Reaction mass of 4,4'-isopropylidenediphenol and phenol

Skin irritation / corrosion

Administrative data

Endpoint:

skin irritation: in vivo

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Justification for type of information:

REPORTING FORMAT FOR THE ANALOGUE APPROACH

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
This read-across is based on the hypothesis that the properties of the target substance Reaction mass of phenol and 4,4’-isopropylidenediphenol can be predicted by studies conducted with the source substances phenol, 4,4’-isopropylidenediphenol (BPA), and 2-acetone, polymer with phenol, because the target substance Reaction mass of phenol and 4,4’-isopropylidenediphenol contains phenol (40-45%, typical concentration ca. 40%) and 4,4’-isopropylidenediphenol (BPA) (20-40%, typical concentration ca. 33%) as main constituents. Both constituents are data rich substances with distinct hazard properties, so that mainly data on the constituents have been applied to characterize the Reaction mass of phenol and 4,4’-isopropylidenediphenol. Since this is a common approach in mixture hazard assessment, is reasonable to apply it also to multi-constituent substances.
Additionally, some data from a structurally related substance (2-acetone, polymer with phenol) containing the same constituents/impurities at different concentrations are available, which are applied to characterize the environmental fate and ecotoxicity of the impurities present in the Reaction mass of phenol and 4,4’-isopropylidenediphenol.

This read-across hypothesis corresponds to scenario 2 - different compounds have qualitatively and quantitatively the same type of effects - of the read-across assessment framework i.e. properties of the target substance Reaction mass of phenol and 4,4’-isopropylidenediphenol are predicted to be similar to those of the source substances phenol, 4,4’-isopropylidenediphenol (BPA), and 2-acetone, polymer with phenol.

Therefore, read-across from the available studies with the source substances is considered as an appropriate adaptation to the standard information requirements of the REACH Regulation for the target substance Reaction mass of phenol and 4,4’-isopropylidenediphenol, in accordance with the provisions of Annex XI, 1.5 of the REACH Regulation.


2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
please refer to justification for read-across attached to Iuclid section 13

3. ANALOGUE APPROACH JUSTIFICATION
please refer to justification for read-across attached to Iuclid section 13

4. DATA MATRIX
please refer to justification for read-across attached to Iuclid section 13

Cross-reference

Cross-reference 1

Reason / purpose for cross-reference:

read-across: supporting information

Cross-reference 2

Reason / purpose for cross-reference:

read-across source

Reference

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Remarks:

No study according to current Guidelines but meets scientific standards with acceptable restrictions (partly limited documentation, e.g. no details about the test substance; 24 h exposure). Phenol is a constituent of the reaction mass so that phenol hazard data are applied in the hazard assessment.

Principles of method if other than guideline:

FHSA method of August 12, 1961, pages 7333-7341

GLP compliance:

not specified

Species:

rabbit

Strain:

not specified

Details on test animals or test system and environmental conditions:

no details available

Type of coverage:

not specified

Preparation of test site:

other: abraded or intact

Vehicle:

physiological saline

Controls:

not required

Amount / concentration applied:

test substance moistened with physiological saline

Duration of treatment / exposure:

24 h

Observation period:

up to 72 h after exposure

Number of animals:

6

Details on study design:

intact or abraded areas of the skin of the bellies of rabbits exposed for a maximum period of 24 hours;
no further details

Irritation parameter:

edema score

Basis:

mean

Time point:

24/48/72 h

Remarks on result:

not measured/tested

Irritation parameter:

erythema score

Basis:

mean

Time point:

24/48/72 h

Remarks on result:

not measured/tested

Irritation parameter:

erythema score

Basis:

mean

Time point:

72 h

Score:

4

Max. score:

4

Reversibility:

not reversible

Remarks on result:

other: necrosis of the intact skin; scoring estimated from description of effects

Irritant / corrosive response data:

no further details available

Other effects:

no data about systemic effects

Phenol is a major component of the reaction mass and by its toxicity drives the hazard of the rection mass, so that phenol hazard data are applied in the hazard assessment.

Interpretation of results:

Category 1 (corrosive) based on GHS criteria

Conclusions:

Corrosive properties in rabbits after application of 0.5 g to the intact skin and max. exposure duration of 24 h.

