clothianidin (ISO); (E)-1-(2-chloro-1,3-thiazol-5-ylmethyl)-3-methyl-2-nitroguanidine

Endpoint summary

Description of key information

Oral (OECD 401), mouse: LD50: 389 mg/kg bw (males) and 465 mg/kg bw (females)

Oral (DRF acute neurotoxicity, SS), rat: LD50: > 1216 mg/kg bw (males) and > 523 to < 1216 mg/kg bw (females)

Inhalation (OECD 403, limit test), rat: LC50: > 5.54 mg/L air (analytical)

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

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:

Sep 1996 - Oct 1996

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Version / remarks:

adopted 1987

Deviations:

no

GLP compliance:

yes

Test type:

standard acute method

Limit test:

no

Species:

mouse

Strain:

CD-1

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River (UK) Ltd, Margate, UK
- Females nulliparous and non-pregnant: yes
- Age at study initiation: 5 - 7 weeks
- Weight at study initiation: 25 to 30 g (males), 22 to 26 g (females)
- Fasting period before study: from approximately 4 h prior to dosing until 2 h after completion of dosing
- Housing: up to five mice of the same sex were accommodated in suspended stainless steel mesh cages (dimensions 32 x 16.5 x 13 cm)
- Diet: SQC(E) Rat and Mouse Maintenance Diet No 1 (Special Diets Services Ltd, Witham, UK), ad libitum
- Water: mains water, ad libitum
- Acclimation period: 6 - 9 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 - 25
- Humidity (%): 40 - 70
- Air changes (per hr): at least 15
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 16 Sep 1996 To: 03 Oct 1996 (main study)

Route of administration:

oral: gavage

Vehicle:

other: 5% m/v aqueaous gum arabic

Details on oral exposure:

VEHICLE
- Amount of vehicle: 10 mL/kg bw

Doses:

304, 380, 475, 594 and 742 mg/kg bw

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: regularly during the study at least once within half an hour of dosing, four times within four hours of dosing, twice daily on Days 2, 3 and 4 and once daily from the fifth to last day of the observation period; body weights were recorded on Day -1 (day before dosing), Day 1 (day of dosing), Days 4 and 8 and at termination on Day 15.
- Necropsy of survivors performed: yes

Statistics:

Not reported.

Preliminary study:

A preliminary investigation was conducted using groups of two male and two female fasted mice. Mice were subjected to single oral doses of 300, 450 and 600 mg/kg bw. Two male mice
and one female were found dead on Day 2 following treatment at 600 mg/kg bw. There were no deaths among the mice dosed at 300 or 450 mg/kg bw. Based on the results, suitable dose levels to begin determination of the acute median lethal dose were selected for the main study.

Key result

Sex:

male

Dose descriptor:

LD50

Effect level:

389 mg/kg bw

Based on:

test mat.

95% CL:

348 - 433

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

465 mg/kg bw

Based on:

test mat.

95% CL:

384 - 561

Mortality:

304 mg/kg bw: 0/5 (males); 0/5 (females)
380 mg/kg bw: 2/5 (males); 2/5 (females)
475 mg/kg bw: 5/5 (males); 3/5 (females)
594 mg/kg bw: 5/5 (males); 3/5 (females)
742 mg/kg bw: 5/5 (males); 5/5 (females)

For details, please refer to the attached background material.

Clinical signs:

other: The principal clinical signs of reaction to treatment at all dose levels were decreased activity and palpebral closure starting 0.25 h after treatment. Less common clinical signs included ataxia and tremor at all dose levels starting 0.25 h after treatmen

Gross pathology:

Necropsy of mice found dead, as well as those killed at completion of the 14-day observation period revealed no macroscopic changes consistent with the treatment-related effect. Isolated cases of darkening of the lungs, fluid accumulation in the thoracic cavity, distension of the uterus or cannibalisation of the genitalia were noted. For details, please refer to the attached background material.

Interpretation of results:

Category 4 based on GHS criteria

Conclusions:

The study was performed in accordance with OECD TG 401 under GLP conditions and is considered reliable. Under the conditions chosen, the acute oral LD50 value was determined to be 389 mg/kg bw and 465 mg/kg bw for male and female mice, respectively. According to criteria of the CLP Regulation (EU) No. 1272/2008, classification of the test item for acute oral toxicity category 4 is needed.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

389 mg/kg bw

Quality of whole database:

The available information comprises an adequate and reliable study (Klimisch score 1), and is thus sufficient to fulfill the standard information requirements set out in Annex VII, 8.5, of Regulation (EC) No 1907/2006.

