5-amino-o-cresol

Acute Toxicity: inhalation

Administrative data

Endpoint:

acute toxicity: inhalation

Type of information:

calculation (if not (Q)SAR)

Adequacy of study:

weight of evidence

Study period:

August 2017

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

accepted calculation method

Data source

Reference

Reference Type:

publication

Title:

Hair Dye 4-AMINO-2-HYDROXYTOLUENE Colipa No. A027 Calculation of acute toxicity values using existing in vivo study data

Author:

Nicola J. Hewitt

Year:

2017

Bibliographic source:

Colipa No.1027

Report date:

2017

Materials and methods

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

The acute Oral LD50 was determined at 3600 mg/kg in rats in a Klimisch 2 study. Using this LD50, extrapolation calculation was performed in order to evaluate a LD50 value for inhalation route. Local irritation of the lung mucosal membranes can lead to death; therefore, the potential for 4-AMINO-2-HYDROXYTOLUENE to cause local lung mucous membrane irritation was evaluated by comparing the LC50 calc inhal. for 4-AMINO-2-HYDROXYTOLUENE with the local irritating effect measured in the eye and the conditions of the acute inhalation toxicity maximal tested dose.

GLP compliance:

not specified

Test type:

other: Extrapolation calculation

Limit test:

yes

Test material

Test material information

Constituent 1

Reference substance name:

5-amino-o-cresol

EC Number:

220-618-6

EC Name:

5-amino-o-cresol

Cas Number:

2835-95-2

Molecular formula:

C7H9NO

IUPAC Name:

5-amino-2-methylphenol

Specific details on test material used for the study:

No test material was used for this report, the calculation was performed with the LD50 of a oral acute toxicity test with the test subtance for Inhalation LD50 determination.

Test animals

Species:

rat

Strain:

not specified

Sex:

not specified

Administration / exposure

Route of administration:

inhalation

Type of inhalation exposure:

head only

Vehicle:

not specified

Details on study design:

Extrapolation from oral to inhalation acute toxicity of 4-AMINO-2-HYDROXYTOLUENE:

Values and assumptions used in the calculations:
• 4-AMINO-2-HYDROXYTOLUENE LD50 oral = 3600 mg/kg bw in the rat

• Oral Bioavailability = 84% (at 500 mg/kg bw, using the data from the toxicokinetics study in Wistar rats). This value was selected to achieve a more conservative approach (worst case scenario) because incorporation of this value into E results in a lower LC50 calc inhal. value (with an assumed higher toxicity) than if the value of 95% was selected.

• Required max. exposure conc. to test material (OECD 403): 5 mg/L

• Assumed body weight of the rat: 250 g

• Respiratory volume of the rat : 0.074 L/min

• Required duration (OECD 403) 4 h

• Inhalation Bioavailability (assumed, worst case assumption): 100%

Results and discussion

Effect levels

Sex:

male/female

Dose descriptor:

LC50

Effect level:

42.57 mg/L air

Based on:

test mat.

Exp. duration:

4 h

Remarks on result:

not measured/tested

Any other information on results incl. tables

Result: LC50 calc inhal. 4-AMINO-2-HYDROXYTOLUENE       = 42.57 mg/L

Result: By comparing the LC50 calc inhal. with the results of in vivo eye irritation studies and the required maximum dose tested in the acute inhalation toxicity test, it can be concluded that 4-AMINO-2-HYDROXYTOLUENE would not have a local effect in the lungs.

Applicant's summary and conclusion

Interpretation of results:

Category 5 based on GHS criteria

Remarks:

not classified according to CLP

Conclusions:

The calculated inhalation toxicity value for 4-AMINO-2-HYDROXYTOLUENE (42.57 mg/L) was reflected in the respective oral LD50 values. When these concentrations are combined with the results of in vitro eye irritation studies, it can be concluded that 4-AMINO-2-HYDROXYTOLUENE would not have a local effect in the lungs. Based on the calculated LC50 calc, inhal. value, 4-AMINO-2-HYDROXYTOLUENE should be classified as Acute Tox Cat.5; H333: “may be harmful if inhaled”, according to the Globally Harmonized System of Classification and Labeling (GHS) and Not Classified according to CLP criterias.

Executive summary:

The purpose of the published report was to evaluate the LD50 for inhalation route and potential local effect in lungs using extrapolation calculation approach with avalaible studies of acute toxicity test and eye irritation test in vivo.

The acute Oral LD50 was determined at 3600 mg/kg in rats in a Klimisch 2 study. Using this LD50, extrapolation calculation was performed in order to evaluate a LD50 value for inhalation route.  Local irritation of the lung mucosal membranes can lead to death; therefore, the potential for 4-AMINO-2-HYDROXYTOLUENE to cause local lung mucous membrane irritation was evaluated by comparing the LC50 calc inhal. for 4-AMINO-2-HYDROXYTOLUENE with the local irritating effect measured in the eye and the conditions of the acute inhalation toxicity maximal tested dose.

Maximum volume of exposure in 4 hours:0.074 L/min x 60 min x 4 hours = 17.76 L

Determination of the correction factor oral vs. inhalation route:Ratio of 84% oral : 100% inhalation = 0.84      

Determination of the LC50 calc inhal.:       ( 3600 mg/kg bw x 0.250 kg bw   / 17.76 L) x 0.84

Comparison with eye irritation effects:

4-AMINO-2-HYDROXYTOLUENE is transiently irritating to eyes up to 2.5% (w/w) and the redness had gone within 24 hours (Ref 12).

Conversion of LC50 calc inhal. to % (w/w):

1 L air: 1.2041 kg/m³ = 1204.1 g/m³ = 1204100 mg/m³ = 1204100/1000 L = 1201 mg/L       

1201 mg/L = 100 %

42.57 mg/L air = 3.54 % (w/w)                                                    

The concentration of 3.54% (w/w) 4-AMINO-2-HYDROXYTOLUENE is 1.4-fold higher than the concentration causing transient irritation to the rabbit eye.

Comparison with maximum dose in acute inhalation toxicity protocol:

Required max. exposure conc. to test material (OECD 403):                            5 mg/L

The calculated concentration of 42.57 mg/L of 4-AMINO-2-HYDROXYTOLUENE is 8.5-fold higher than the maximum required test concentration in the acute inhalation toxicity protocol. Therefore, it is concluded, that at the maximum test concentration of 5 mg/L 4-AMINO-2-HYDROXYTOLUENE is unlikely to cause local lung toxicity.

The calculated inhalation toxicity value for 4-AMINO-2-HYDROXYTOLUENE (42.57 mg/L) was reflected in the respective oral LD50 values. When these concentrations are combined with the results of in vitro eye irritation studies, it can be concluded that 4-AMINO-2-HYDROXYTOLUENE would not have a local effect in the lungs. Based on the calculated LC50 calc, inhal. value, 4-AMINO-2-HYDROXYTOLUENE should be classified as Acute Tox Cat.5; H333: “may be harmful if inhaled”, according to the Globally Harmonized System of Classification and Labeling (GHS) and Not Classified according to CLP criterias.