to 0, 100, 300 or 800 ppm (approx. 590, 1770 or 4720 mg/m³) p-dichlorobenzene, 6 h/day on gestation day 6 -18.
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Test material form:
other: solid
Details on test material:
IUCLID4 Test substance: other TS: purity = 99.9 %

Test animals

Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
TEST ANIMALS
- Weight at study initiation: 3.5 - 4.5 kg
- Housing: individually
- Diet ad libitum
- Water ad libitum
- Acclimation period: 2 weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22
- Humidity (%): 59
- Photoperiod (hrs dark / hrs light) 12 / 12:

Administration / exposure

Route of administration:
inhalation
Type of inhalation exposure (if applicable):
whole body
Vehicle:
air
Details on exposure:
p-dichlorobenzene was vaporized by passing air through glass tubes packed with small pieces of p-dichlorobenzene,. the vapor was swept from the tubes with conmpressed air into the air inlet ducts of the chamberes to achieve adequate vaporization
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
the concentration in each chamber was determined at least once per hour by using a gas chromatograph
Details on mating procedure:
Rabbits were artificially inseminated as described by Gibson et al 1966:Toxicol Appl Pharmacol 9, 398-408
Duration of treatment / exposure:
d 6 - 18 of gestation
Frequency of treatment:
6 h/d
Duration of test:
at least up to day 29 of gestation
Doses / concentrations
Remarks:
Doses / Concentrations:
100, 300 or 800 ppm (590, 1770 or 4720 mg/m³)
Basis:

No. of animals per sex per dose:
control : 28, 100, 300 ppm: 24 each; 800 ppm 28
Control animals:
yes, concurrent vehicle
Details on study design:
Groups of inseminated female rabbits were exposed to 0, 100, 300 or 800 ppm (approx. 590, 1770 or 4720 mg/m³) p-dichlorobenzene, 6 h/day on gestation day 6 -18.
Duration of test: section on d 29 of gestation

Examinations

Maternal examinations:
mortality, body weight development. clinical signs
Ovaries and uterine content:
corpora lutea, implantation sites, Resorptions
Fetal examinations:
number of litters, sex ratio, fetal body weight, fetal crown-rump length, visceral and skeletal anomalies
Statistics:
Bartlett's test, ANOVA, Dunnett's test,Wicoxon-Bonferroni test
Indices:
no data

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
A single pregnant rabbit in the 300-ppm exposure group was found dead after exposure on Day 10 of gestation. Gross pathologic examination of
this animal revealed multiple large intrathoracic abcesses which presumably interfered with both the circulatory and respiratory systems. According to the authors these lesions were not considered to be treatment related.
No other significant changes in gross appearance or demeanor
were observed among PDCB-exposed rabbits.
800 ppm-group:
pregnant rabbits gained significantly less weight than controls on Days 6 through 8 of gestation
In general, rabbits in the 800-ppm group gained slightly (not significant) less weight
than controls (28 vs 185 g) during the period
of exposure, Days 6 through 18 of gestation.
100, 300, 800 ppm-groups:
There were no significant effects on the absolute or relative weights of the liver or kidneys in any of the exposed groups compared to controls.

Effect levels (maternal animals)

Dose descriptor:
NOAEC
Effect level:
300 ppm
Basis for effect level:
other: maternal toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Details on embryotoxic / teratogenic effects:
No signs of embryotoxicity.
The number of corpora lutea, implantation, number of live foetuses foetus and litter weight, and the sex ratios were not significantly different from those of the control group. A statistically significant increased number of resorptions was noted only at 300 ppm(within the normal interval of the historical controls of the laboratory), not considered to be indicative of an embryolethal effect. Minor abnormalities were noted at 800 ppm, including ther retro-oesophgeal subclavianartery (5% of the foetuses (6/119) versus 2 % in the laboratory control group), deformation of paws on flexion (5% of the foetuses versus 0% in control group), not considered to be indicative of a teratogenic response.
However, the total number of major birth defects and of skeletal and visceral birthdefects as a whole was not significantly different in treated and control groups

Effect levels (fetuses)

Dose descriptor:
NOAEC
Effect level:
>= 800 ppm
Basis for effect level:
other: teratogenicity

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Any other information on results incl. tables

RS-Freetext:
No treatment-related mortality; no significant changes in
gross appearance or demeanor; slight maternal toxicity at
800 ppm as indicated by significantly decreased body weight
gain during the first 3 d of exposure; no significant
effects on the absolute or relative liver or kidney weight
at any exposure level; a significant increase in the
incidence of implantations undergoing resorption at 300 ppm
(63 % of the litters contained resorptions; controls: 29 %;
historical controls: 40 % (range 0 - 70 %)) was not
considered to be indicative of an embryolethal effect; not
significantly altered litter size, and fetal weight and
crown-rump length among litters of exposed animals compared
to controls; no significantly increased incidences of major
malformations at all exposure levels; a significant increase
in the incidence of a retroesophageal right subclavian
artery at 800 ppm (5 litters versus 1 in control) was not
considered to be indicative of a teratogenic response.

Applicant's summary and conclusion

Executive summary:

p-Dichlorobenzene was evaluated for teratogenic potential in New Zealand White rabbits. Groups of inseminated female rabbits were exposed to 0, 100, 300 or 800 ppm (approx. 590, 1770 or 4720 mg/m³) p-dichlorobenzene, 6 h/day on gestation day 6 -18. Slight maternal toxicity was observed in groups of rabbits exposed to 800 ppm of the test substance as evidenced by significantly decreased body weight gain during the first 3 days of exposure. The maternal NOAEC was found to be 300 ppm; the NOAEC for teratogenicity is 800 ppm because p-dichlorobenzene vapor was not enbryotoxic or teratogenic in rabbits at any of the exposure levels used in this study.