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Administrative data

Key value for chemical safety assessment

Effects on fertility

Link to relevant study records
Reference
Endpoint:
toxicity to reproduction
Data waiving:
other justification
Justification for data waiving:
other:
Reproductive effects observed:
not specified
Effect on fertility: via oral route
Endpoint conclusion:
no study available
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

No effects on reproductive organs and tissues were observed in any of the repeated dose studies. In the pre-natal developmental toxicity study no statistically relevant effects on reproductive performance were observed.


Short description of key information:
Chronic toxicity (18 month) study rat: No effects on spermatogenesis and no effects on follicular maturation and evolution of corpus luteum were obeserved.
Sub-chronic toxicity study rat (VEB Oschersleben): no effects on testis and ovarium
Sub-chronic toxicity study mouse (RCC): no effects on testis

Pre-natal developmental toxicity:
Reproductive performance of dams:
The conception rate varied between 88% (15 mg/kg group) and 100% (45 and 90 mg/kg groups).
There were no substance-related and/or statistically significant differences of biological relevance between the groups in conception rate, in the mean number of corpora lutea and implantation sites, in the values calculated for the pre- and the postimplantation losses or in the number of resorptions and viable fetuses. The differences evident are considered to be incidental and within the normal range of deviations for animals of this strain and age.

Effects on developmental toxicity

Description of key information
Pre-natal developmental toxicity:
90 mg/kg: marked maternal toxicity; embryo-/fetotoxicity, including clear indications for teratogenicity
45 mg/kg: marked maternal toxicity; embryo-/fetotoxicity, no indications for any substance-related teratogenic effect
3 -Methyl-pyrazol caused marked signs of maternal toxicity at 90 mg/kg body weight/day and was still clearly toxic to the dams at 45 mg/kg body weight/day; 15 mg/kg body weight/day were tolerated by the dams without any adverse substance-related effects. Signs of embryo-/fetotoxicity, including clear indications for teratogenicity, occurred at the highest dose level; besides reduced fetal body weights and signs for a delayed ossification of the fetal skeletons, malformations of the urogenital tract, the cardiovascular system and the thoracic vertebral bodies were seen in a considerable number of high dose fetuses. In the 45 mg/kg fetuses embryo-/fetotoxic effects, but no indications for any substance-related teratogenic effect were observed, whereas no signs of developmental toxicity were found at the dose of 15 mg/kg body weight/day.
Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1992-02-21 - 1992-10-16
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP-study
Qualifier:
according to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Limit test:
no
Species:
rat
Strain:
Wistar
Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
The test substance was administered to the animals orally (by gavage) once a day during the period of major organogenesis (day 6 to day 15 p.c.). The volume administered each day was 10 ml/kg body weight. The calculation of the volume administered was based on the individual body weight determined at the beginning of the administration period (day 6 p.c.).
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Analytical verifications of the stability of the aqueous test substance solutions over a period of
3 hours were carried out during the study. Furthermore, samples of the test substance solutions were sent to the analytical laboratories of BASF Aktiengesellschaft twice during and - in addition to times scheduled in the study protocol - also after the end of the study period for verification of the concentrations.*

The test substance solutions were analyzed by GC.
Details on mating procedure:
Mating took place from about 16.00 hours to about 7.30 hours on the following day. If sperm were detected microscopically in the vaginal smear in the morning, the animals were considered to be fertilized. This day was designated "day 0" (beginning of the study) and the following day "day 1" post coitum (p.c.).
Duration of treatment / exposure:
The test substance was administered to the animals orally (by gavage) once a day during the period of major organogenesis (day 6 to day 15 p.c.).
Duration of test:
20 days post coitum)
Remarks:
Doses / Concentrations:
15, 45 and 90 mg/kg body weight
Basis:
analytical conc.
No. of animals per sex per dose:
25 pregnant female rats per dose group
Control animals:
yes, concurrent vehicle
Maternal examinations:
Food consumption, body weight, body weight gain , clinical symptoms, mortality, preimplantation loss, postimplantation loss, gross pathology
Ovaries and uterine content:
Weight of uterus before it was opened,
number and distribution of implantation sites classified as : live fetuses, dead implantations (early resorptions, late resorptions, dead fetuses)
Fetal examinations:
Macroscopic examination, determination of sex, viability, condition of the placentae, examination of the umbilical cords, the fetal membranes and fluids, placental weights, soft tissue examination of the fetuses, skeletal examination of the fetuses
Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
Dose group: 90 mg/kg
-reduced food consumption
-significantly lower body weights

