Reaction mass of m-cresol and 2-chloro-m-cresol and 6-chloro-m-cresol

Endpoint summary

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records

Reference

Endpoint:

skin sensitisation: in vivo (non-LLNA)

Type of information:

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

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: The study was performed similar to OECD guideline 406 (GPMT) at a time GLP was not enacted. Minor deviations from OECD guideline 406 occured.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 406 (Skin Sensitisation)

Deviations:

yes

Remarks:

concentration used for induction was not irritating

GLP compliance:

no

Remarks:

study was conducted prior to the enactment of GLP principles

Type of study:

guinea pig maximisation test

Species:

guinea pig

Strain:

other: Pirbright White

Sex:

male/female

Details on test animals and environmental conditions:

TEST ANIMALS
- Source: Lippische Versuchstierzucht, Extertal, Germany
- Sex: ♂ (1st experiment), ♀ (2nd experiment)
- Weight at study initiation: 400 g (1st experiment); 300 g (2nd experiment)

Route:

intradermal and epicutaneous

Vehicle:

other: Lutrol 300/ethanol (3:1)

Concentration / amount:

Intradermal induction (Day 0): 25% (1st experiment) and 1% CMK (2nd experiment) in vehicle and in Freund's adjuvant, respectively
Topical induction (Day 7): 25% (1st experiment) and 1% CMK (2nd experiment) in vehicle
Topical challenge (Day 21):
1st experiment: 25% (right flank), 12.5% CMK (left flank) in vehicle
2nd experiment: 50% (right flank), 25% CMK (left flank) in vehicle

Route:

other: epicutaneous

Vehicle:

other: Lutrol 300/ethanol (3:1)

Concentration / amount:

Intradermal induction (Day 0): 25% (1st experiment) and 1% CMK (2nd experiment) in vehicle and in Freund's adjuvant, respectively
Topical induction (Day 7): 25% (1st experiment) and 1% CMK (2nd experiment) in vehicle
Topical challenge (Day 21):
1st experiment: 25% (right flank), 12.5% CMK (left flank) in vehicle
2nd experiment: 50% (right flank), 25% CMK (left flank) in vehicle

No. of animals per dose:

15

Details on study design:

The skin irritating potential of the test substance was assessed in a pre-test with concentrations of 12.5%, 25%, 50% and 100% applied for 24 h under occlusive conditions.
The study followed the Magnusson-Kligman method which is basically compliant with OECD Guideline 406 (GPMT). However, this guideline was not available when the study was conducted.
The study comprised of two experiments each conducted on 15 Pirbright White guinea pigs. In the 1st experiment, male animals received intradermal (in vehicle and in Freund´s adjuvant) and topical induction treatments (in vehicle) with 25% test substance. In the 2nd experiment, females were induced with a 1% test substance via the same procedure. Both experiments included respective vehicle control groups (Lutrol 300/ethanol (3:1) with 15 animals each. The topical induction exposure lasted 48 h. The challenge treatment two weeks after the last induction application was performed with 25% (right flank) or 12.5% (left flank) test item in vehicle in the 1st experiment and with 50% (right flank) or 25% (left flank) test item in vehicle in the 2nd experiment. Each challenge exposure lasted 6 h. Animals of the control groups were challenged in the same way. The Magnusson-Kligman scoring system was used to rate the skin reactions. Scoring of the treated skin was performed 24 and 48 h after challenge.

Challenge controls:

Yes

Positive control substance(s):

no

Reading:

1st reading

Hours after challenge:

24

Group:

other: challenge control

Dose level:

0% (12.5+25% challenge)

No. with + reactions:

0

Total no. in group:

15

Clinical observations:

No findings

Remarks on result:

other: Reading: 1st reading. . Hours after challenge: 24.0. Group: other: challenge control. Dose level: 0% (12.5+25% challenge). No with. + reactions: 0.0. Total no. in groups: 15.0. Clinical observations: No findings.

Reading:

1st reading

Hours after challenge:

24

Group:

test chemical

Dose level:

25% (12.5% challenge)

No. with + reactions:

1

Total no. in group:

15

Clinical observations:

No findings

Remarks on result:

other: Reading: 1st reading. . Hours after challenge: 24.0. Group: test group. Dose level: 25% (12.5% challenge). No with. + reactions: 1.0. Total no. in groups: 15.0. Clinical observations: No findings.

Reading:

1st reading

Hours after challenge:

24

Group:

test chemical

Dose level:

25% (25% challenge)

No. with + reactions:

7

Total no. in group:

15

Clinical observations:

No findings

Remarks on result:

other: Reading: 1st reading. . Hours after challenge: 24.0. Group: test group. Dose level: 25% (25% challenge). No with. + reactions: 7.0. Total no. in groups: 15.0. Clinical observations: No findings.

