Registration Dossier

No results from repeated-dose toxicity tests are available for the oral and dermal route of exposure.

For inhalation an exploratory subacute vapour inhalation study and a subacute inhalation toxicity (28-Day Study) according to OECD Guideline 412 are available.

Administration/exposure - 5d per week/ 6 hours per day for 28 days; Type of exposure: dynamic head-nose only vapor exposure.
Result: NOAEC = 0.83 mg phenyl isocyanate/m³ air (male + female rats); LOAEC = 2.79 mg phenyl isocyanate/m³ air (male + female rats).

Endpoint conclusion:

no study available

Reference

Endpoint:

short-term repeated dose toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: guideline study - well documented

Qualifier:

according to guideline

Guideline:

OECD Guideline 412 (Subacute Inhalation Toxicity: 28-Day Study)

Principles of method if other than guideline:

Ten male and female rats per group were exposed nose/head only to mean analytical concentrations of 0.35, 0.83, 2.79 and 10.07 mg phenyl isocyanate/m³ for 4 weeks (6h/d, 5 exposures per week). During the study, the body weights were determined and clinical signs were recorded. At the end of the study ophthalmological examinations were performed and clinicochemical and hematological parameters were determined and a urinalysis performed. During sacrifice, gross pathological examinations of rats were made and selected organs were collected for gravimetric and histopathological examinations.

GLP compliance:

yes

Species:

rat

Strain:

Wistar

Sex:

male/female

Route of administration:

inhalation

Type of inhalation exposure:

nose/head only

Vehicle:

air

Analytical verification of doses or concentrations:

yes

Duration of treatment / exposure:

4 weeks

Frequency of treatment:

6h/d, 5d/w

Dose / conc.:

0 mg/m³ air

Dose / conc.:

0.35 mg/m³ air (analytical)

Dose / conc.:

0.83 mg/m³ air (analytical)

Dose / conc.:

2.79 mg/m³ air (analytical)

Dose / conc.:

10.07 mg/m³ air (analytical)

Dose / conc.:

0.2 mg/m³ air (nominal)

Dose / conc.:

0.7 mg/m³ air (nominal)

Dose / conc.:

2.5 mg/m³ air (nominal)

Dose / conc.:

7.5 mg/m³ air (nominal)

No. of animals per sex per dose:

10 male and 10 female animals/group

Control animals:

yes, concurrent vehicle

Details on study design:

Post-exposure period: no

Positive control:

None

Observations and examinations performed and frequency:

Body weights, clinical signs, rectal temperature, ophthalmological examinations, clinicochemical, hematological parameters, urinalysis.

Sacrifice and pathology:

Gross pathological examinations, selected organs were collected for gravimetric and histopathological examinations.

Statistics:

A statistical calculation of the determined parameters was conducted.

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

Up to 7.5 mg/m³ no findings. In the 7.5 mg/m³ group a decrease of the general condition was observed.

Mortality:

mortality observed, treatment-related

Description (incidence):

In the 7.5 mg/m³ group 70% of the male rats and 50% of the female rats died intercurrent or were killed in moribund state.

Description (incidence and severity):

In the 2.5 mg/m³ group no toxicological relevant influence on the body weights were observed. In the 7.5 mg/kg bw group a statistical significant decrease of the body weights were seen.

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

effects observed, treatment-related

Description (incidence and severity):

In the 2.5 mg/m³ no findings. In the 7.5 mg/m³ group a hyperemia of the iris and a reddened ocular fundus were observed.

Haematological findings:

effects observed, treatment-related

Description (incidence and severity):

In the 7.5 mg/m³ group the erythrocyte concentration, hematocrit and, hemoglobin and reticulocyte concentration were increased. Additional the rats revealed an increased coagulation time. the differential blood count showed an increase of the monocytes.

Clinical biochemistry findings:

effects observed, treatment-related

Description (incidence and severity):

In the 7.5 mg/m³ group a statistically relevant decrease of the albumin, protein and chloride concentration of the plasma was observed, as well as an increase of the plasma ASAT (aspartate aminotransferase) and GLDH (glutamate dehydrogenase) activity. Additional the bilirubin and sodium concentrations were increased.

Urinalysis findings:

effects observed, treatment-related

Description (incidence and severity):

Urine was more acidic in the 7.5 mg/m³ group.

Behaviour (functional findings):

effects observed, treatment-related

Description (incidence and severity):

In the 7.5 mg/m³ a decrease of the reflexes were observed.

