4-isocyanato-2-methyl-1-{4-[(trifluoromethyl)thio]phenoxy}benzene

Endpoint summary

Description of key information

Acute oral toxicity:

A single oral administration of the test substance by gavage to male and female rats at 200 mg/kg bw and 2000 mg/kg bw was tolerated without mortalities. Transient clinical signs were observed at doses of 200 mg/kg bw and above. There was no effect on body weight gain. The gross pathology investigations performed at the end of the follow-up period did not afford any findings indicative for a specific test compound effect. The LD50 was determined to be > 2000 mg/kg bw in both sexes.

Acute inhalation toxicity:

The acute inhalation toxicity of the aerolized test item, tested in a GLP-compliant study according to OECD TG 403, is high in rats of both sexes. Lethalities occurred on the day of exposure and, less frequently, during the first observation day. A gender-specific difference in susceptibility to intoxication by inhalation was not be ascertained. The death of the animals was regarded to be causally related to the respiratory tract irritation. The silmultaneous occurence of bradypnea and hypothermia are consistent with an assessment that the substance also induces sensory irritation to the respiratory tract. The LC50 for both sexes combined was calculated to be 348 mg/m³ (4h)./m³.

Acute dermal toxicity:

A single dermal administration of the test substance to male and female rats at the limit-dose 1310 mg/kg (due to local irritation) was tolerated without mortalities, compound-related clinical findings, effects on body weight gain and gross pathological findings. According to OECD TG 402 the dermal LD50 of the test substance is therefore > 1310 mg/kg body weight.

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:

June 1993

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: 24 February, 1987

Qualifier:

according to guideline

Guideline:

EU Method B.1 (Acute Toxicity (Oral))

Version / remarks:

as amended by Directive 92/69/EEC (31 July, 1992)

GLP compliance:

yes

Test type:

standard acute method

Limit test:

no

Specific details on test material used for the study:

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: room temperature
- Solubility and stability of the test substance in the solvent/vehicle: Homegeneity and stability was confirmed by analytical examination and assured at room temperature for a period at least 2 hours..


TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Final preparation: The applied formulation was well mixed by shaken and by pumping the syringe several times before removal of the dosage.

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Winkelmann GmbH, Borchen, Germany
- Weight at study initiation: 173-191 g (males), 176 -191 g (females)
- Fasting period before study: ca. 16 hours before and 2 hours after treatment
- Housing: 5 animals/cage (polycarbonat cages type III)
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21° +- 1.5° C
- Humidity (%): 40-70%
- air exchange rate: at least10 times per hour
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on oral exposure:

once 5 ml/kg bw

Doses:

200 mg/kg bw and 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
- Necropsy of survivors performed: yes (gross pathology examination)
- behavior and appearance: several times on the day of treatment and at least once a day thereafter
- body weights: before administration and on day 4 and 8 after administration and afterwards the weekly and all animals that died or were sacrificed.

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

Male: 200 mg/kg bw; Number of animals: 5; Number of deaths: 0
Male: 2000 mg/kg bw; Number of animals: 5; Number of deaths: 0
Female: 200 mg/kg bw; Number of animals: 5; Number of deaths: 0
Female: 2000 mg/kg bw; Number of animals: 5; Number of deaths: 0

Clinical signs:

other: apathy, spastc duct, difficulties with respiration soft faeces dose mg/kg / number with symptom / duration time males 200/ 5/ 2 d – 4d 2000/ 5/ 4h – 2d females 200/ 0/ 2000/ 5/ 4h – 2d

Gross pathology:

No findings indicative for a specific test compound effect.

Executive summary:

A single oral administration of the test substance by gavage to male and female rats at 200 mg/kg bw and 2000 mg/kg bw was tolerated without mortalities. Transient clinical signs were observed at doses of 200 mg/kg bw and above. There was no effect on body weight gain. The gross pathology investigations performed at the end of the follow-up period did not afford any findings indicative for a specific test compound effect. The LD50 was determined to be > 2000 mg/kg bw in both sexes.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

discriminating dose

Value:

2 000 mg/kg bw

Quality of whole database:

only one study available

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:

August 1993

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

Test type:

standard acute method

Limit test:

no

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Harlan-Winkelmann, Borchen, Germany
- Strain: Hsd Win:Wu (SPF-Cpb)
- Diet (e.g. ad libitum): yes
- Water (e.g. ad libitum): yes
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22° +- 2° C
- Humidity (%): approx. 60%
- air exchange rate: at least10 times per hour
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

nose/head only

Vehicle:

other: conditioned compressed air

Mass median aerodynamic diameter (MMAD):

1.4 µm

Geometric standard deviation (GSD):

1.8

Analytical verification of test atmosphere concentrations:

yes

Duration of exposure:

4 h

Remarks on duration:

the post exposure period of observation was a minimum of 2 weeks

Concentrations:

Actual Conc.: 0, 356, 401, 555, 1023 mg/m³
Garvimetric Con.: 0, 377, 440, 583, 1077 mg/m³

No. of animals per sex per dose:

5

Control animals:

yes

Details on study design:

- Duration of observation period following administration: a minimum of 2 weeks
- Frequency of observations and weighing: clinical signs several times on the day of exposure and twice daily thereafter and before exposure , on day 3, and 7, and weekly thereafter.
- Rectal temperatures: directly after cessation of exposure
- Necropsy of survivors performed: yes

Sex:

male/female

Dose descriptor:

LC50

Effect level:

348 mg/m³ air

Based on:

test mat.

