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Key value for chemical safety assessment

Effects on fertility

Description of key information

No adverse effects on reproductive toxicity were observed with a read across substance.

The substance is a member of the ZDDP category for which full details are provided in the updated category justification document presented as an attachment in IUCLID Section 13. An integrated testing strategy is proposed on 4 substances which adequately span the variation and so represent the category. The testing proposed will be sequential: Initially, OECD 417 toxicokinetic studies will be conducted on the selected 4 substances to further support and confirm appropriateness of the category.  This work will then be followed by OECD 408 90-day studies with the 4 selected substances, and then by OECD 414 pre-natal developmental toxicity on the same 4 substances in rats, and on at least 2 of these substances in rabbits as a second species.  Testing according to OECD 443 Extended One Generation Reproductive toxicity studies will then be considered based on results of the tests described above and an updated testing proposal for the OECD 443 data requirement will be submitted at the completion of these proposed studies.

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
30 mg/kg bw/day
Additional information

The reproductive toxicity of this substance was evaluated with rats at doses as high as 200 mg/kg/day in accordance with OECD Guideline 421. Adverse effects on reproduction were observed only at doses that caused maternal toxicity. Treatment-related mortality and clinical signs were noted in the parents at dose levels of 100 and 200 mg/kg/day by mortality and clinical signs. Treatments-related inhibition of body weight gain in males and signs of gastric irritation also was observed at the 200 mg/kg/day dose level. No parental toxicity was found at the 30 mg/kg/day dose level. Slightly reduced fertility indices were observed at the 200 mg/kg/day dose level. Reproductive performance (fertility, mating, days between pairing and coitus, gestation and parturition) was unaffected by treatment at the 30 and 100 mg/kg/day dose levels. Based on the results of this study, a dose level of 30 mg/kg/day was considered to be the NOAEL (no observable adverse effect level) for parental and neonatal toxicity.


Short description of key information:
The oral administration of EC 224-235-5 to rats by gavage at doses as high as 200 mg/kg/day in the parental generation. Treatment-related mortality and clinical signs were noted in the parents at dose levels of 100 and 200 mg/kg/day by mortality and clinical signs. Reproductive performance (fertility, mating, days between pairing and coitus, gestation and parturition) was unaffected by treatment at the 30 and 100 mg/kg/day dose levels. Based on the results of this study, a dose level of 30 mg/kg/day was considered to be the NOAEL for parental and neonatal toxicity.

Effects on developmental toxicity

Description of key information
The oral administration of EC 224-235-5 to rats by gavage at doses as high as 200 mg/kg/day in the parental generation. Treatment-related mortality and clinical signs were noted in the parents at dose levels of 100 and 200 mg/kg/day by mortality and clinical signs. No parental toxicity was found at the 30 mg/kg/day dose level. Neonatal mortality in the F1 generation was observed at the 100 and 200 mg/kg/day dose levels. Neonatal clinical signs of toxicity also were noted at the 200 mg/kg/day dose level as evidenced by clinical signs. No neonatal toxicity was observed at a dose level of 30 mg/kg/day. Based on the results of this study, a dose level of 30 mg/kg/day was considered to be the NOAEL for neonatal toxicity. 
Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
30 mg/kg bw/day
Additional information

The potential of this substance to affect development was evaluated with rats at doses as high as 200 mg/kg/day in accordance with OECD Guideline 421. Adverse effects on development were observed only at doses that caused maternal toxicity. Treatment-related mortality and clinical signs were noted in the parents at dose levels of 100 and 200 mg/kg/day by mortality and clinical signs. Treatments-related inhibition of body weight gain in males and signs of gastric irritation also was observed at the 200 mg/kg/day dose level. No parental toxicity was found at the 30 mg/kg/day dose level. Neonatal mortality in the F1 generation was observed at the 100 and 200 mg/kg/day dose levels. Neonatal clinical signs of toxicity also were noted at the 200 mg/kg/day dose level as evidenced by clinical signs. No neonatal toxicity was observed at a dose level of 30 mg/kg/day. Based on the results of this study, a dose level of 30 mg/kg/day was considered to be the NOAEL (no observable adverse effect level) for parental and neonatal toxicity.

 

Justification for classification or non-classification

In accordance to Directive 67/548/EEC and EU CLP (Regulation (EC) No. 1272/2008), classification of this substance is not required.