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

In the 7.5 mg/m³ group, the weights of liver, thymus, testis/ovaries and spleen were decreased, the liver weights were increased. No findings in the 2.5 mg/m³ group.

Gross pathological findings:

effects observed, treatment-related

Description (incidence and severity):

In the 7.5 mg/m³ group, lungs was dark red discoloured, congestion of the cerebral blood vessels, dark spleen and decreased thymus. No findings in the 2.5 mg/m³ group.

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

<= 2.79 mg/m³: no findings
2.79 mg/m³: histopathological alterations in the nasal septum (hyperplasia)
10.07 mg/³: metaplasia of the epithelium (nasal septum, larynx, trachea, stem bronchus), increased number of alveolar macrophages and swollen septum (lung), proliferating connective tissue, perivascular infiltration of round cells and accumulation of mucus (lobar bronchus).

Histopathological findings: neoplastic:

no effects observed

Other effects:

no effects observed

Key result

Dose descriptor:

NOAEC

Effect level:

0.83 mg/m³ air (analytical)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: no effects observed

Key result

Dose descriptor:

LOAEL

Effect level:

2.79 mg/m³ air (analytical)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

gross pathology

histopathology: non-neoplastic

Key result

Critical effects observed:

yes

Lowest effective dose / conc.:

2.79 mg/m³ air (analytical)

System:

other: respiratory tract

Organ:

lungs

nasal cavity

trachea

Treatment related:

yes

Dose response relationship:

yes

Relevant for humans:

yes

<= 2.79 mg/m³: no mortality, no clinical signs; 2.79 mg/m³: histopathological alterations in the nasal septum (hyperplasia) 10.07 mg/³: 5/10 (females) and 7/10 (males) died, elevated temperature, decreased body weights, changed haematological and clinical biochemistry parameters, decreased organ weights (liver, thymus, gonads, spleen), increased lung weight, metaplasia of the epithelium (nasal septum, larynx, trachea, stem bronchus), increased number of alveolar macrophages and swollen septum (lung), proliferating connective tissue, perivascular infiltration of round cells and accumulation of mucus (lobar bronchus).

Conclusions:

At a concentration <= 2.79 mg/m³ no mortality and no clinical signs were seen. Starting with 2.79 mg/m³ histopathological alterations in the nasal septum (hyperplasia) were evident. At a concentration of 10.07 mg/m³ 5/10 females and 7/10 males died. An elevated temperature, decreased body weights, changed haematological and clinical biochemistry parameters, decreased organ weights (liver, thymus, gonads, spleen), increased lung weight, metaplasia of the epithelium (nasal septum, larynx, trachea, stem bronchus), increased number of alveolar macrophages and swollen septum (lung), proliferating connective tissue, perivascular infiltration of round cells and accumulation of mucus (lobar bronchus) were observed.
The effects observed in the respiratory system are mainly caused by irritation/corrosion. Therefore according to CLP classification criteria (Regulation (EC) No 1272/2008) a classification is not justified.

Executive summary:

Ten male and female rats per group were exposed nose/head only to mean analytical concentrations of 0.35, 0.83, 2.79 and 10.07 mg phenyl isocyanate for 4 weeks (6h/d, 5 exposures per week). During the study, the body weights were determined and clinical signs were recorded. At the end of the study ophthalmological examinations was performed and clinicochemical and hematological parameters were determined and an urinalysis performed. During sacrifice, gross pathological examinations of rats were made and selected organs were collected for gravimetric and histopathological examinations.

The NOAEL = 0.83 mg phenyl isocyanate/m³ air is based on the most sensitive parameter (hyperplasia of goblet cells in the turbinalia area).

Endpoint conclusion:

no adverse effect observed

Study duration:

subacute

Species:

rat

Quality of whole database:

GLP guideline study

Reference

Endpoint:

short-term repeated dose toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: guideline study - well documented

Qualifier:

according to guideline

Guideline:

OECD Guideline 412 (Subacute Inhalation Toxicity: 28-Day Study)

Principles of method if other than guideline:

Ten male and female rats per group were exposed nose/head only to mean analytical concentrations of 0.35, 0.83, 2.79 and 10.07 mg phenyl isocyanate/m³ for 4 weeks (6h/d, 5 exposures per week). During the study, the body weights were determined and clinical signs were recorded. At the end of the study ophthalmological examinations were performed and clinicochemical and hematological parameters were determined and a urinalysis performed. During sacrifice, gross pathological examinations of rats were made and selected organs were collected for gravimetric and histopathological examinations.