Dose group: 45 mg/kg
-reduced food consumption
Dose descriptor:
NOAEL
Effect level:
15 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEL
Effect level:
15 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: developmental toxicity
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:yes

Details on embryotoxic / teratogenic effects:
Dose group 90 mg/kg:
-reduced fetal body weights
-delayed ossification
-malformations of the urogenital tract, cardiovascular system, thoracic vertebral bodies

Dose group: 45 mg/kg
-significantly lower fetal body weights
-no teratogenic effects
Abnormalities:
not specified
Developmental effects observed:
not specified
Conclusions:
Under the conditions of the described test, the no observable adverse effect level (NOAEL) on the maternal and fetal organism was 15 mg/kg body weight/ day.
Executive summary:

3 -Methyl-pyrazol caused marked signs of maternal toxicity at 90 mg/kg body weight/day and was still clearly toxic to the dams at 45 mg/kg body weight/day; 15 mg/kg body weight/day were tolerated by the dams without any adverse substance-related effects. Signs of embryo-/fetotoxicity, including clear indications for teratogenicity, occurred at the highest dose level; besides reduced fetal body weights and signs for a delayed ossification of the fetal skeletons, malformations of the urogenital tract, the cardiovascular system and the thoracic vertebral bodies were seen in a considerable number of high dose fetuses. In the 45 mg/kg fetuses embryo-/fetotoxic effects, but no indications for any substance-related teratogenic effect were observed, whereas no signs of developmental toxicity were found at the dose of 15 mg/kg body weight/day.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
15 mg/kg bw/day
Species:
rat
Quality of whole database:
The key study is GLP-compliant and of high quality.
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

No (non-maternal mediated) developmental effects were seen in the pre-natal developmental toxicity study.


Justification for selection of Effect on developmental toxicity: via oral route:
Only one reliable GLP-study available.

Justification for classification or non-classification

According to the Guidance of the Application of the CLP criteria, ECHA, Version 3.0, 11/2012, for the purpose of classification for reproductive toxicity, allocation of substances into category 2 is defined as follows (citiation):

Category 2: “Suspected human reproductive toxicant"

"Substances are classified in Category 2 for reproductive toxicity when there is some evidence from humans or experimental animals, possibly supplemented with other information, of an adverse effect on sexual function and fertility, or on development, and where the evidence is not sufficiently convincing to place the substance in Category 1. If deficiencies in the study make the quality of evidence less convincing, Category 2 could be the more appropriate classification. Such effects shall have been observed in the absence of other toxic effects, or if occurring together with other toxic effects the adverse effect on reproduction is considered not to be a secondary non-specific consequence of the other toxic effects.”

Furthermore it is stated that (citation): “Classification shall not automatically be discounted for substances that produce developmental toxicity only in association with maternal toxicity, even if a specific maternally mediated mechanism has been demonstrated. In such a case, classification in Category 2 may be considered more appropriate than Category 1.”

In the pre-natal developmental toxicity study with 3 -Methylpyrazole after oral gavage clear maternal toxicity (reduced body weights and food and water consumption) was evident at the tested doses of 90 and 45 mg/kg bw/d. Therefore it can be stated that the effects on offspring ( decreased pup weights, urogenital and cardiovascular malformations, sceletal deformations, delayed ossification) are related to the toxic effect of 3 -Methylpyrazol on the maternal organism such that the observed effects are probably of an indirect (secondary) nature.

Since other suspicious facts for developmental toxicity from literature (urogenital syndrom) are available, 3 -Metylpyrazol is classified as "Suspected human reproductive toxicant" (Repr. Tox. Cat.2).

Additional information