Reading:

2nd reading

Hours after challenge:

48

Group:

other: challenge control

Dose level:

0% (12.5% challenge)

No. with + reactions:

0

Total no. in group:

15

Clinical observations:

No findings

Remarks on result:

other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: other: challenge control. Dose level: 0% (12.5% challenge). No with. + reactions: 0.0. Total no. in groups: 15.0. Clinical observations: No findings.

Reading:

2nd reading

Hours after challenge:

48

Group:

other: challenge control

Dose level:

0% (25% challenge)

No. with + reactions:

1

Total no. in group:

15

Clinical observations:

No findings

Remarks on result:

other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: other: challenge control. Dose level: 0% (25% challenge). No with. + reactions: 1.0. Total no. in groups: 15.0. Clinical observations: No findings.

Reading:

2nd reading

Hours after challenge:

48

Group:

test chemical

Dose level:

25% (12.5% challenge)

No. with + reactions:

3

Total no. in group:

15

Clinical observations:

No findings

Remarks on result:

other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: test group. Dose level: 25% (12.5% challenge). No with. + reactions: 3.0. Total no. in groups: 15.0. Clinical observations: No findings.

Reading:

2nd reading

Hours after challenge:

48

Group:

test chemical

Dose level:

25% (25% challenge)

No. with + reactions:

13

Total no. in group:

15

Clinical observations:

No findings

Remarks on result:

other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: test group. Dose level: 25% (25% challenge). No with. + reactions: 13.0. Total no. in groups: 15.0. Clinical observations: No findings.

Reading:

1st reading

Hours after challenge:

24

Group:

other: challenge control

Dose level:

0% (25 + 50% challenge)

No. with + reactions:

0

Total no. in group:

15

Clinical observations:

No findings

Remarks on result:

other: Reading: 1st reading. . Hours after challenge: 24.0. Group: other: challenge control. Dose level: 0% (25 + 50% challenge). No with. + reactions: 0.0. Total no. in groups: 15.0. Clinical observations: No findings.

Reading:

1st reading

Hours after challenge:

24

Group:

test chemical

Dose level:

1% (25% challenge)

No. with + reactions:

0

Total no. in group:

15

Clinical observations:

No findings

Remarks on result:

other: Reading: 1st reading. . Hours after challenge: 24.0. Group: test group. Dose level: 1% (25% challenge). No with. + reactions: 0.0. Total no. in groups: 15.0. Clinical observations: No findings.

Reading:

1st reading

Hours after challenge:

24

Group:

test chemical

Dose level:

1% (50% challenge)

No. with + reactions:

4

Total no. in group:

15

Clinical observations:

No findings

Remarks on result:

other: Reading: 1st reading. . Hours after challenge: 24.0. Group: test group. Dose level: 1% (50% challenge). No with. + reactions: 4.0. Total no. in groups: 15.0. Clinical observations: No findings.

Reading:

2nd reading

Hours after challenge:

48

Group:

other: challenge control

Dose level:

0% (25 + 50% challenge)

No. with + reactions:

0

Total no. in group:

15

Clinical observations:

No findings

Remarks on result:

other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: other: challenge control. Dose level: 0% (25 + 50% challenge). No with. + reactions: 0.0. Total no. in groups: 15.0. Clinical observations: No findings.

Reading:

2nd reading

Hours after challenge:

48

Group:

test chemical

Dose level:

1% (25% challenge)

No. with + reactions:

0

Total no. in group:

15

Clinical observations:

No findings

Remarks on result:

other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: test group. Dose level: 1% (25% challenge). No with. + reactions: 0.0. Total no. in groups: 15.0. Clinical observations: No findings.

Reading:

2nd reading

Hours after challenge:

48

Group:

test chemical

Dose level:

1% (50% challenge)

No. with + reactions:

2

Total no. in group:

15

Clinical observations:

No findings

Remarks on result:

other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: test group. Dose level: 1% (50% challenge). No with. + reactions: 2.0. Total no. in groups: 15.0. Clinical observations: No findings.

The highest non-irritating concentration after topical dermal application for 24 h was determined as 50%. An short overview of the results is given in the table below.

Table 1: Animals with skin reactions after the challenge phase:

	Control		Experiment 1		Control		Experiment 2
Induction concentration	0%		25%		0%		1%
Challenge concentration	12.5%	25%	12.5%	25%	25%	50%	25%	50%
Time after challenge
24 h	0/15	0/15	1/15	7/15	0/15	0/15	0/15	0/15
48h	0/15	1/15	3/15	13/15	0/15	0/15	4/15	2/15

Interpretation of results:

sensitising

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

CLP: Skin sens 1B, H317
DSD: Xi, R43

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (sensitising)

Additional information:

The relevant data on skin sensitisation for Preventol KMX and the read across substance 4-chloro-3-methylphenol are summarized in the table below. The read across justification and additional data for m-cresol are attached to the Chemical Safety Report in Annex I. As m-cresol is only a minor component of Preventol KMX these data are not considered for the assessment of the irritating potential of Preventol KMX.