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:

06 - 21 Feb 1997

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study with acceptable restrictions

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

Version / remarks:

adopted 2009

Deviations:

yes

Remarks:

animals were slightly younger than recommended by the guideline, 5 animals/sex instead of 3 examined, actual concentration of test substance not reliable due to technical issues

Qualifier:

according to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

Version / remarks:

adopted 1981

Deviations:

no

GLP compliance:

yes

Test type:

traditional method

Limit test:

yes

Species:

rat

Strain:

other: Crl:CDBR

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River (UK) Ltd, Margate, UK
- Females nulliparous and non-pregnant: not specified
- Age at study initiation: approximately 7 weeks at exposure
- Weight at study initiation: 239 - 278 g (males), 201 - 225 g (females)
- Fasting period before study: none
- Housing: groups of five in stainless steel mesh cages of size 55 x 34 x 20 cm, floor area 1870 cm²
- Diet: SQC Rat and Mouse Maintenance Diet No 1 (Special Diets Services Ltd, Witham, UK), ad libitum
- Water: mains water, ad libitum
- Acclimation period: 8 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 - 25
- Humidity (%): 40 - 70
- Air changes (per hr): at least 15
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 06 Feb 1997 To: 21 Feb 1997

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

head only

Vehicle:

air

Mass median aerodynamic diameter (MMAD):

2.78 µm

Geometric standard deviation (GSD):

2.38

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: cylindrical aluminium exposure chamber
- Exposure chamber volume: approximately 40 L internal volume
- Method of holding animals in test chamber: not specified
- Source and rate of air (airflow): compressed air between 18 and 22 L/min
- System of generating particulates/aerosols: generated from a micronised powder aerosolised by a Wright Dust Feed generator
- Method of particle size determination: by an Andersen 298 Cascade Impactor
- Treatment of exhaust air: test atmospheres were filtered using a cartridge paniculate filter, exhausted to the outside of the building and vented
- Temperature, humidity, pressure in air chamber: 19 - 21 °C, 35-66 , not specified

TEST ATMOSPHERE
- Brief description of analytical method and equipment used: concentration of the test article was determined gravimetrically
- Samples taken from breathing zone: yes

TEST ATMOSPHERE
- Particle size distribution: The mass median aerodynamic diameter was between 1-3 µm within the first, third and fourth hour of exposure. However, during the second hour of exposure, the mass median aerodynamic diameter was 8.40 µm. The cause of this anomalous sample was unknown.
- MMAD (Mass median aerodynamic diameter) / GSD (Geometric st. dev.): 2.78 µm / 2.38 µm

Analytical verification of test atmosphere concentrations:

yes

Remarks:

The concentration of the test article was determined gravimetrically. The samples were obtained at least hourly, over a period of 2 min, during exposure.

Duration of exposure:

4.5 h

Remarks on duration:

Intermittent jamming of the generator occurred during the first hour of the exposure, assuming target concentrations below 5 mg/L. Due to these obervations, the duration of the exposure to the test substance was extended by 30 min to 4.5 h.

Concentrations:

10.4 mg/L (nominal concentration)
6.141 mg/L (mean measured gravimetric concentration, excluding samples taken during period of technical difficulties in aerosol generation)
5.538 mg/L (mean measured gravimetric concentration, including samples taken during period of technical difficulties in aerosol generation)

No. of animals per sex per dose:

5

Control animals:

yes

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Clinical signs were recorded approximately hourly during exposure, and for the remainder of the exposure day. Subsequently, animals were observed daily until study termination. Body weights were recoreded before and after exposure on Day 1, on Day 2, 8 and 15, and before necropsy.
- Necropsy of survivors performed: yes
- Other examinations performed: histopathology (lungs) of animals which showed gross lesions

Statistics:

As there were no deaths, the median lethal concentration (LC50) was not calculated.

Key result

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 5.54 mg/L air (analytical)

Based on:

test mat.

Exp. duration:

4.5 h

Mortality:

There were no deaths during the study.

Clinical signs:

other: ataxia, semi-closed eyes, hunched body posture, lethargy, staining of animals, reduced water and/or food consumption.

Remarks:

All animals recovered by Day 5.

Body weight:

During the days following exposure, group mean body weight loss in the treated group was greater than in the control group. At Day 2 group mean body weight in the male and female treated group was 91 and 92% of the pre-exposure weight compared with 101 and 99% respectively for the comparable control group. At Day 8 the animals in the treated group regaining their pre-exposure body weight. Overall, body weight gain of the treated group during the two week observation period was similar to that observed in the control group. For details, please refer to the attached background material.

