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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:
1 (reliable without restriction)

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2004
Report date:
2004

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Principles of method if other than guideline:
Study was designed to comply with OECD 414 dated Jan. 22, 2001.
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Resorcinol
EC Number:
203-585-2
EC Name:
Resorcinol
Cas Number:
108-46-3
Molecular formula:
C6H6O2
IUPAC Name:
benzene-1,3-diol
Details on test material:
Resorcinol (AO11) >95% purity.

Test animals

Species:
rat
Strain:
Sprague-Dawley

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: purified water
Duration of treatment / exposure:
6-19 days of gestation
Frequency of treatment:
Daily
Duration of test:
20 days
No. of animals per sex per dose:
24 per group
Control animals:
yes, concurrent vehicle
Details on study design:
A total of 96 pregnant Sprague-Dawley female rats were allocated to four groups (24 per group). Three groups were administered with the test item,
Resorcinol (A011), by gavage once daily from day 6 to day 19 of gestation, inclusive, at the dose-level of 40, 80 or 250 mg/kg/day. One group of
females was only administered with the vehicle, purified water, at the same constant dose volume of 5 mL/kg; individual volumes were adjusted
according to the most recently recorded body weight.

Examinations

Maternal examinations:
The females were sacrificed on day 20 of gestation and subjected to a macroscopic examination.
Fetal examinations:
The numbers of corpora lutea, implantations and live fetuses were recorded. The fetuses were removed from the uterus, weighed, sexed and
externally examined. Half of the fetuses underwent soft tissue examination while the remaining fetuses received a skeletal examination.
Statistics:
Statistical analysis:  Mean values were compared by one-way analysis of variance and the Dunnett test (mean values being considered as normally
distributed and variances being considered as homogeneous). Percentage values were compared by the Fisher exact probability test.

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Details on maternal toxic effects:
Maternal body weight and food consumption: At 250 mg/kg/day, the net body weight change was significantly lower (p>0.05%, -19%) than the
control group value. There were no other treatment effects on maternal body weight, body weight gain or food consumption.

Macroscopic post-mortem examination: No findings recorded at maternal necropsy were considered to be treatment-related.

Pregnancy data: All the group mean numbers of implantations and live fetuses and the extent of pre- and post-implantation losses were comparable with the controls.

Effect levels (maternal animals)

Dose descriptor:
NOAEL
Effect level:
80 mg/kg bw/day
Basis for effect level:
other: maternal toxicity

Results (fetuses)

Effect levels (fetuses)

Dose descriptor:
NOAEL
Effect level:
250 mg/kg bw/day
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

Mortalities and clinical observations: No premature deaths occurred during the study and no clinical observations were considered to be treatment-related.

Fetal data: 

In the treated groups, the mean numbers of corpora lutea, implantation sites, live fetuses, resorptions (early and late) were similar to the control group values.

The mean male and female fetus weights were significantly greater at 250 mg/kg/day, when compared to the controls. This observation was considered to be the consequence of the low control group values (outside the range of the last version of Historical Control Data 3.8 g - 4.5 g, and within the range of the control group values during the period where this study was conducted: 3.6 g - 3.9 g), rather than, an effect of the treatment. The probability to mask an effect in fetal body weights resulting from the low control group value was evaluated but was considered to be with a
very low probability according to the homogeneity of individual fetal body weights, the absence of a dose-related trend in fetal body weights or the good general ossification of the skeletons. The percentage of male fetuses was similar to controls for all groups. As a result, it was concluded
that there were no effects of treatment on fetal body weight.

Fetal abnormalities:
 

No external, soft tissue or skeletal malformations or variations were considered to be treatment-related.

There was a significantly increase in the incidence of fetuses with an incompletely ossified interparietal at 40 and 80 mg/kg/day, when compared to controls (p0.05 and p0.01, respectively). The incidence of incompletely ossified parietals was also significantly greater at 80 mg/kg/day, when compared to controls (p0.05). In the absence of any effects at 250 mg/kg/day these observations were not considered to be treatment-related.

There was a significantly greater incidence of incompletely ossified 5th sternebra at 250 mg/kg/day, when compared to controls (p0.01). The thoraco-lumbar region is known to be particularly labile in the rat and, in the absence of other variations or malformations, this observation was not
considered to be treatment-related.

No fetal malformations or variants were considered to be related to treatment.

Applicant's summary and conclusion

Conclusions:
The maternal No Observed Adverse Effect Level (NOAEL) of Resorcinol (A011) administered by oral route (gavage) to pregnant female rats was
considered to be 80 mg/kg/day based on statistically significant body weight changes and the developmental NOAEL was considered to be
250 mg/kg/day (highest dose tested).