Registration Dossier

Administrative data

Description of key information

Oral (OECD 420), female rat: LD50 > 2000 mg/kg bw

Dermal (OECD 402), rat: LD50 > 2000 mg/kg bw (limit test)

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).

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records
Reference
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
19 June - 11 July 2019
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 420 (Acute Oral Toxicity - Fixed Dose Method)
Version / remarks:
adopted 17 December 2001
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.1 bis (Acute Oral Toxicity - Fixed Dose Procedure)
Version / remarks:
30 May 2008
Deviations:
no
GLP compliance:
yes (incl. certificate)
Remarks:
Hess. Ministerium für Umwelt, Klimaschutz, Landwirtschaft und Verbraucherschutz, Wiesbaden, Germany
Test type:
fixed dose procedure
Limit test:
no
Species:
rat
Strain:
Wistar
Remarks:
Han TM
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Envigo RMS B.V., Inc, AD Horst, The Netherlands
- Females nulliparous and non-pregnant: yes
- Age at study initiation: 9 - 11 weeks
- Weight at study initiation: 207.6 - 274.7 g (females)
- Fasting period before study: animals were fasted overnight prior to administration
- Housing: 1 - 5 animals of the same sex per cage in Makrolon Type IV cages, with wire mesh top, granulated soft wood bedding
- Diet: 2018C Teklad Global 18% protein rodent diet, ad libitum
- Water: tap water, ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 + 4
- Humidity (%): 28 -72
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg bw

DOSAGE PREPARATION: DMPSA-K2 solution, dose calculation was adjusted to purity

- Rationale for the selection of the starting dose: Based on available information on the toxicity of the test item, 300 mg/kg bw was chosen as the initial starting dose, since a severe toxicity which may necessitate humane euthanasia was not expected at this dose level.
Doses:
300 and 2000 mg/kg bw
No. of animals per sex per dose:
1 (300 mg/kg bw)
5 (2000 mg/kg bw)
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Clinical observations and inspections for morbidity / mortality were performed at least three times within the first six hours after application (i.e., 30 minutes and 1 hour, 2 hours and 4 – 6 hours after dosing), thereafter at least once daily for 14 days. Bodyweights were determined Day 0 (prior to dosing), Day 7, and Day 14.
- Necropsy of survivors performed: yes
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
At both doses 300 and 2000 mg/kg bw, there were no deaths observed during the study.
Clinical signs:
300 mg/kg bw: There were no clinical signs observed.
2000 mg/kg bw: One animal showed reduced activity. These signs were first noted approximately one hour after dosing. Recovery, as judged by external appearance and behavior, was complete by day 1 after dosing.
Body weight:
At both doses 300 and 2000 mg/kg bw, the animals showed expected gains in body weight over the observation period.
Gross pathology:
300 mg/kg bw: No abnormalities were noted at the macroscopic examination at study termination.
2000 mg/kg bw: One animal showed discoloration (red dots) in the thymus. No abnormalities were noted at necropsy in the remaining animals.

Table 1: Summary of results

 

Females

 

Animal number

Dose

[mg/kg bw]

Mortality

Clinical signs

Description

Necropsy finding

Description

 

 

 

number

number

 

number

 

Sighting study

1

300

0/1

0/1

-

0/1

-

2

2000

0/1

1/1

reduced activity within 6 h after treatment

0/1

-

Main study

3

2000

0/4

 

0/4

-

1/4

-

4

2000

-

 

-

5

2000

-

 

-

6

2000

-

 

discoloration thymus (red dots)

Interpretation of results:
other: no classification required according to Regulation (EC) No. 1272/2008
Conclusions:
CLP: not classified
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
The available information comprises an adequate and reliable study (Klimisch score 1), and is thus sufficient to fulfil the standard information requirements set out in Annex VII, 8.5, of Regulation (EC) No 1907/2006.

Acute toxicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
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:
read-across source
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Remarks on result:
other: No mortality occurred in rats.
Interpretation of results:
other: CLP/EU GHS criteria not met, no classification required according to Regulation (EC) No. 1272/2008
Conclusions:
The read-across approach is detailed in the analogue justification. The target and source substances are considered unlikely to differ in their dermal toxicity potential. In the acute dermal toxicity study conducted with the source substance (CAS 2241455-89-8) in rats, the dermal LD50 was >2000 mg/kg bw. 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 be hazardous following acute exposure via the dermal route.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
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, 8.5, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006.

Additional information

Oral route

Reaction mass of dipotassium 2-(3,4-dimethyl-1H-pyrazol-1-yl) succinate and dipotassium 2-(4,5-dimethyl-1H-pyrazol-1-yl)succinate was tested for its acute oral toxicity in a study according to OECD Guideline 420 and in compliance with GLP in female Wistar rats (2019).

The toxicity of the test substance was assessed by stepwise treatment. The first animal was treated at a dose of 300 mg/kg bw. Since no mortality or clinical sign of systemic toxicity occurred, a second animal was treated at a dose of 2000 mg/kg bw. Again no mortality was observed within the 14 day observation period. Thus in a further step four animals were treated at 2000 mg/kg bw. All animals survived until the scheduled necropsy.All animals showed expected gains in body weight over the observation period.One animal showed reduced activity one hour after dosing, but recovered completely by Day 1 after dosing. Gross pathology showed discoloration (red dots) in the thymus of one animal at the 2000 mg/kg bw dose. No abnormalities were observed in the remaining animals. In conclusion, an experimental LD50>2000 mg/kg bw was derived for acute oral toxicity.

 

Justification for read-across

There are no experimental data available regarding the acute dermal toxicity 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, 8.5 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).

 

Dermal route

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) was tested for its acute dermal toxicity in a study according to OECD Guideline 402 and in compliance with GLP in male and female Wistar rats (2012). 5 animals per sex were dermally exposed to 2000 mg/kg bw (limit test) test substance for 24 h under semiocclusive conditions. After 24 h the test substance was removed from the skin with cottonseed oil. No mortality occurred during the study and no toxicologically relevant abnormalities were found at macroscopic post-mortem examination of the animals. The body weight development of male and female animals was within the expected range. No signs of local effects as dermal irritation and no other clinical signs indicating systemic toxicity were observed in any animal. In conclusion, an experimental LD50 > 2000 mg/kg bw was deduced for acute dermal toxicity.

 

The target and source substances are considered unlikely to differ in their acute dermal toxicity potential. Therefore, an acute dermal LD50 value of > 2000 mg/kg bw was considered in the hazard assessment and for classification and labelling purposes of 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).

Justification for classification or non-classification

The available data on acute oral toxicity and read across data on acute dermal toxicity do not meet the criteria for classification according to Regulation (EC) 1272/2008 and are therefore conclusive but not sufficient for classification.