GLP compliance:

yes

Species:

rat

Strain:

Wistar

Sex:

male/female

Route of administration:

inhalation

Type of inhalation exposure:

nose/head only

Vehicle:

air

Analytical verification of doses or concentrations:

yes

Duration of treatment / exposure:

4 weeks

Frequency of treatment:

6h/d, 5d/w

Dose / conc.:

0 mg/m³ air

Dose / conc.:

0.35 mg/m³ air (analytical)

Dose / conc.:

0.83 mg/m³ air (analytical)

Dose / conc.:

2.79 mg/m³ air (analytical)

Dose / conc.:

10.07 mg/m³ air (analytical)

Dose / conc.:

0.2 mg/m³ air (nominal)

Dose / conc.:

0.7 mg/m³ air (nominal)

Dose / conc.:

2.5 mg/m³ air (nominal)

Dose / conc.:

7.5 mg/m³ air (nominal)

No. of animals per sex per dose:

10 male and 10 female animals/group

Control animals:

yes, concurrent vehicle

Details on study design:

Post-exposure period: no

Positive control:

None

Observations and examinations performed and frequency:

Body weights, clinical signs, rectal temperature, ophthalmological examinations, clinicochemical, hematological parameters, urinalysis.

Sacrifice and pathology:

Gross pathological examinations, selected organs were collected for gravimetric and histopathological examinations.

Statistics:

A statistical calculation of the determined parameters was conducted.

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

Up to 7.5 mg/m³ no findings. In the 7.5 mg/m³ group a decrease of the general condition was observed.

Mortality:

mortality observed, treatment-related

Description (incidence):

In the 7.5 mg/m³ group 70% of the male rats and 50% of the female rats died intercurrent or were killed in moribund state.

Description (incidence and severity):

In the 2.5 mg/m³ group no toxicological relevant influence on the body weights were observed. In the 7.5 mg/kg bw group a statistical significant decrease of the body weights were seen.

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

effects observed, treatment-related

Description (incidence and severity):

In the 2.5 mg/m³ no findings. In the 7.5 mg/m³ group a hyperemia of the iris and a reddened ocular fundus were observed.

Haematological findings:

effects observed, treatment-related

Description (incidence and severity):

In the 7.5 mg/m³ group the erythrocyte concentration, hematocrit and, hemoglobin and reticulocyte concentration were increased. Additional the rats revealed an increased coagulation time. the differential blood count showed an increase of the monocytes.

Clinical biochemistry findings:

effects observed, treatment-related

Description (incidence and severity):

In the 7.5 mg/m³ group a statistically relevant decrease of the albumin, protein and chloride concentration of the plasma was observed, as well as an increase of the plasma ASAT (aspartate aminotransferase) and GLDH (glutamate dehydrogenase) activity. Additional the bilirubin and sodium concentrations were increased.

Urinalysis findings:

effects observed, treatment-related

Description (incidence and severity):

Urine was more acidic in the 7.5 mg/m³ group.

Behaviour (functional findings):

effects observed, treatment-related

Description (incidence and severity):

In the 7.5 mg/m³ a decrease of the reflexes were observed.

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

In the 7.5 mg/m³ group, the weights of liver, thymus, testis/ovaries and spleen were decreased, the liver weights were increased. No findings in the 2.5 mg/m³ group.

Gross pathological findings:

effects observed, treatment-related

Description (incidence and severity):

In the 7.5 mg/m³ group, lungs was dark red discoloured, congestion of the cerebral blood vessels, dark spleen and decreased thymus. No findings in the 2.5 mg/m³ group.

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

<= 2.79 mg/m³: no findings
2.79 mg/m³: histopathological alterations in the nasal septum (hyperplasia)
10.07 mg/³: metaplasia of the epithelium (nasal septum, larynx, trachea, stem bronchus), increased number of alveolar macrophages and swollen septum (lung), proliferating connective tissue, perivascular infiltration of round cells and accumulation of mucus (lobar bronchus).

