α,α,α-trifluoro-3-tolyl isocyanate

Endpoint summary

Description of key information

A reliable acute oral toxicity study is available for evaluation. Several acute inhalation studies were conducted. For the most reliable study (Hoechst, 1992) a LC50 = 79 mg/m³ is stated based on an expert statement of Prof. Pauluhn. The LC50 = 79 mg/m³ is taken for risk assessment. The acute dermal toxicity study is not assignable (reliability 4) because only data from a secondary source are available.

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

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: scientifically acceptable and well documented

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Principles of method if other than guideline:

Six groups of 10 female young adult Wister rats (avarage weight 88 g) each reveived per gavage a single dose of 2500, 4000, 5000, 6300, 8000 or 100000 mg/kg bw m-trifluoromethylphenylisocyanate. The animals were observed for mortality, weight and clinical signs through day 14. A necropsy was performed on animals during the post-observation time.

GLP compliance:

not specified

Test type:

standard acute method

Species:

rat

Strain:

Wistar

Sex:

female

Route of administration:

oral: gavage

Vehicle:

other: sesam oil

Doses:

2500, 4000, 5000, 6300, 8000 or 100000 mg/kg bw

No. of animals per sex per dose:

10 female rats per dose

Control animals:

not specified

Sex:

female

Dose descriptor:

LD50

Effect level:

6 604 mg/kg bw

Animals which died during tests had a prone position and balance disturbances. Additionally evidence of an inactive behaviour was seen. An increased vascular network of the stomach and intestine was found macroscopically.

Interpretation of results:

GHS criteria not met

Executive summary:

Six groups of 10 female young adult Wister rats (avarage weight 88 g) each reveived per gavage a single dose of 2500, 4000, 5000, 6300, 8000 or 100000 mg/kg bw m-trifluoromethylphenylisocyanate. The animals were observed for mortality, weight and clinical signs through day 14. A necropsy was performed on animals during the post-observation time.

Animals which died during tests had a prone position and balance disturbances. Additionally evidence of an inactive behaviour was seen. An increased vascular network of the bowel and intestine was found macroscopically. LD 50 = 6604 mg/kg bw (rat, female).

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

6 604 mg/kg bw

Quality of whole database:

Scientifically acceptable and well documented.

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Reference 1

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

other: secondary source

Qualifier:

according to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

GLP compliance:

not specified

Test type:

standard acute method

Species:

rat

Strain:

Wistar

Sex:

male/female

Route of administration:

inhalation: vapour

Type of inhalation exposure:

not specified

Vehicle:

not specified

Analytical verification of test atmosphere concentrations:

not specified

Duration of exposure:

4 h

Concentrations:

no data

No. of animals per sex per dose:

no data

Control animals:

not specified

Sex:

male/female

Dose descriptor:

LC50

Effect level:

< 87 mg/m³ air

Exp. duration:

4 h

Result : 70 % mortality, serious damage of the lungs.

Executive summary:

In a guideline study according OECD 403 rats inhaled an arosol (vapour inhalation) of alpha,alpha,alpha-trifluoro-3-tolyl isocyanate.

LC50 < 87 mg/m³.

Reference 2

Endpoint:

acute toxicity: inhalation

Type of information:

other: Expert statement Prof. Pauluhn

Adequacy of study:

weight of evidence

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

test procedure in accordance with national standard methods with acceptable restrictions

Principles of method if other than guideline:

The objective of this Expert Opinion is to re-analyze existing data regarding the acute inhalation toxicity data of phenyl isocyanate (PhI) from Pauluhn (1991) for coherence with contemporary testing guidelines OECD (2009a,b) and whether the available data are suited be to bridge the 4-hour LC50 of PhI to its congeneric monoisocyanate 3-trifluoromethyl phenyl isocyanate (3-TPI). The acute inhalation toxicity of the latter was reported by Hofmann & Jung (1992). These authors report a 4-hour point estimate LC70 of 87 mg/m³ (rats). For PhI, a markedly lower LC50 value was reported by Pauluhn (1991). As already elucidated with other isocyanates (for details see Pauluhn, 2019), this difference was related to analytical shortcomings that lowered the collection efficiency of the sampled isocyanate by approximately 50%. Notably, the actual determination of nominal concentrations of PhI fulfills most of the criteria for qualifying also as actual (analytical) concentration. Nominal concentration-based re-analysis of the PhI study yielded a 4-hour LC50 of 50 mg PhI/m³. When accounting for the 1.53-fold higher molecular weight of 3-TPI, the PhI-based equivalent 4-hour LC50 of 3-TPI was 79 mg/m³. Hence, both LC50’s converged favorably when compared on molar concentrations (parts per million volume, ppm). The coherence of empirical data from 3-TPI (4-hour LC70 of 87 mg/m³) with its PhI-based calculated LC50 of 79 mg/m³ or 10.2 ppm and PhI (4-hour LC50 of 50 mg/m³ or 10.2 ppm) implicitly supports the course taken.

