Registration Dossier

Administrative data

Key value for chemical safety assessment

Toxic effect type:
dose-dependent

Effects on fertility

Description of key information

NOAEL (reproduction, sub-acute, rat, oral) ≥ 800 mg/kg bw/day

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
800 mg/kg bw/day
Study duration:
subacute
Species:
rat
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

OECD Guideline 422 (2016): 0, 100, 300 and 800 mg/kg bw/day was administered to Sprague-Dawley rats for 36 days (males) and 50-60 days (females), including a two-week pre-pairing phase, a mating phase, gestation (ca. 22 days) and a post partum phase (14 days) after which all surviving dams were sacrificed along with their litter.

No mortality occurred among males, whereas one control female was sacrificed for difficulties in delivery. One female from each group did not fall pregnant. One high-dose animal experienced total litter resorption. No significant changes in body weight were observed, except a decrease of 24 % body weight during the last week of gestation among high-dose females, probably as a result of foetal toxicity. Oestrous cycle, reproductive parameters and spermatogenic observations were unchanged between control and treatment groups. Increased absolute and relative prostate and seminal vesicle weight (29 % and 38 %, respectively) was observed, and increased triiodothyronine was observed in the high-dose group of males by 54 % (group mean), however these observations were not considered toxicologically relevant. Based on these findings, the NOAEL for reproductive toxicity was considered to be at least 800 mg/kg/day (males and females).

Effects on developmental toxicity

Description of key information

NOAEL (development, sub-acute, rat, oral) < 100 mg/kg bw/day

LOAEL (development, sub-acute, rat, oral) = 100 mg/kg bw/day

Effect on developmental toxicity: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LOAEL
100 mg/kg bw/day
Study duration:
subacute
Species:
rat
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

OECD Guideline 422 (2016): 0, 100, 300 and 800 mg/kg bw/day was administered to Sprague-Dawley rats for 36 days (males) and 50-60 days (females), including a two-week pre-pairing phase, a mating phase, gestation (ca. 22 days) and apost partumphase (14 days) after which all surviving dams were sacrificed along with their litter. The NOAEL for developmental toxicity could not be established due to the following observations in some to all treatment groups:

Total litter loss < 2 days post-partum (1 x mid-dose and 7 x high-dose); total litter resorption (1 x high-dose litter); 8, 9, 8 and 1 animals from the control, low-, mid- and high-dose groups, respectively, had live pups on day 14 post-partum; decreased body weight in last week of gestation among high-dose females, probably due to foetal toxicity); decreased thyroxine (male, mid-dose pups), increased thyroid stimulating hormone (dose-related, not significant); dose-related pup loss at birth; decreased total/live litter size (high-dose); post-natal loss < day 14 post-partum (treatment pups); all but one high-dose dam lost all pups; decreased mean pup/litter weights (treatment groups); increased ano-genital distance (treatment groups); dose-dependent symptoms (smaller than others, cold to touch and with apparently no food intake); autolysis of all abdominal and thoracic organs (almost all deceased mid- and high-dose pups).

Justification for classification or non-classification

According to CLP Regulation (EC) No 1272/2008, reproductive toxicity includes adverse effects on sexual function and fertility in adult males and females, as well as developmental toxicity in the offspring.

For the purpose of classification for reproductive toxicity, substances may be allocated to one of two categories. Within each category, effects on sexual function and fertility, and on development, are considered separately.

- Category 1: Known or presumed human reproductive toxicant. Substances are classified in Category 1 for reproductive toxicity when they are known to have produced an adverse effect on sexual function and fertility, or on development in humans or when there is evidence from animal studies, possibly supplemented with other information, to provide a strong presumption that the substance has the capacity to interfere with reproduction in humans. The classification of a substance is further distinguished on the basis of whether the evidence for classification is primarily from human data (Category 1A) or from animal data (Category 1B).

- 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.

Based on the available information, no significant effect on fertility was observed and adverse effect on development was observed at all concentrations tested (100 to 800 mg/kg bw/day).

This specific effect, not connected with other general toxicity effects is not clear and completely justified by all parameters. More investigations are needing, in order to verify the tested substance, the mechanism and origin of the effectes with specific, more coplete tests. Those tests have been started on a very similar substance, therefore any decision on classification is for the time being inconclusive and will be updated with the results of running tests and if needing, more specific testing proposals within the ned of 2020.