Registration Dossier

Administrative data

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:
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

Referenceopen allclose all

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:
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.

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 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
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.