GLP compliance:

no

Test type:

other: Expert statement.

Specific details on test material used for the study:

Not applicable - expert statement.

Species:

other: Not applicable - expert statement.

Strain:

other: Not applicable - expert statement.

Details on test animals or test system and environmental conditions:

Not applicable - expert statement.

Route of administration:

other: Not applicable - expert statement.

Type of inhalation exposure:

other: Not applicable - expert statement.

Vehicle:

other: Not applicable - expert statement.

Details on inhalation exposure:

Not applicable - expert statement.

Concentrations:

Not applicable - expert statement.

No. of animals per sex per dose:

Not applicable - expert statement.

Control animals:

other: Not applicable - expert statement.

Details on study design:

Not applicable - expert statement.

Statistics:

Not applicable - expert statement.

Sex:

male/female

Dose descriptor:

LC50

Effect level:

79 mg/m³ air

Based on:

test mat.

Exp. duration:

4 h

Remarks on result:

other: Not applicable - expert statement.

Mortality:

LC50 = 79 mg/m³.

Clinical signs:

other: Not applicable - expert statement.

Body weight:

Not applicable - expert statement.

Gross pathology:

Not applicable - expert statement.

Other findings:

Not applicable - expert statement.

The objective of this Expert Opinion is to re-analyze existing data regarding the acute inhalation toxicity data of phenyl isocyanate (PhI) from Pauluhn (1991) for coherence with contemporary testing guidelines OECD (2009a,b) and whether the available data are suited be to bridge the 4-hour LC50 of PhI to its congeneric monoisocyanate 3-trifluoromethyl phenyl isocyanate (3-TPI). The acute inhalation toxicity of the latter was reported by Hofmann & Jung (1992). These authors report a 4-hour point estimate LC70 of 87 mg/m³ (rats). For PhI, a markedly lower LC50 value was reported by Pauluhn (1991). As already elucidated with other isocyanates (for details see Pauluhn, 2019), this difference was related to analytical shortcomings that lowered the collection efficiency of the sampled isocyanate by approximately 50%. Notably, the actual determination of nominal concentrations of PhI fulfills most of the criteria for qualifying also as actual (analytical) concentration. Nominal concentration-based re-analysis of the PhI study yielded a 4-hour LC50 of 50 mg PhI/m³. When accounting for the 1.53-fold higher molecular weight of 3 TPI, the PhI-based equivalent 4-hour LC50 of 3-TPI was 79 mg/m³. Hence, both LC50’s converged favorably when compared on molar concentrations (parts per million volume, ppm). The coherence of empirical data from 3-TPI (4-hour LC70 of 87 mg/m³) with its PhI-based calculated LC50 of 79 mg/m³ or 10.2 ppm and PhI (4-hour LC50 of 50 mg/m³ or 10.2 ppm) implicitly supports the course taken.

Executive summary:

The objective of this Expert Opinion is to re-analyze existing data regarding the acute inhalation toxicity data of phenyl isocyanate (PhI) from Pauluhn (1991) for coherence with contemporary testing guidelines OECD (2009a,b) and whether the available data are suited be to bridge the 4-hour LC50 of PhI to its congeneric monoisocyanate 3-trifluoromethyl phenyl isocyanate (3-TPI). The acute inhalation toxicity of the latter was reported by Hofmann & Jung (1992). These authors report a 4-hour point estimate LC70 of 87 mg/m³ (rats). For PhI, a markedly lower LC50 value was reported by Pauluhn (1991). As already elucidated with other isocyanates (for details see Pauluhn, 2019), this difference was related to analytical shortcomings that lowered the collection efficiency of the sampled isocyanate by approximately 50%. Notably, the actual determination of nominal concentrations of PhI fulfills most of the criteria for qualifying also as actual (analytical) concentration. Nominal concentration-based re-analysis of the PhI study yielded a 4-hour LC50 of 50 mg PhI/m³. When accounting for the 1.53-fold higher molecular weight of 3-TPI, the PhI-based equivalent4-hour LC50 of 3-TPI was 79 mg/m³. Hence, both LC50’s converged favorably when compared on molar concentrations (parts per million volume, ppm). The coherence of empirical data from 3-TPI (4-hour LC70 of 87 mg/m³) with its PhI-based calculated LC50 of 79 mg/m³ or 10.2 ppm and PhI (4-hour LC50 of 50 mg/m³ or 10.2 ppm) implicitly supports the course taken.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LC50

