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Administrative data

Key value for chemical safety assessment

Toxic effect type:
dose-dependent

Effects on fertility

Description of key information

For this endpoint information from a structural similar compound is available. The study for this similar compound was performed according to GLP and the methods applied are fully compliant with OECD TG 422. For the analogue, a Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test in the rat revealed an NOAEL (systemic toxicity and reproduction parameters) = 15 mg/kg body weight/day. Comparing the systemic toxicity data for the source and target compound shows no effects on adrenal glands and overall increased effect levels for the target compound. The read across for the reproductive toxicity and, in particular for effects on fertility observed for the source compound as secondary effect, thus reflects a worst-case scenario for the target molecule.

Link to relevant study records
Reference
Endpoint:
screening for reproductive / developmental toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Justification for type of information:
For this endpoint information from a structural similar compound is available. The study for this similar compound was performed according to GLP and the methods applied are fully compliant with OECD TG 421.
See chapter 13 report for a more detailed justification.
Reason / purpose:
read-across source
Key result
Dose descriptor:
NOAEL
Remarks:
reporductive performance
Effect level:
15 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
reproductive performance
Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
45 mg/kg bw/day (actual dose received)
System:
hepatobiliary
Organ:
liver
Treatment related:
yes
Dose response relationship:
yes
Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
45 mg/kg bw/day (actual dose received)
System:
endocrine system
Organ:
adrenal glands
Treatment related:
yes
Dose response relationship:
yes
Description (incidence and severity):
see source record for details
Key result
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
135 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no treatment-related effects were seen
Key result
Critical effects observed:
no
Key result
Reproductive effects observed:
yes
Lowest effective dose / conc.:
45 mg/kg bw/day (actual dose received)
Treatment related:
yes
Relation to other toxic effects:
reproductive effects as a secondary non-specific consequence of other toxic effects
Dose response relationship:
yes
Conclusions:
For this endpoint information from a structural similar compound is available. The study for this similar compound was performed according to GLP and the methods applied are fully compliant with OECD TG 421.
In conclusion, the source compound showed a no adverse effect level (NOAEL) regarding systemic toxicity and reproduction parameters of 15 mg/kg.
See chapter 13 report for a more detailed justification.
Effect on fertility: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
15 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
OECD Guideline study under GLP conditions
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test performed for the structural analogue

Daily oral treatment by gavage of 15 mg/kg of the test item to rats according to the study design was tolerated whereas doses of 45 or 135 mg/kg caused cortical atrophy of the adrenal glands was observed in both sexes. A statistical significant weight reduction of both absolute and relative weights correlates to this effect. The most prominent findings regarding reproduction parameters was an increased number of resorptions in at 45 and 135 mg/kg. Related to this, the number of live pups and litter weights were decreased in these groups on days 0 and 4 p.p.. In addition, the following findings were noted: a slightly higher variation of pregnancy duration and a reduced number of females with live young was observed at 135 mg/kg. Prenatal loss (implantations minus live births) was increased at 45 and 135 mg/kg. Post-natal loss (live births minus alive at post natal day 4) was only noted at 45 mg/kg and 135 mg/kg, however, only at a very low incidence. The number of corpora lutea and implants was slightly reduced at 135 mg/kg, whereas the number of resorptions was increased at 45 and 135 mg/kg. No treatment-related effects on male or female fertility were observed. In conclusion, the no adverse effect level (NOAEL) regarding systemic toxicity and reproduction parameters is considered to be 15 mg/kg bw/d for the structural analogue substance.

 

At dose levels of 45 and 135 mg/kg reduced body weight gain and morphological changes in the adrenal cortex were identified as treatment-related changes in the dams. For both effects a dose-dependency could be established. Fetal effects consisted predominately of early resorptions and occurred only at dose levels which also produced maternal toxicity. The maternal effects suggest that the metabolic demand in pregnant animals was not fully met and subsequently early resorptions occurred. Cortical adrenal atrophy is considered to lead to reduced levels of circulating glucocorticoids. Adrenal insufficiency has been shown to be associated with substantial reproductive impaiment. Since glucocorticoides are important for protein and carbohydrate metabolism as well as for pregnancy, parturition and lactation, it is reasonable to conclude that the reproductive effects are secondary to the maternal toxicity rather than an expression of intrinsic reproductive toxicity of the test item.

 

Under the condictions of this study, the test item showed no effects attributable to specific reproduction and /or developmental toxicity.

Effects on developmental toxicity

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available

Justification for classification or non-classification

Classification, Labelling, and Packaging Regulation (EC) No 1272/2008

The available experimental test data obtained for the registered compound (OECD 407) and for the structural analogue (OECD 422) are reliable and suitable for classification purposes under Regulation (EC) No 1272/2008. Based on available data on toxicity to reproduction the test item does not require classification according to Regulation (EC) No 1272/2008 (CLP), as amended for the twelfth time in Regulation (EU) 2019/521.