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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)
Rationale for reliability incl. deficiencies:
other: The GLP-study was performed according to an internationally accepted guideline (US EPA 83-3). All study parameters are well documented and are based on the specific guideline.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1988
Report Date:
1988

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
EPA OPP 83-3 (Prenatal Developmental Toxicity Study)
Deviations:
no
GLP compliance:
yes
Limit test:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent

Test animals

Species:
rat
Strain:
other: Bor: WISW (SPF Cpb)

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: 0.5 % aqueous Cremophor-EL emulsion
Analytical verification of doses or concentrations:
yes
Details on mating procedure:
Mating was carried out overnight: one male was placed with two females in a type III Makrolon cage. If sperm were detected in the vaginal swab on the morning after mating this counted as day zero of pregnancy.
Duration of treatment / exposure:
25 inseminated Wistar rats per group received 1,2,4-triazole on days 6 to 15 of pregnancy in daily oral doses of 0, 10, 30 or 100 mg/kg bodyweight.
Frequency of treatment:
once daily
Duration of test:
The females underwent Caesarian section on day 20 of pregnancy.
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day (nominal)
Dose / conc.:
10 mg/kg bw/day (nominal)
Dose / conc.:
30 mg/kg bw/day (nominal)
Dose / conc.:
100 mg/kg bw/day (nominal)
No. of animals per sex per dose:
25 females per dose group
Control animals:
yes, concurrent vehicle
Details on study design:
Doses of 0, 10, 30 and 100 mg/kg bodyweight were chosen for the tests. The
compound was orally administered as oral administration is well-suited and
internationally-recognised in embryotoxicological studies. Dosages were fixed
on the basis of a preliminary study using doses of 1000 and 3000 mg/kg which
had a high maternal toxicity.
The investigations were carried out in the Laboratory of Reproduction
Toxicology, the Institute of Toxicology, Agrochemicals , of the Fachbereich
Toxikologie, , Wuppertal, Friedrich-Ebert-Strasse 217 - 333 during the
period February to March 1985. They were carried out in agreement with the
OECD guidelines for good laboratory practice

Examinations

Maternal examinations:
Appearance and behaviour, mortality, body weight-gain
Ovaries and uterine content:
The females underwent Caesarian section on day 20 of pregnancy. The following investigations were carried out:

a. Determination of number of nidations

b. Determination of number of foetuses/embryos that survived or died (dams without surviving foetuses were evaluated as not pregnant)

c. Determination of sex of all surviving foetuses

d. Determination of weight of each foetus and average foetal weight per litter as well as runts (for definition see page 19)

e. Determination of total and average placental weight per litter

f. Detailed examination of all foetuses for external malformations

g. Investigation of a number of foetuses for visceral malformations according to the modified WILSON technique (1,2)

h. Evisceration of remaining foetuses and evaluation of abdominal and chest organs with subsequent cleaning of the foetuses with dilute potassium hydroxide solution and staining of the bone system with alizarin red S and evaluation of the bone system (DAWSON).
Statistics:
The following statistical methods were used to test for significance:
a. Distribution-free rank sum test according to WILCOXON
(WILCOXON-MANN-WHITNEY-U-TEST), e.g. for weight-gain, number of
nidations, foetuses and resorptions.
The calculations were carried out in the Institute of Biometrics PH-DB, BAYER
AG within the framework of an evaluation programme developed for
embryotoxicitY tests.
b. Chi-squared test (correction after YATES), e.g. for number of runts
c. Chi-squared test (correction after YATES or so-called exact test
according to FISHER - depending on frequency expected) for numbers of
fertilised and pregnant animals.
These calculations were carried out with an HP 97 in case there were abnormal
differences compared with the controls.
Statistical significance has been taken as a probability of 5% or less of this
difference occurring by chance.