Value:

79 mg/m³ air

Quality of whole database:

Several acute inhalation studies are conducted. For the most reliable study (Hoechst, 1992) a LC50 = 79 mg/m³ is stated based on an expert statement of Prof. Pauluhn. The LC50 = 79 mg/m³ is taken for risk assessment.

Acute toxicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Quality of whole database:

The acute dermal toxicity study is not assignable (reliability 4) because only data from a secondary source are available. Therefore the data from the acute dermal toxicity study are not suitable for the determination of a dose descriptor.

Additional information

In the most reliable acute oral toxicity study an oral LD50 = 6604 mg/kg bw for rats was determined. The oral studies from Gurova et al., which were only available in Russian a lower LD50 = 975 mg/kg bw was found. For these studies only limited details were available and therefore the studie are disregarded.

For acute inhalation toxicity secondary data of 4 studies in rats are available which all have limitations.

In the acute inhalation studies LC50 values of > 36 mg/m³, < 87 mg/m³ and < 328 mg/m³ were determined. Based on the expert statement of Prof. Pauluhn, a LC50 of 79 mg/m³ is taken for risk assessment.

'The objective of this Expert Opinion [by Prof. Pauluhn] is to re-analyze existing data regarding the acute inhalation toxicity data of phenyl isocyanate (PhI) from Pauluhn (1991) for coherence with contemporary testing guidelines OECD (2009a,b) and whether the available data are suited be to bridge the 4-hour LC50 of PhI to its congeneric monoisocyanate 3-trifluoromethyl phenyl isocyanate (3-TPI). The acute inhalation toxicity of the latter was reported by Hofmann & Jung (1992). These authors report a 4-hour point estimate LC70 of 87 mg/m³ (rats). For PhI, a markedly lower LC50 value was reported by Pauluhn (1991). As already elucidated with other isocyanates (for details see Pauluhn, 2019), this difference was related to analytical shortcomings that lowered the collection efficiency of the sampled isocyanate by approximately 50%. Notably, the actual determination of nominal concentrations of PhI fulfills most of the criteria for qualifying also as actual (analytical) concentration. Nominal concentration-based re-analysis of the PhI study yielded a 4-hour LC50 of 50 mg PhI/m³. When accounting for the 1.53-fold higher molecular weight of 3-TPI, the PhI-based equivalet 4-hour LC50 of 3-TPI was 79 mg/m³. Hence, both LC50’s converged favorably when compared on molar concentrations (parts per million volume, ppm). The coherence of empirical data from 3-TPI (4-hour LC70 of 87 mg/m³) with its PhI-based calculated LC50 of 79 mg/m³ or 10.2 ppm and PhI (4-hour LC50 of 50 mg/m³ or 10.2 ppm) implicitly supports the course taken'.

The LC50 = 79 mg/m³ is taken for risk assessment.

The acute dermal toxicity studies are not assignable (reliability 4) because only data from secondary sources are available. Therefore the dermal toxicity study is not suitable for the determination of a dose descriptor.

In a MSDS for the acute dermal toxicity a LD50 > 210 mg/kg bw was stated.

Justification for classification or non-classification

Due to the result of the most reliable acute oral toxicity study a classification is not justified.

Based on the expert statement by Prof. Pauluhn for the most reliable study (Hoechst, 1992) a LC50 = 79 mg/m³ is stated. The LC50 = 79 mg/m³ is taken for risk assessment. For the classification of the acute inhalation toxicity a conservative approach on a weight-of-evidence consideration is adopted.  According to CLP classification criteria (Regulation (EC) No 1272/2008) a classification as Acute Tox. 1 (H330: Fatal if inhaled) is proposed.

For acute dermal toxicity according to CLP classification criteria (Regulation (EC) No 1272/2008) a classification as Acute Tox. 3 (H311: Toxic in contact with skin) is proposed.