Methyl 2-[(1,5-dihydro-3-methyl-5-oxo-1-phenyl-4H-pyrazol-4-ylidene)ethylidene]-1,3,3-trimethylindoline-5-carboxylate

Endpoint summary

Description of key information

Macrolex Orange R is not toxic in acute oral and inhalation studies.

In the acute oral study 5 male and 5 female Wistar rates were dosed with 5000 mg/kg test item. No symptoms or mortality were observed. Consequently the discriminating dose is 5000 mg/kg (highest dose tested).

A study on the acute inhalation toxicity of Macrolex Orange R on rats has been conducted in accordance with OECD Test Guideline no. 403 (2009). The reparability of the aerosol was adequate and in compliance with the test guidelines [the mass median aerodynamic diameter (MMAD) was 3.70 µm, the geometric standard deviation (GSD) was 2.14]. Rats exposed to the test item did not show clinical signs at 2441 mg/m³. During the clinical observation test item-dependent orange discoloration was seen on nose and muzzle as well as on the head and forelegs. No findings were seen at the functional observation battery. No toxicological relevant test item-related changes in incremental body weight gain were observed. Significantly decreased body temperatures were found in animals exposed to 2441 mg/m³ test item when compared to the control animals. Mortality did not occur at 2441 mg/m³. No gross-pathological findings were observed at necropsy in animals exposed to 2441 mg/m³ Macrolex Orange R.

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:

1983

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Principles of method if other than guideline:

5 male and 5 female Wistar rates were dosed with 5000 mg/kg test item and a volume of 20 ml/kg; vehicle: Lutrol. Animals were observed for 14 days.

GLP compliance:

no

Test type:

other: Limit test with 5000 mg/kg

Limit test:

yes

Specific details on test material used for the study:

Macrolex Orange 51032 (Oek.-Nr.: 826-152)
Solid powder

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

5 male and 5 female Wistar rates were dosed with 5000 mg/kg test item and a volume of 20 ml/kg; vehicle: Lutrol. Animals were observed for 14 days.

Route of administration:

oral: gavage

Vehicle:

other: Lutrol

Details on oral exposure:

5 male and 5 female Wistar rates were dosed with 5000 mg/kg test item and a volume of 20 ml/kg; vehicle: Lutrol. Animals were observed for 14 days.

Doses:

5000 mg/kg

No. of animals per sex per dose:

5 male and 5 female Wistar rates

Control animals:

no

Details on study design:

5 male and 5 female Wistar rates were dosed with 5000 mg/kg test item and a volume of 20 ml/kg; vehicle: Lutrol. Animals were observed for 14 days.

Statistics:

no

Key result

Sex:

male/female

Dose descriptor:

discriminating dose

Effect level:

5 000 mg/kg bw

Based on:

test mat.

Remarks on result:

not determinable due to absence of adverse toxic effects

Mortality:

no

Clinical signs:

other: no effect

Gross pathology:

no effect

Other findings:

no

Mortality: 0/10

Symthomes: 0/10

Interpretation of results:

GHS criteria not met

Executive summary:

In the acute oral study 5 male and 5 female Wistar rates were dosed with 5000 mg/kg test item. No symptoms or mortality were observed. Consequently the discriminating dose is 5000 mg/kg (highest dose tested)

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

discriminating dose

Value:

5 000 mg/kg bw

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2017

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

GLP compliance:

yes (incl. QA statement)

Test type:

fixed concentration procedure

Limit test:

yes

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

Three male and three female rats were simultaneously exposed under nose-only conditions for 4 h. This procedure is in compliance with the limit test described in OECD Test Guideline No. 403 and OECD GD#39 (2009).

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

nose only

Vehicle:

clean air

Mass median aerodynamic diameter (MMAD):

3.7 µm

Geometric standard deviation (GSD):

2.14

Remark on MMAD/GSD:

Primary goal of the limit test is to generate an aerosol with a MMAD between 1-4 µm at 2000 mg/m³. Aerosol testing at greater than 2000 mg/m³ should only be attempted if a respirable particle size is achievable. Consequently animals were exposed to 2441 mg/m³ of an aerosol with a MMAD of 3.70 µm. Higher concentrations have been tested in pretest without animals and resulted in MMAD >4 µm.

Details on inhalation exposure:

Gravimetric analysis of filter samples and the real-time monitoring of the aerosol test atmosphere from the breathing zone area indicated that the exposure conditions were temporally stable over the 4-h exposure period.