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Mean weight-gain in the study groups during administration and throughout
pregnancy is given in the following table (for individual results see tables 1
to 4 in appendix):
Study group mean weight-gain of
pregnant animals in grams during
administration entire pregnancy
Control 28.2 92.9
10 mg/kg 25.4 86.6
30 mg/kg 26.8 90.0
100 mg/kg 21.8* 79.8*
* p < 0.05
Treatment with 1,2,4-triazole impaired the weight-gain of the pregnant animals
in the 100 mg/kg group.

Maternal developmental toxicity

Number of abortions:
no effects observed
Description (incidence and severity):
1,2,4-triazole produces no effect on the number of pregnancies. One animal in
group 2 was not evaluated as medication was not properly administered.
Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
The weight-gain of the dams in the 100 mg/kg group was lower than the control animals throughout the entire pregnancy as well as during administration.The following parameters were unaffected up to a dose of 30 mg/kg
1,2,4-triazole:
number of surviving foetuses per litter
number of resorptions per litter
mean foetal and placental weight per litter
number of foetuses with slight bone changes per litter
number of runts per litter (for definition see page 19)
number of foetuses with malformations per litter

Effect levels (maternal animals)

Key result
Dose descriptor:
NOAEL
Effect level:
30 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
body weight and weight gain
other: maternal toxicity
Remarks on result:
other: decrease maternal body weight

Results (fetuses)

Fetal body weight changes:
effects observed, treatment-related
Description (incidence and severity):
The significantly lower foetal weight and the simultaneously greater number of
runts in the 100 mg/kg group can be seen in conjunction with maternal
toxicity. The lower number of male foetuses in the 10 mg/kg and 100 mg/kg
group must be coincidenta
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:yes

Details on embryotoxic / teratogenic effects:
Foetal weight in the 100 mg/kg group was reduced and there was a higher incidence of runts.
1,2,4-triazole T5019339

Effect levels (fetuses)

Key result
Dose descriptor:
NOAEL
Effect level:
30 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
female
Basis for effect level:
fetal/pup body weight changes
other: decrease fetal body weight and increase number of runts

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Key result
Developmental effects observed:
yes
Lowest effective dose / conc.:
100 mg/kg bw/day (nominal)
Treatment related:
yes
Relation to maternal toxicity:
developmental effects as a secondary non-specific consequence of maternal toxicity effects
Dose response relationship:
yes
Relevant for humans:
no

Applicant's summary and conclusion

Conclusions:
Conclusion from study report:
25 inseminated Wistar rats per group received 1,2,4-triazole on days 6 to 15 of pregnancy in daily oral doses of 0, 10, 30 or 100 mg/kg bodyweight.

The dams were examined with regard to bodyweight, appearance and behaviour. The foetuses obtained by Caesarian section on day 20 of pregnancy were investigated for embryotoxic effects by weighing and by observing the external and internal morphological changes.

No treatment-related fatalities occurred. The weight-gain of the dams in the 100 mg/kg group was lower than the control animals throughout the entire pregnancy as well as during administration.

Foetal weight in the 100 mg/kg group was reduced and there was a higher incidence of runts.

There was no evidence of possible teratogenicity. 30 mg/kg produced no damage in either dams or foetuses.
Executive summary:

25 inseminated Wistar rats per group received 1,2,4-triazole on days 6 to 15 of pregnancy in daily oral doses of 0, 10, 30 or 100 mg/kg bodyweight. The dams were examined with regard to bodyweight, appearance and behaviour. The foetuses obtained by Caesarian section on day 20 of pregnancy were investigated for embryotoxic effects by weighing and by observing the external and internal morphological changes. No treatment-related fatalities occurred. The weight-gain of the dams in the 100 mg/kg group was lower than the control animals throughout the entire pregnancy as well as during administration. Foetal weight in the 100 mg/kg group was reduced and there was a higher incidence of runts. There was no evidence of possible teratogenicity. 30 mg/kg produced no damage in either dams or foetuses.