Executive summary:

No study according to current Guidelines but meets scientific standards with acceptable restrictions (partly limited documentation, e.g. no details about the test substance; 24 h exposure).

Six rabbits received 0.5 g phenol moistened with physiological saline to the intact or abraded skin of the belly (exposure period max. 24 h and scoring 24 and 72 after exposure. Since the material produced necrosis of the intact skin, it is classified by the authors as a corrosive substance.

Conclusion: Corrosive properties in rabbits after application of 0.5 g to the intact skin and max. exposure duration of 24 h.

Cross-reference 3

Reason / purpose for cross-reference:

read-across source

Reference

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

Qualifier:

according to guideline

Guideline:

EU Method B.4 (Acute Toxicity: Dermal Irritation / Corrosion)

GLP compliance:

yes

Species:

rabbit

Strain:

Himalayan

Details on test animals or test system and environmental conditions:

TEST ANIMALS
-General information: Three male animals approximately 5-10 months of age with initial body weights of 2.4-2.6 kg were used.
-Diet: Ad libitum before and after the exposure period. Standard rabbit diet of Altromin 2023 (ALTROMIN GmbH, D-32791 Lage/Lippe). Food was analysed at least twice per year for contaminants.
-Drinking water: Water was offered ad libitum before and after the exposure period. Water samples were analysed twice per year for contaminants and once per year for a bacteriological investigation.
-Housing: Before and after the exposure period, animals were kept singly in cages measuring 425 mm x 600 mm x 380 mm (manufacturer: Dipl. Ing. W. EHRET GmbH, D-16352 Schonwalde). During the exposure period, animals were kept singly in restrainers which allowed free movement of the head but prevented a complete body turn. The cages excluded irritation of the skin by excrement and urine.
-Acclimation period: At least 20 days.

ENVIRONMENTAL CONDITIONS
-Temperature: 17-23 degrees C
-Humidity: 30-70%
-Photoperiod: 12 hours light (150 lux at approximately 1.5 meter room height)/12 hours dark

Type of coverage:

semiocclusive

Preparation of test site:

shaved

Vehicle:

water

Controls:

no

Amount / concentration applied:

500 mg BPA per animal. 4000 mg of the test compound was mixed with 2 ml water and 750 mg of this paste was applied per animal.

Duration of treatment / exposure:

Four hours.

Observation period:

72 hours.

Number of animals:

Three male animals.

Details on study design:

Three male Himalayan rabbits were shaved on the dorsal trunk area. Only animals with healthy, intact skin were used. Approximately 24 hours after shaving, a dose of 500 mg BPA per animal was applied to the test site (approximate area of 6 square cm) and covered with a gauze patch that was held in place with non-irritating tape for the duration of the exposure period. The surrounding untreated skin served as a control. The exposure time was four hours. After exposure, the patch was removed and the scores of the resulting reactions were taken 60 minutes, 24, 48, and 72 hours after patch removal.

Irritation parameter:

erythema score

Basis:

mean

Time point:

other: 60 minutes

Score:

0

Irritation parameter:

erythema score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

4

Irritation parameter:

edema score

Basis:

mean

Time point:

other: 60 minutes

Score:

0

Irritation parameter:

edema score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

4

Irritant / corrosive response data:

No substance-related lesions were observed at any time point. All animals had skin irritation scores of zero at all time points for both erythema and edema.

Other effects:

There were no systemic intolerance reactions.

BPA is one of the two main components (ca. 33%) of the reaction mass so that its hazard data are relevant for the hazard assessment of the reaction mass. This BPA study has been included as supporting study to demonstrate that BPA is not irritating to skin so that phenol (corrosive) data are used for hazard characterisation of the reaction mass.

Interpretation of results:

GHS criteria not met

Conclusions:

The authors concluded that there were no substance-related lesions from the acute skin irritation test with BPA.

Executive summary:

Three male Himalayan rabbits were shaved in the dorsal trunk area and 24 hours later, 500 mg BPA per animal was applied to the test site. The surrounding untreated skin served as a control. The exposure period was four hours, after which the patch was removed and the resulting reactions were examined and scored at 60 minutes, 24, 48, and 72 hours after patch removal. The skin irritation scores for each animal were zero for erythema and edema at all time points. The authors concluded that there were no BPA-related lesions at any time point and there were no systemic intolerance reactions.

