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Key value for chemical safety assessment

Effects on fertility

Description of key information

- Reproduction / developmental toxicity screening test, oral (gavage), rat (Crl:WI(Han)) m/f (OECD TG 421; GLP), dose levels: 0, 10, 30, 60 mg/kg bw/d: parental NOAEL: 60 mg/kg; fertility NOAEL, females: 60 mg/kg; developmental NOAEL: 60 mg/kg bw

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:
The available study was conducted according to guideline and is of high quality.
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

In a Reproduction/Developmental Toxicity Screening Test according to OECD guideline 421 (adopted July 2015) 2,4-Bismaleimidotoluene (100% a.i.) was administered to groups of 10 Wistar rats/sex/dose by gavage at dose levels of 0, 30 and 60 mg/kg bw/d. 

The mean number of corpora lutea was not significantly different from that in the dose groups compared with the control animals. However,  a  slightly  reduced  fertility  index  (number  of  females  pregnant  /  number  of females  copulated  X  100)  of  80  %  in  the  MD  group  compared  to  90  %  in  all  other groups. In the absence of dose response dependency, the finding was not considered to be of toxicological relevance.

During  the  treatment  period  of  this  study,  few  mortalities/moribund  sacrifice  were observed.  Histopathologically, the cause of death/morbidity in two animals was considered to be due to gavaging error (tracheal inflammation, thymic inflammation with plant  particles).  The  cause  of  death/morbidity  could  not  be  established  for  the  other animals. The deaths were considered not treatment related.

Diarrhoea and moving the bedding as predominant clinical signs were observed in males and females. Other observed clinical signs were also present in the control group and, thus, considered incidental. Moving the bedding was observed transiently after dosing in the MD and HD and therefore considered to be a sign of discomfort due to local reaction to the test item rather than a systemic adverse effect.

No test item related or statistically significant effect on food consumption was observed in males and females during the whole study period, except for a statistically significant increase  in  group  mean  food  consumption  in  female  MD  group  observed  during premating day 7-14 when compared with the controls. Due to lack of dose dependency and  consistency,  this  statistically  significant  effect  on  female  food  consumption  was considered to be incidental and not related to the treatment with test item.

There were no effects on the survival of the pups from PND 1 through PND 13 in the dose groups when compared to the control group.  A marginally higher mean mortality of pups between PND 4 and PND 13 was observed in the HD group (1.01%) compared to the control group (0.00%).However, this effect did not achieve statistical significance.  There  were  also  few  mortalities/missing  pups  observed  from  LD  and  MD  group,  and  as  a  result  a  higher mean mortality of pups between PND 0 and PND 4 was observed in the LD and MD groups (2.81 and 0.89 %, respectively) compared to the control group (0.00%). Due to lack  of  dose  dependency  and  consistency,  this  effect  in  LD  and  MD  group  was  not considered to be treatment related.

No treatment-related changes were noted in any of the remaining  parameters investigated in this study (i.e. body weight development, estrous cycle, litter data [ total number of pups born, number of male pups, number of female pups, sex ratio, number of live pups, still births and runts on PND 0 as well as number of male pups, number of female pups, number of live pups and sex ratio on PND 4 and PND 13], litter weight, precoital interval and duration of gestation, pre- and post-natal data [ number  of  corpora  lutea, number  of  implantation  sites,  number  of  live  pups  (PND  0,  PND  4  and  PND  13)  and percentage of pre- and post-implantation loss], thyroid hormone analysis, macroscopic changes, organ weights, gross lesions).

 

Based on these results, the following NOAELs were derived:

parental NOAEL: 60 mg/kg

fertility NOAEL, females: 60 mg/kg

developmental NOAEL: 60 mg/kg

Effects on developmental toxicity

Description of key information

- Reproduction / developmental toxicity screening test, oral (gavage), rat (Crl:WI(Han)) m/f (OECD TG 421; GLP), dose levels: 0, 10, 30, 60 mg/kg bw/d: parental NOAEL: 60 mg/kg; fertility NOAEL, females: 60 mg/kg; developmental NOAEL: 60 mg/kg bw

Effect on developmental toxicity: 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:
The study was conducted according to guideline and is 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

Justification for classification or non-classification

Based on the results of the existing relevant study with 2,4 -Bismaleimidotoluene does not need to be classified for toxicity to reproduction, developmental toxicity and teratogenicity according to the criteria given in regulation (EC) 1272/2008. Therefore labelling is not necessary.