Gross pathology:

A red thymus and a pale lung were observed in a male control and a male treated animal, repectively. These gross findings were consistent with the expected pattern of background observations in rats of this strain and age, and were not considered to be treatment related.

Other findings:

- Organ weights: absolute and relative lung weights of the control and treated animals were comparable
- Histopathology: As a gross lesions (res thymus and pale lung) were noted in one control and one treated male rat, further microscopic examination was performed in these two males. Histopathological examination was unremarkable and revealed no evidence of test article toxicity in the treated male.

Interpretation of results:

other: CLP/EU GHS criteria not met, no classification required according to Regulation (EC) No 12 72/2008

Conclusions:

The study is similar to OECD 403 and was performed under GLP conditions. Based on the results of the study, the acute inhalation LC50 value is considered to be > 5.54 mg/L air in male and female rats. According to criteria of the CLP Regulation (EU) No. 1272/2008, classification of the test item for acute inhalation toxicity is not required

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LC50

Value:

>= 5.54 mg/L air

Physical form:

inhalation: dust / mist

Quality of whole database:

The available information comprises an adequate and reliable study (Klimisch score 2), and is thus sufficient to fulfil the standard information requirements set out in Annex VIII, 8.5, of Regulation (EC) No 1907/2006.

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Study period:

Sep 1996 - Oct 1996

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Version / remarks:

adopted 2017

Deviations:

yes

Remarks:

dosing was not stepwise, 5 animals/sex were used

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Version / remarks:

adopted 1987

Deviations:

no

GLP compliance:

yes

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

other: Crl:CD.BR

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River (UK) Ltd, Margate, UK
- Females nulliparous and non-pregnant: yes
- Age at study initiation: 6 - 9 weeks (males), 9 - 11 weeks (females)
- Weight at study initiation: 261 - 273 g (males), 225 - 245 g (females)
- Fasting period before study: none
- Housing: individually in suspended stainless steel mesh cages (dimensions 30 x 28 x 24 cm)
- Diet: SQC(E) Rat and Mouse Maintenance Diet No 1 (Special Diets Services Ltd, Witham, UK), ad libitum
- Water: mains water, ad libitum
- Acclimation period: 9 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 - 25
- Humidity (%): 40 - 70
- Air changes (per hr): at least 15
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 16 Sep 1996 To: 03 Oct 1996

Type of coverage:

semiocclusive

Vehicle:

water

Details on dermal exposure:

TEST SITE
- Area of exposure: 5 x 5 cm of the clipped dorsum of the rat
- % coverage: 10
- Type of wrap if used: retained in place by an elasticated, open-weave, adhesive bandage

REMOVAL OF TEST SUBSTANCE
- Washing: animals were brushed free of residues of the test article and swabbed with moist cotton wool
- Time after start of exposure: 24 h

TEST MATERIAL
- Amount(s) applied: 2000 mg/kg bw
- Constant volume or concentration used: no
- For solids, paste formed: no, but the dermal test site was moistened by application of 0.2 mL distilled water immediately before application of the test article

VEHICLE
- Amount(s) applied: 0.2 mL

Duration of exposure:

24 h

Doses:

- 2000 mg/kg bw

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Clinical signs were recorded at least once within half an hour of dosing, four times within four hours of dosing, twice daily on Days 2, 3 and 4 and once daily from the fifth to last day of the observation period. Body weights were recorded on Day -1 (day before dosing), Day 1 (day of dosing), Days 4 and 8 and at termination on Day 15.
- Necropsy of survivors performed: yes

Statistics:

Not reported.

Preliminary study:

A preliminary investigation was conducted with two male and two female rats. Animals were treated with a dose of 1800 mg/kg bw. No animal died following a single dermal application of the test substance. Based on the results of this investigation, the regulatory limit dose level of 2000 mg/kg bw was selected for the main study.

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No animal died following a single dermal application of 2000 mg/kg bw.

Clinical signs:

other: There were no clinical signs of systemic or dermal reactions to treatment.

Gross pathology:

No macroscopic changes were apparent during necropsy of the animals killed at completion of the observation period.

Other findings:

Local effects: No overt changes or irritation reactions were noted at the dermal sites of topical application of the test article.

Interpretation of results:

other: According to the classification criteria of the CLP Regulation (EU) No. 1272/2008, no classification is required.

