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Key value for chemical safety assessment

Toxic effect type:
dose-dependent

Effects on fertility

Description of key information

Based on the findings in the screening study no effects on fertility were observed.

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
60 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
One screening 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

Short description of key information:
The parental NOAEL of reproductive toxicity was considered to be 60 mg/kg/day for male and female rats. No higher doses were tested.

Justification for selection of Effect on fertility via oral route:
Only one study available

Effects on developmental toxicity

Description of key information
Based on the findings of a screening study and a prenatal developmental toxicity study, no adverse effects on development were observed.
Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
150 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
one screening 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

Mode of Action Analysis / Human Relevance Framework

The OECD 407 reported adverse effects at 75 mg/kg bw, but it showed in the OECD 408 that these reported effects (increased kidney size, decreased adrenal gland, effect on serum potassium) do not prolong in longer exposure. Therefore these effects are rated as non-adverse for long-time exposure. In addition, the OECD 408 uses more animals per dose group, and hence presents a statistically more robust data basis.


The NOAEL for Hazard assessment is 150 mg/kg bw/day, derived from the OECD 408 90 day study.


Effects seen in the OECD 408 study are either rated as non-adverse (effects seen only in high dose group) or present a species and sex specific effect  (hyaline droplets in male rats, all groups including control).https://ntp.niehs.nih.gov/nnl/urinary/kidney/rtaccum/kidney-renal-tubule-accumulation-hyaline-pdf_508.pdf


An alteration of Thyroid hormone levels is seen in the OECD 414 study only in the highest dose level. In addition severe toxicity was observed in this dose group. 9 of 22 female animals died or were euthanised for humane reason during the exposure period. Therefore, no statistical evaluation was done for this dose group by the conducting laboratory.


Although the exact mechanism leading to death is not further investigated, it is assumed that the surviving animals were affected to a lesser extent as well.


In addition no effect on hormone levels was seen in any other dose group of the OECD 414 study or in the OECD 408 study. For the previously conducted OECD 421 and 407 studies, no information on thyroid hormone levels is available.


 


The alteration of the hormone levels is therefore rated as a secondary effect of the general toxicity of the substance leading to the death of the animals.

Justification for classification or non-classification

The presented data for toxicity to reproduction is reliable and an adequate guideline study. The observations within the study are conclusive but not sufficient for a classification according to Regulation (EC) No. 1272/2008.

Additional information