Cross-reference 4

Reason / purpose for cross-reference:

read-across source

Reference

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Remarks:

No Guideline study but meets scientific standards with acceptable restrictions (partly limited documentation, e.g. no details about the test substance; only 1 minute dermal exposure). Phenol is a constituent of the reaction mass so that phenol hazard data are applied in the hazard assessment.

Principles of method if other than guideline:

Assessment of skin decontamination procedures after short term exposure to phenol

GLP compliance:

not specified

Species:

rat

Strain:

other: CFE

Details on test animals or test system and environmental conditions:

12-14 weeks old
pathogen free rats
certified diet and water ad libitum
no further data

Type of coverage:

open

Preparation of test site:

shaved

Vehicle:

unchanged (no vehicle)

Controls:

not required

Amount / concentration applied:

undiluted (phenol molten at 45°C)
1 ml/kg bw (appr. 1050 mg/kg bw)

Duration of treatment / exposure:

1 minute

Observation period:

7-10 days

Number of animals:

5 males and 5 females per experimental design

Details on study design:

After 1 minute the exposure was terminated by a) spraying for 45 s with an appropriate solvent, b) quickly wiped over, or c) swabbed over (piece of cotton soaked with the solvent).
Licking of exposed skin was prevented by collar.

Irritation parameter:

erythema score

Basis:

mean

Time point:

24/48/72 h

Remarks on result:

not measured/tested

Irritation parameter:

edema score

Basis:

mean

Time point:

24/48/72 h

Remarks on result:

not measured/tested

Irritation parameter:

other: local effects

Basis:

mean

Time point:

other: not clearly stated

Reversibility:

not reversible

Remarks:

(necrosis)

Remarks on result:

other: mild to severe burns depending on decontamination type

Irritant / corrosive response data:

severe burns after quick wiping
mild burns after 120 s swabbing with water or other solvents

Other effects:

systemic effects were reported using water as solvent for spraying-decontamination of quick wiping: hematuria & convulsions.

Phenol is a major component of the reaction mass and by its toxicity drives the hazard of the rection mass, so that phenol hazard data are applied in the hazard assessment.

Interpretation of results:

Category 1 (corrosive) based on GHS criteria

Conclusions:

Severe burns were reported in rats after exposure to the undiluted test substance for 1 minute.

Executive summary:

No Guideline study but meets scientific standards with acceptable restrictions (partly limited documentation, e.g. no details about the test substance; only 1 minute dermal exposure).

The study was related to the decontamination properties of different solvents and to the methods of application of these solvents. Five rats per sex per experimental design received 1 ml/kg bw (presumably less than 0.5 ml per animal assuming a body weight of 300 -500 g) to the shaved skin; the exposure was terminated in each experiment after 1 minute by spraying the appropriate solvent, swabbing the solvent for 10 -120 seconds or quick wipning with a ptch soaked with the solvent. Phenol induced mild to severe burns depending on the solvent used for decontamination and the method used for application of the solvent. However, there is evidence that chemical burns were induced by phenol even after an exposure period of 1 minute.

Severe burns were reported in rats after exposure to the undiluted test substance for 1 minute.

Materials and methods

Test material

Test material information

Constituent 1

Reference substance name:

Reaction mass of 4,4'-isopropylidenediphenol and phenol

EC Number:

904-653-0

IUPAC Name:

Reaction mass of 4,4'-isopropylidenediphenol and phenol

Results and discussion

In vivo

Results

Results 1

Irritation parameter:

edema score

Basis:

mean

Time point:

24/48/72 h

Remarks on result:

positive indication of irritation

Remarks:

corrosive

Results 2

Irritation parameter:

erythema score

Basis:

mean

Time point:

24/48/72 h

Remarks on result:

positive indication of irritation

Remarks:

corrosive

Applicant's summary and conclusion

Interpretation of results:

Category 1 (corrosive) based on GHS criteria

Conclusions:

No experimental data are available for the target substance Reaction mass of phenol and 4,4’-isopropylidenediphenol. However, based on the general principles of mixture toxicology, data on the main constituents of this multi-constituent substance are used as surrogate. Due to the corrosive properties of Phenol, the the target substance Reaction mass of phenol and 4,4’-isopropylidenediphenol is also considered to be corrosive.