Conclusions:

The study was performed in accordance with OECD TG 402 under GLP conditions and is considered reliable. Under the conditions chosen, it was concluded that the acute median lethal dose (LD50) of the test substance is > 2000 mg/kg bw in both male and female rats. According to criteria of the CLP Regulation (EU) No. 1272/2008, no classification of the test item for acute dermal toxicity is warranted.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

>= 2 000 mg/kg bw

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 VIII, 8.5, of Regulation (EC) No 1907/2006.

Additional information

To assess acute toxicity of the test substance, data after oral, inhalation and dermal exposure to the test substance are considered.

Acute toxicity: oral

The acute oral toxicity of the test substance was determined according to OECD guideline 401 and in compliance with GLP (M-027394-01-1). Groups of five male and female mice were administered single oral doses of 304, 380, 475, 594 and 742 mg/kg bw. At the lowest dose tested, no deaths occurred. Dose level of 380 mg/kg bw or above caused mortality in both sexes. No male mice survived the treatment at 475 mg/kg bw or above, whereas no female mice survived a single oral dose of 742 mg/kg bw. All deaths occurred between 2 h after treatment and the afternoon of Day 2. Treatment related clinical signs were decreased activity and palpebral closure at all dose levels. Less common clinical signs included ataxia and tremor at all dose levels and lethargy, prone posture, twitching and breathing changes (dyspnoea, hyperpnoea or bradypnoea) among the mice treated with the highest dose level. The survivors completely recovered from these clinical signs by Day 2 of the study. Furthermore, the surviving male mice gained body weight during the observation period. Several female mice made no body weight gain during either the first or second week of the observation period. Necropsy of the animals found dead after treatment revealed no common macroscopic changes attributed to a treatment-related effect. Similarly, necropsy of the survivors revealed no macroscopic changes. Based on the mortality observed during the study, the LD50 value (acute median lethal oral dose) of 389 mg/kg bw for males and 465 mg/kg bw for females was derived.

The acute oral toxicity of the test substance was also investigated in rats. An acute oral toxicity study in rats was conducted in accordance with the OECD guideline 401 and in compliance with GLP (M-027393-01-1). Five male and five female rats per dose group were orally treated with single doses of 1758, 2283, 2965, 3850 and 5000 mg/kg bw. Death occurred among single female rats at 2965 and 5000 mg/kg bw. One female rat at 3850 mg/kg bw and one male rat at 5000 mg/kg bw were considered moribund on Day 12 and were therefore killed on humane grounds. Both animals showed a progressive loss of body weight throughout the observation period. The clinical signs of reaction to treatment were palpebral closure, decreased activity and tremor followed at a later stage by wasted appearance and hair loss. All rats dosed with 1758, 2283 or 2965 mg/kg bw recovered by Day 15 from all clinical signs except hair loss. A few clinical signs such as palpebral closure, hunched posture, wasted appearance and hair loss persisted at Day 15 among the rats treated with 3850 and 5000 mg/kg bw. With regard to body weight, all animals except one male displayed a reduction in weight on Day 4 or 5 of the observation period. During this period at least one male in each group lost more than 4% of body weight and at least one female in each group lost more than 7% of body weight. The majority of rats gained body weight after Day 4 or Day 5, however three females treated at the lower dose levels (1758 or 2283 mg/kg bw), six females dosed at the higher dose levels (3850 or 5000 mg/kg bw) and one male rat treated at 5000 mg/kg bw showed a sustained loss of body weight on Day 8. By Day 12 one female rat dosed at 3850 mg/kg body weight had lost 23% of initial (Day 1) body weight and one male dosed at 5000 mg/kg body weight had lost 33% of initial body weight. Both animals were considered moribund and were killed on humane grounds. Between Day 8 and 15, large gains in body weight were recorded for all surviving rats except a single female at the low dose level. Necropsy of all rats revealed no macroscopic changes considered consistent with an effect of the test substance. Because no group showed mortalities of greater than 20%, it was concluded that the LD50 value was greater than 5000 mg/kg bw for both male and female rats.

