Registration Dossier

Diss Factsheets

Toxicological information

Developmental toxicity / teratogenicity

Currently viewing:

Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
3 (not reliable)
Rationale for reliability incl. deficiencies:
other: Female rats were treated only one time. Less than 20 females/group were used. The purity of substance is unknown.

Data source

Reference
Reference Type:
publication
Title:
Structure-activity relationships in the developmental toxicity of substituted phenols: in vivo effects
Author:
Kavlock R.J
Year:
1990
Bibliographic source:
Teratology, 41(1), 43-59.

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
Developmental toxicity
GLP compliance:
not specified
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Pyrocatechol
EC Number:
204-427-5
EC Name:
Pyrocatechol
Cas Number:
120-80-9
Molecular formula:
C6H6O2
IUPAC Name:
pyrocatechol
Details on test material:
Obtained from Aldrich, purity unspecified.

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratory, Raleigh, NC.
- Age at study initiation: 65-70 timed pregnant primaparous rats
- Weight at study initiation: 180-200 g
- Housing: individually in solid-bottom cages on wood shaving bedding
- Diet: Purina laboratory chow ad libitum
- Water: ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24°C
- Humidity (%): 40-50%
- Photoperiod (hrs dark / hrs light): 12:12 hours photoperiod

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: water, Tween 20, propylene glycol, and ethanol in a ratio of 4:4:1:1
Details on exposure:
- Treated rats were given either 333, 667, or 1000 mg/kg catechol by oral intubation on day 11 of gestation.
- The control group consisted of 20 females, while 15 were included in each treated group.
- Intubation volume was 10 mg/kg b.w.; control animals received vehicle alone.
Analytical verification of doses or concentrations:
no
Details on mating procedure:
No details.
The day that sperm were found in the vaginal smear was considered day 1 of pregnancy
Duration of treatment / exposure:
day 11 of gestation
Frequency of treatment:
single
Duration of test:
until weaning
No. of animals per sex per dose:
12-16 females in treated groups, 15-20 females in control group.
Control animals:
yes, concurrent vehicle

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: yes
- Time schedule: females carefully observed for several hours after dosing to observe any signs of toxicity (tremors, convulsions, vocalizations, labored breathing, salivation, lacrimation, . . .)

BODY WEIGHT: Yes
- Time schedule for examinations: Females were weighed on days 10, 11, 12, 14, 17, and 21 of gestation to provide information on the adult toxicity of catechol

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice at weaning
- Organs examined: number of implantation scars in the uterus

No more data.
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Number of implantations: Yes
No more information
Fetal examinations:
The viability and weight of the offspring were determined on postnatal days 1, 3, and 6. Litters were maintained until weaning and examined for previously undetected external malformations. Perinatal loss of offspring was calculated as the difference between the number of implantation sites and
the litter size on postnatal day 6.
Statistics:
- The maternal weight change, perinatal loss, and litter biomass on post natal days 1 and 6 were subjected to linear regression analysis.

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
One, 5, and 10 of 15 rats died in the 333, 667, and 1000 mg/kg b.w. catechol treated groups, respectively.
13, 9, and 5 of 15 rats were pregnant in the 333, 667, and 1000 mg/kg b.w. catechol treated groups, respectively.
Body weight gains were significantly reduced 24 h or 72 h after treatment in all catechol-treated groups: At 24h maternal body weight change (g) were: 5 +/- 1, -8 +/- 3, -12 +/- 2, -16 +/- 5, for 0, 333, 667, 1000 mg/kg respectively and at 72h: 20 +/- 1, 11 +/- 3, -7 +/- 6, -29 +/- 7 for 0, 333, 667, 1000 mg/kg respectively.

Effect levels (maternal animals)

Dose descriptor:
LOAEL
Effect level:
< 333 mg/kg bw (total dose)
Based on:
test mat.
Basis for effect level:
body weight and weight gain
mortality

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:yes

Details on embryotoxic / teratogenic effects:
- Offspring toxicity:
At the postnatal day 1 pup weights(g) were 6.5 +/- 0.1, 6.6 +/- 0.1, 6.4 +/- 0.1, 5.7 +/- 0.3, for 0, 333, 667, 1000 mg/kg respectively and at the postnatal day 6: 12.5 +/- 0.4, 13.0 +/- 0.4, 12.8 +/- 0.4, 11.6 +/- 0.4 for 0, 333, 667, 1000 mg/kg respectively.
At the postnatal day 1, the litter size was significantly reduced in the 1000 mg/kg b.w. treated group.
At the postnatal day 2, the litter size was significantly reduced from the 667 mg/kg b.w. treated group.
Perinatal loss was significantly induced from the 667 mg/kg b.w. treated group.
At the postnatal day 1, the litter biomass was significantly reduced from the 667 mg/kg b.w. treated group.
- A syndrome of malformation involving the limbs, tail and urogenital system was observed for catechol. The limb effects, which predominantly were observed in the hindlimbs, consisted of paralysis and/or palsy. In the animals with palsy, the limb function would alternate between normal strides and a several second period of tetany. Because limb function matures postnatally, this effect was not evident in the newborn but required a week to 10 days to become obvious.
The litter incidence of hindlimb paralysis and/or short kinky tails was 23.1%, 66.7% and 80.0% for 333, 667 and 1000 mg/kg respectively of catechol.
- The significance level chosen was p < 0.05.

Effect levels (fetuses)

Dose descriptor:
NOEL
Effect level:
333 mg/kg bw (total dose)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
changes in litter size and weights

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Any other information on results incl. tables

The test was a quantitative approach relating the physical-chemical  properties of molecules to biological effects, and was applied to a series of 

substituted phenols tested for developmental toxicity.

Applicant's summary and conclusion