Analysis of the aerosol particle-size distribution from the breathing zone samples demonstrates that the aerosol generated was in the respirable range. Repeated measurements made during one exposure demonstrated temporally stable particle-size distributions. The total gravimetric concentration recovered by the cascade impactor was similar to that concentration found by filter analyses. From this finding it can be concluded that interstage wall losses occurring within the low-pressure critical orifice cascade impactor or potential anisokinetic sampling errors appear to be negligible.

Temperature values in the inhalation chamber were in the range suggested by the testing guidelines. Humidity values were lower than suggested by the test guidelines due to the use of dry pressurized air for particle dispersion. This deviation from the guideline had no apparent negative impact on the outcome of study.

Analytical verification of test atmosphere concentrations:

yes

Duration of exposure:

4 h

Concentrations:

2441 mg/m³

No. of animals per sex per dose:

3 males and 3 females

Control animals:

yes

Details on study design:

A study on the acute inhalation toxicity of Macrolex Orange R (henceforward referred to as test item) on rats has been conducted in accordance with OECD Test Guideline no. 403 (2009). Test procedures were adapted so as to comply also with the Method B.2 of the Annex to Regulation (EC) No 440/2008, and especially OECD Guidance Document no. 39 (2009). One group of rats was nose-only exposed to the solid aerosol of the test item at 2441 mg/m³. This procedure is in accordance with the limit test of the OECD Test Guideline no. 403 (2009). Primary goal of the limit test is to generate an aerosol with a MMAD between 1-4 µm at 2000 mg/m³. Aerosol testing at greater than 2000 mg/m³ should only be attempted if a respirable particle size is achievable. Consequently animals were exposed to 2441 mg/m³ of an aerosol with a MMAD of 3.70 µm. Higher concentrations have been tested in pretest without animals and resulted in MMAD >4 µm. Rats exposed to dry conditioned air only under otherwise identical circumstances served as controls.

Key result

Sex:

male/female

Dose descriptor:

LC0

Effect level:

2 441 mg/m³ air (analytical)

Based on:

act. ingr.

Exp. duration:

4 h

Mortality:

no

Clinical signs:

other: During the clinical observation test item-dependent orange discoloration was seen on nose and muzzle as well as on the head and forelegs. No findings were seen at the functional observation battery.

Body weight:

No toxicological relevant test item-related changes in incremental body weight gain were observed.

Gross pathology:

No gross-pathological findings were observed

Other findings:

Significantly decreased body temperatures were found in animals exposed to 2441 mg/m³ test item when compared to the control animals.

Interpretation of results:

GHS criteria not met

Executive summary:

A study on the acute inhalation toxicity of Macrolex Orange R (henceforward referred to as test item) on rats has been conducted in accordance with OECD Test Guideline no. 403 (2009). Test procedures were adapted so as to comply also with the Method B.2 of the Annex to Regulation (EC) No 440/2008, and especially OECD Guidance Document no. 39 (2009). One group of rats was nose-only exposed to the solid aerosol of the test item at 2441 mg/m³. This procedure is in accordance with the limit test of the OECD Test Guideline no. 403 (2009). Primary goal of the limit test is to generate an aerosol with a MMAD between 1-4 µm at 2000 mg/m³. Aerosol testing at greater than 2000 mg/m³ should only be attempted if a respirable particle size is achievable. Consequently animals were exposed to 2441 mg/m³ of an aerosol with a MMAD of 3.70 µm. Higher concentrations have been tested in pretest without animals and resulted in MMAD >4 µm. Rats exposed to dry conditioned air only under otherwise identical circumstances served as controls. The results can be summarized as follows:

LC50 inhalation (aerosol, 4 h)

LC50: >2441 mg/m³ test item

The respirability of the aerosol was adequate and in compliance with the test guidelines [the mass median aerodynamic diameter (MMAD) was 3.70 µm, the geometric standard deviation (GSD) was 2.14]. Rats exposed to the test item did not show clinical signs at 2441 mg/m³. During the clinical observation test item-dependent orange discoloration was seen on nose and muzzle as well as on the head and forelegs. No findings were seen at the functional observation battery. No toxicological relevant test item-related changes in incremental body weight gain were observed. Significantly decreased body temperatures were found in animals exposed to 2441 mg/m³ test item when compared to the control animals. Mortality did not occur at 2441 mg/m³. No gross-pathological findings were observed at necropsy in animals exposed to 2441 mg/m³ Macrolex Orange R.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

discriminating conc.

Value:

2 441 mg/m³ air

Additional information

no study available

Justification for classification or non-classification

The discriminating dose in an acute oral toxicity study was 5000 mg/kg (highest dose tested) and the discriminationg concentration in an acute inhalation study was 2441 mg/m³ (highest concentration tested). No calssification is warrented.