Moreover, data on acute toxicity in rats are available based on a dose-range finding study, which  was performed in compliance with GLP and partly to OECD 401 (M-027750-03-1). Five male and female Fischer 344 rats received single oral doses of 250, 500 and 1000 mg/kg bw. These nominal doses corresponded to actual doses of 290, 523 and 1216 mg/kg bw. Surviving animals were sacrificed on day 4, when recovery was clearly evident and it was apparent that additional animals would not die as the result of treatment. At the lowest dose tested, no death occurred. One female died after treatment with 523 mg/kg bw. At 1216 mg/kg bw, all females and 2/5 males died. Treatment-related clinical signs included tremor, decreased activity, locomotor incoordination, nasal discharge, lacrimation, as well as nasal and oral stains. The earliest clinical signs were evident 3 hours after treatment. Animals continued to exhibit marked evidence of toxicity 24 hours after treatment with incomplete recovery at 72 hours. Gross pathological changes were not examined in the present study. Based on the mortalities observed during the study, the acute median lethal oral dose was estimated to be > 1216 mg/kg bw in males and > 523 to < 1216 mg/kg bw in females.

Overall, based on the available data, the mouse seemed to be more vulnerable towards acute toxicity following oral administration than rats. Acute oral LD50 values of 389 mg/kg bw and 465 mg/kg bw were derived in male and female mice, respectively. In rats, LD50 values of > 5000 mg/kg bw in both sexes were determined according to OECD 401. However, the available dose-range finding study indicates a higher sensitivity in rats resulting in LD50 values of > 1216 mg/kg bw and > 523 to < 1216 mg/kg bw in male and female rats, respectively. Thus, following a worst-case approach, the study performed in mice is selected as key study and data obtained in rats are considered as supporting evidence.   

Acute toxicity: inhalation

A GLP-conform acute inhalation toxicity study was performed according to OECD guideline 403 (M-027390-01-1). Five male and five female rats were exposed head-only to a single dose of the test atmosphere generated from the micronized test article (powder) for 4.5 h. The test article concentration was 6.141 mg/L, which was measured by gravimetric concentration. However, due to technical difficulties in aerosol generation, this concentration refers to the mean measured gravimetric concentration excluding samples taken during period of technical difficulties in aerosol generation. By including all measured values, the mean gravimetric concentration was 5.538 mg/L. The mass median aerodynamic diameter of the particle was 2.78 µm with a median geometric standard deviation of 2.38. No mortality occurred during the study. Clinical signs attributed to the treatment included ataxia, semi-closed eyes, hunched body posture and lethargy. All animals recovered from Day 5 to the end of the observation period. The body weight of the treated animals decreased following exposure of the test article. At Day 2 group mean body weight in the male and female treated groups was 91 and 92% of the pre-exposure weight compared with 101 and 99% respectively for the comparable control groups. However, this effect was assumed to be due to the reduced food and water consumption, which was observed during four days following exposure. By Day 8, animals in the treated group regaining their pre-exposure body weight. After the observation period of 14 days, the group mean body weight in the male and female treated groups was 129 and 111% of the pre-exposure weight compared with 133 and 114% respectively for the comparable control groups. There was no treatment-related macroscopic or microscopic evidence of toxicity. Therefore, the LC50 value was considered to be greater than 5.54 mg/L air for male and female rats.

Acute toxicity: dermal

A GLP-conform acute dermal toxicity study was performed according to OECD guideline 402 (M-027396-01-1). A limit dose of 2000 mg/kg bw was topically applied for 24 h to the clipped skin of five male and female rats under semi-occlusive dressing. Neither mortality nor clinical signs of systemic reaction to treatment were observed during the 14 days of observation. In addition, body weight gain was not affected in test animals. Further, macroscopical examinations did not reveal abnormalities. Thus, the LD50 value in rats was considered to be greater than 2000 mg/kg bw.

Conclusion:

After oral administration of the test substance to mice and rats acute toxicity was observed. Although the test substance exhibited a lower mortality rate in rats compared to mice, both species showed similar clinical signs associated with the treatment. The mouse seemed to be more vulnerable towards acute oral toxicity and hence, the test substance meets the classification criteria for acute oral toxicity, Cat. 4. This is in line with the harmonized classification. The test substance is not expected to induce toxicity following inhalation or dermal exposure.

Justification for classification or non-classification

The available data on acute toxicity meet the criteria for classification according to Regulation (EC) 1272/2008, and are therefore sufficient for classification of the test substance for acute oral toxicity category 4, H302 with an ATE of 390 mg/kg bw. No classification is needed with respect to acute dermal and inhalation toxicity.

According to the RAC opinion (2021), classification as STOT-SE 1, H370 is warranted based on the neurological effects observed in the acute neurotoxicity studies following a weight-of-evidence approach (please refer to details provided under "7.9.1 Neurotoxicity" in the techncal dossier and "5.10.1.1 Neurotoxicity" in the CSR).