Histopathological findings: neoplastic:

no effects observed

Other effects:

no effects observed

Key result

Dose descriptor:

NOAEC

Effect level:

0.83 mg/m³ air (analytical)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: no effects observed

Key result

Dose descriptor:

LOAEL

Effect level:

2.79 mg/m³ air (analytical)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

gross pathology

histopathology: non-neoplastic

Key result

Critical effects observed:

yes

Lowest effective dose / conc.:

2.79 mg/m³ air (analytical)

System:

other: respiratory tract

Organ:

lungs

nasal cavity

trachea

Treatment related:

yes

Dose response relationship:

yes

Relevant for humans:

yes

<= 2.79 mg/m³: no mortality, no clinical signs; 2.79 mg/m³: histopathological alterations in the nasal septum (hyperplasia) 10.07 mg/³: 5/10 (females) and 7/10 (males) died, elevated temperature, decreased body weights, changed haematological and clinical biochemistry parameters, decreased organ weights (liver, thymus, gonads, spleen), increased lung weight, metaplasia of the epithelium (nasal septum, larynx, trachea, stem bronchus), increased number of alveolar macrophages and swollen septum (lung), proliferating connective tissue, perivascular infiltration of round cells and accumulation of mucus (lobar bronchus).

Conclusions:

At a concentration <= 2.79 mg/m³ no mortality and no clinical signs were seen. Starting with 2.79 mg/m³ histopathological alterations in the nasal septum (hyperplasia) were evident. At a concentration of 10.07 mg/m³ 5/10 females and 7/10 males died. An elevated temperature, decreased body weights, changed haematological and clinical biochemistry parameters, decreased organ weights (liver, thymus, gonads, spleen), increased lung weight, metaplasia of the epithelium (nasal septum, larynx, trachea, stem bronchus), increased number of alveolar macrophages and swollen septum (lung), proliferating connective tissue, perivascular infiltration of round cells and accumulation of mucus (lobar bronchus) were observed.
The effects observed in the respiratory system are mainly caused by irritation/corrosion. Therefore according to CLP classification criteria (Regulation (EC) No 1272/2008) a classification is not justified.

Executive summary:

Ten male and female rats per group were exposed nose/head only to mean analytical concentrations of 0.35, 0.83, 2.79 and 10.07 mg phenyl isocyanate for 4 weeks (6h/d, 5 exposures per week). During the study, the body weights were determined and clinical signs were recorded. At the end of the study ophthalmological examinations was performed and clinicochemical and hematological parameters were determined and an urinalysis performed. During sacrifice, gross pathological examinations of rats were made and selected organs were collected for gravimetric and histopathological examinations.

The NOAEL = 0.83 mg phenyl isocyanate/m³ air is based on the most sensitive parameter (hyperplasia of goblet cells in the turbinalia area).

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEC

0.83 mg/m³

Study duration:

subacute

Species:

rat

Quality of whole database:

GLP guideline study

Endpoint conclusion:

no study available

Endpoint conclusion:

no adverse effect observed

The effects observed in the respiratory system are mainly caused by irritation/corrosion.

No results from repeated-dose toxicity tests are available for the oral and dermal route of exposure.

An exploratory subacute vapour inhalation study (0, 0.12, 0.57 or 3.14 mg/m³ phenyl isocyanate for 6 hours per day for 5 days) with male rats demonstrated that rats exposed to 0.12 or 0.57 mg/m³ exhibited no symptoms. Until 3.14 mg/m³ no toxicological relevant changes of body weight were evident. The animals exposed to 3.14 mg/m³ phenyl isocyanate had a discharging nose, body weight gain was normal, organ weight of heart, lung and liver normal, an increased protein- LDH- and gamma-GT content in the lung lavage 2 -3 days after termination of exposure was found, no deviation at 28th/29th day.

From these examinations it is concluded, that only animals exposed to 3.14 mg/m³ showed signs of an irritation of the upper (discharge of the nose) and the lower (increased gGT content) respiratory tract. A concentration of 0.57 mg phenyl isocyanate/m³ was tolerated without adverse effects.

In a subacute inhalation study ten male and female rats per group were exposed nose/head only to mean analytical concentrations of 0.35, 0.83, 2.79 and 10.07 mg phenyl isocyanate/m³ for 4 weeks (6h/d, 5 exposures per week). On the basis of the most sensitive parameter (hyperplasia of goblet cells in the turbinalia area) 0.83 mg/m³ phenyl isocyanate were regarded as the no-adverse-effect-level.

In a subacute inhalation repeated dose toxicity study were male rats were exposed to phenyl isocyanate for 4 weeks (6h/d, 5 exposures per week a NOAEC = 0.83 mg phenyl isocyanate/m³ air and a LOAEC = 2.79 mg phenyl isocyanate/m³ air in male + female rats) were found. The effects observed in the respiratory system are mainly caused by irritation/corrosion. Therefore according to CLP classification criteria (Regulation (EC) No 1272/2008) a classification is not justified.