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Description of key information

Oral (OECD 422), rat: NOAEL ≥ 1000 mg/kg bw/day

Read-across from Reaction mass of 2-(3,4-dimethyl-1H-pyrazol-1-yl)succinic acid and 2-(4,5-dimethyl-1H-pyrazol-1-yl)succinic acid (CAS 2241455 -89 -8).

In order to fulfil the standard information requirements, read across to a testing proposal for a GLP-compliant subchronic toxicity study (90-day) in rats via the oral route with the source substance Reaction mass of 2-(3,4-dimethyl-1H-pyrazol-1-yl)succinic acid and 2-(4,5-dimethyl-1H-pyrazol-1-yl)succinic acid (EC 940-877-5, CAS 2241455-89-8) following OECD guideline 408 is considered according to Annex IX, Column 1, Section 8.6.2. Up to date a draft decision on this testing proposal is available (DEV-01 -2120055695-48-000-TPE-1_DEC_REG_TPE).

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: oral
Remarks:
combined repeated dose and reproduction / developmental screening
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
refer to analogue justification provided in IUCLID section 13
Reason / purpose for cross-reference:
read-across source
Key result
Dose descriptor:
NOAEL
Remarks:
systemic
Effect level:
>= 1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: NOAEL corresponds to the highest dose tested.
Critical effects observed:
no
Conclusions:
The read-across approach is detailed in the analogue justification. The target and source substances are considered unlikely to differ in their oral repeated dose toxicity potential. In the available combined repeated dose and reproduction / developmental screening study in rats with the source substance (CAS 2241455-89-8) a systemic NOAEL of > 1000 mg/kg bw/day was determined. Applying the read-across approach, the target substance reaction mass of dipotassium 2-(3,4-dimethyl-1H-pyrazol-1-yl) succinate and dipotassium 2-(4,5-dimethyl-1H-pyrazol-1-yl)succinate (EC 950-225-1) is not expected to differ in the systemic toxicity potential after repeated oral administration.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
The available information comprises an adequate and reliable study (Klimisch score 1) from an analogue substance which is based on (bio)transformation to common compounds .The selected study is thus sufficient to fulfil the standard information requirements set out in Annex VIII, 8.6, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006.

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Justification for read-across

There are no experimental data available regarding the repeated dose potential of Reaction mass of dipotassium 2-(3,4-dimethyl-1H-pyrazol-1-yl) succinate and dipotassium 2-(4,5-dimethyl-1H-pyrazol-1-yl)succinate (EC 950-225-1). Thus, read-across from an appropriate analogue substance Reaction mass of 2-(3,4-dimethyl-1H-pyrazol-1-yl)succinic acid and 2-(4,5-dimethyl-1H-pyrazol-1-yl)succinic acid (CAS 2241455-89-8) is conducted in accordance with Regulation (EC) No 1907/2006, Annex XI, 1.5 in order to fulfil the standard information requirements defined in Regulation (EC) No 1907/2006, Annex VIII, 8.6. The read-across is based on common (bio)transformation compounds of source and target substance. A detailed justification for the analogue read-across approach is provided in the technical dossier (see IUCLID Section 13).

 

A combined repeated dose oral toxicity study with the reproduction/developmental toxicity screening test was performed with the analogue substance Reaction mass of 2-(3,4-dimethyl-1H-pyrazol-1-yl)succinic acid and 2-(4,5-dimethyl-1H-pyrazol-1-yl)succinic acid according to OECD Guideline 422 and in compliance with GLP in Crl:WI(Han) rats (2013).

Ten animals per dose were treated per gavage with 100, 300, and 1000 mg/kg bw/day, respectively, 7 days per week. Male animals were treated for 28 days, beginning during the 14 days of the pre-mating period. Females were treated for a maximum period of 54 days, from 14 days of pre-mating period until post-natal day 4. The doses were selected based on data from a Dose Range Finding Study, where 3 animals per sex and dose (100, 300, and 1000 mg/kg bw/day) were treated in the same way as in the main study. No mortality and clinical findings was observed. Slightly reduced body weight gain was observed in the 300 and 1000 mg/kg bw/day dose groups. 1/3 animals of the high dose group did not deliver pubs and lost them during pregnancy. Based on these results 100, 300, and 1000 mg/kg bw/day were chosen as appropriate dose levels for the main study.

In the main study, no mortality was observed throughout the study period. Slight piloerection, moving the bedding and salivation were observed in various animals of the treatment groups. No test item related influence on male body weight development or body weight gain could be detected. Food consumption was significantly decreased in the high dose group during pre-mating days 1-7. In female animals, a statistically significant decreased body weight gain could be observed in the high dose group during pre-mating days 1-7. Furthermore, during lactation days 0-4 a decrease in body weight was observed for treatment groups but not for control animals. However, this decrease in body weight was not dose dependent and not considered to be test item related. No change in food consumption could be measured for treatment groups when compared to the control group. Slight decrease of spleen weights in males and slightly increased relative thyroid/parathyroid weights in females in individual dose groups were considered as toxicologically not relevant. No test item-related histopathological findings were noted in the organs evaluated in this study. No relevant effects were observed in any of the parameters of the functional observation battery before and at the end of the treatment period.

In conclusion, no adverse effects on systemic toxicity after repeated exposure were observed. Therefore a NOAEL of ≥ 1000 mg/kg bw/day was deduced for systemic toxicity in the OECD 422 study.

 

The target and source substances are considered unlikely to differ in their repeated dose toxicity potential. Therefore, a NOAEL of ≥ 1000 mg/kg bw/day was considered for the hazard assessment and Classification and labelling purposes for the target substance Reaction mass of dipotassium 2-(3,4-dimethyl-1H-pyrazol-1-yl) succinate and dipotassium 2-(4,5-dimethyl-1H-pyrazol-1-yl)succinate (EC 950-225-1).

 

 

In order to fulfil the standard information requirement (Annex IX, Column I, 8.6.2) for Reaction mass of dipotassium 2-(3,4-dimethyl-1H-pyrazol-1-yl) succinate and dipotassium 2-(4,5-dimethyl-1H-pyrazol-1-yl)succinate (EC 950-225-1), a read-across to a testing propsal for a GLP-compliant repeated dose toxicity study in the rat via the oral route following OECD Guideline 408 with the source substance Reaction mass of 2-(3,4-dimethyl-1H-pyrazol-1-yl)succinic acid and 2-(4,5-dimethyl-1H-pyrazol-1-yl)succinic acid (CAS 2241455-89-8) is included in the dossier. The target and source substances are considered unlikely to differ in their repeated dose toxicity potential. As soon as the study results are available, they will be included in the dossier.

Justification for classification or non-classification

Based on read-across, the available data on the repeated dose toxicity do not meet the criteria for classification according to Regulation (EC) 1272/2008, and are therefore conclusive but not sufficient for classification