Exp. duration:

4 h

Mortality:

see Table 1: Summary of acute inhalation toxicity

Clinical signs:

other: All groups: bradypnoea, laboured breathing, irregular bretahing pattern, reduced motility, nose/muzzle with red incrustations.

Body weight:

Significant depressions in body weight gain from all groups on post-exposure day 3 and all groups recovered by day 7.

Gross pathology:

Animals sacrified at the end of the observation period: Lungs from individual animals: pinpoint dark red zones, individual dark red zone, slightly collapsed, pale.

Other findings:

rectal temperature: All groups that had statistically representative populations of survivors showed significant decrements in rectal temperature from values of controls.

 Table 1: Summary of acute inhalation toxicity

Group	Sex	Analytical Concentration (mg/m³)	Result	Onset and Duration of Signs	Onset of Lethalities
1	male	0	0/0/0
2	male	356	0/5/5	4h -3d
3	male	401	3/5/5	4h -3d	1d
4	male	555	5/1/5	4h -3d	0d - 1d
5	male	1023	5/0/5		0d
1	female	0	0/0/5
2	female	356	0/5/5	4h -6d
3	female	401	0/5/5	4h -11d
4	female	555	4/4/5	5h-9d	0d - 1d
5	female	1023	5/0/5		0d

Values given in the Result column are:

1st = number of dead animals

2nd = number of animals with signs after cessation of exposure

3rd = number of animals exposed

Executive summary:

The acute inhalation toxicity of the aerolized test item, tested in a GLP-compliant study according to OECD TG 403, is high in rats of both sexes. Lethalities occurred on the day of exposure and, less frequently, during the first observation day. A gender-specific difference in susceptibility to intoxication by inhalation was not be ascertained. The death of the animals was regarded to be causally related to the respiratory tract irritation. The silmultaneous occurence of bradypnea and hypothermia are consistent with an assessment that the substance also induces sensory irritation to the respiratory tract. The LC50 for both sexes combined was calculated to be 348 mg/m³ (4h)./m³.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LC50

Value:

348 mg/m³ air

Quality of whole database:

only one study available.

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

other information

Study period:

July - August 1993

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Qualifier:

according to guideline

Guideline:

EU Method B.3 (Acute Toxicity (Dermal))

GLP compliance:

yes

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Winkelmann GmbH, Borchen, Germany
- Weight at study initiation: 252-261 g (males), 236 -250 g (females)
- Housing: conventionally in polycarbonate cages and during the test period individually.
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21° +- 1.5° C
- Humidity (%): 40-70%
- air exchange rate: at least 10 times per hour
- Photoperiod (hrs dark / hrs light): 12/12

Type of coverage:

occlusive

Vehicle:

other: the sample is combined with cellulose and mixed to a paste

Details on dermal exposure:

TEST SITE
- Area of exposure: 30.3 cm²

REMOVAL OF TEST SUBSTANCE
- Washing (if done): Yes, with soap and water
- Time after start of exposure: 24 hours

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 10.9 - 11.28 mg/cm² (males); 10.2 - 10.81 mg/cm² (females)

Duration of exposure:

24 h

Doses:

1310 mg/kg bw (2000 mg/kg bw mixed with cellulose) is the MTD due to local irritation.

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: at least once a day (clinical observation); before administration, on day 4 and 8 after administration and then weekly
- Necropsy of survivors performed: yes

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 1 310 mg/kg bw

Based on:

test mat.

Remarks on result:

other: 1310 mg/kg bw is the limit dose level due to local irritation

Mortality:

Male: 2000 mg/kg bw; Number of animals: 5; Number of deaths: 0
Female: 2000 mg/kg bw; Number of animals: 5; Number of deaths: 0

Clinical signs:

other: no systemic effect

Gross pathology:

The pathological examination at the end of the study showed no change, which refer to a test-substance-specific effect.

Other findings:

Local findings:
distinct effects of irritation

Executive summary:

A single dermal administration of the test substance to male and female rats at the limit-dose 1310 mg/kg (due to local irritation) was tolerated without mortalities, compound-related clinical findings, effects on body weight gain and gross pathological findings. According to OECD TG 402 the dermal LD50 of the test substance is therefore > 1310 mg/kg body weight.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

discriminating dose

Value:

1 310 mg/kg bw

Quality of whole database:

only one study available

Justification for classification or non-classification

Based on the study results for acute oral toxicity no classification according to Regulation (EC) No. 1272/2008 (CLP), ANNEX I, is warranted.

Based on the study results for acute oral toxicity also no classification for acute dermal toxicity according to Regulation (EC) No. 1272/2008 (CLP), ANNEX I, is warranted.

With regard to the dermal LD50 -value > 1310 mg/kg bw, which was already determined in 1993, the substance would be allocated to Category 4 according to the numeric criteria. Skin corrosivity prevented an accurate result for classification purposes because with regard to animal welfare reason it was impossible to apply 2000 mg/kg bw. From today´s perspective, according to REACH Regulation column 2 of Section 8.5.3 of Annex VIII the waiving of acute dermal toxicity testing is allowed if the substance does not meet the criteria for classification for acute oral toxicity (see above). No further testing nor classification for acute dermal toxicity is required.

Based on the study results for acute inhahaltion toxicity a classification in Category 2 (H330: Fatal if inhaled) according to Regulation (EC) No. 1272/2008 (CLP), ANNEX I, is warranted