Table 1: Comparison of relevant data on irritation/corrosion of Preventol KMX and 4-chloro-3-methylphenol

Endpoint	Preventol KMX	4-chloro-3-methylphenol
Skin sensitisation	Read across to 4-chloro-3-methylphenol: Sensitising	Sensitising

 

Skin sensitisation:

No data on skin sensitisation for Preventol KMX (reaction mass of 6-chloro-m-cresol, 2-chloro-m-cresol and m-cresol) are available. The possibility of a read-across to Preventol CMK (4-chloro-3-methylphenol) in accordance with Regulation (EC) No 1907/2006 Annex XI 1.5. Grouping of substances and read-across approach was assessed. There it is given that a read-across approach is possible for substances, whose physicochemical, toxicological and ecotoxicological properties are likely to be similar or follow a regular pattern as a result of structural similarity. Preventol KMX contains of approximately 58% 6-chloro-m-cresol, 30% 2-chloro-m-cresol, 9% m-cresol and smaller amounts of p-cresol (approx. 2.5%), 4-chloro-3-methylphenol (approx. 0.5%) and other impurities (approx. 0.5%). A literature search and QSAR predictions were performed for 2-chloro-m-cresol, 6-chloro-m-cresol using m-cresol and 4-chloro-3-methylphenol as reference substances. Next to physico-chemical properties, environmental fate, ecotoxicity, toxicity, and metabolism of chlorocresols and chlorophenols in various databases, special emphasis was set on determining the effects of different positions of chlorine on aromatic ring structures as this is the determinant difference between the 3 chlorocresol constituents, which may influence outcome in physicochemical and toxicological behaviour. The aim was to evaluate the read-across from 4-chloro-3-methylphenol to Preventol KMX and to ensure a safe and legally valid analogue approach.

The chlorocresols are found to be similar in structure and the available data shows that the substances are similar in physico-chemical properties, environmental fate, metabolism and predicted affected pathways. Literature revealed no evidence of relevant influence of the position of chlorination on ring structures on the toxicological properties of a substance. Thus, the position of the chlorination is not regarded to significantly modulate the toxic effects of the chlorocresols. Since the discussed chlorocresols differ only in the position of the chlorination, the toxicological properties of the substances can be expected to be similar. This assumption is also supported by the fact that results of available studies are in the same range for Preventol KMX compared to results of 4-chloro-3-methylphenol. Hence, 4-chloro-3-methylphenol is determined as a suitable read-across substance to predict toxicity endpoints in the chemical risk assessment of reaction mass of 6-chloro-m-cresol, 2-chloro-m-cresol and m-cresol (Preventol KMX). A detailed justification for the read-across is provided in the technical dossier (see IUCLID Section 13), as well as in the Chemical Safety Report (see Part B).

 

Relevant study of interest for 4-chloro-3-methylphenol:

Skin sensitisation:

A reliable study performed similar to OECD Guideline 406 (GPMT) was performed with 4-chloro-3-methylphenol. The study followed the Magnusson-Kligman method and comprised of two experiments each conducted on 15 Pirbright White guinea pigs. In the 1st experiment, male animals received intradermal (in vehicle and in Freund´s adjuvant) and topical induction (in vehicle) treatments with 25% test substance. In the 2nd experiment, female animals were induced with a 1% test substance via the same procedure. The topical induction exposure lasted 48 h and both experiments included respective vehicle control groups (Lutrol 300/ethanol (3:1)) with 15 animals each. The challenge treatment two weeks after the last induction application was performed with 25% (right flank) or 12.5% (left flank) test item in vehicle in the 1st experiment and with 50% (right flank) or 25% (left flank) test item in vehicle in the 2nd experiment. Each challenge exposure lasted 6 h. Animals of the control groups were challenged in the same way. The Magnusson-Kligman scoring system was used to rate the skin reactions. Scoring of the treated skin was performed 24 and 48 h after challenge. In a pre-experiment the highest non-irritating concentration after topical dermal application for 24 h was determined as 50%. 

Skin reactions in experiment 2 which was performed with 1 % test item in the induction phase were seen on max. 4/15 animals (= 27%). Thereforeaccording to CLP 1272/2008/EC and directive 67/548/EECthe test substance would not be in need for classification. Upon induction with 25% skin reactions were observed on 7/15 and 13/15 animals 24 and 48 h after challenge with 25%. Therefore the test substance has to be classified as may cause an allergic skin reaction: H317,category 1B according to CLP 1272/2008/EC and as Xi, R43 according to the dangerous substance directive 67/548/EEC.

Migrated from Short description of key information:
No data on skin sensitisation for Preventol KMX are available. However, a read-across approach to 4-chloro-3-methylphenol was judged to be scientifically reliable (for details see Discussion below). In a reliable study performed similar to OECD Guideline 406 (GPMT) skin reactions were observed on more than 30% of the guinea pigs upon intradermal induction with a concentration above 1%. Thus the test substance is classified as H317: may cause an allergic skin reaction, category 1B according to CLP 1272/2008/EC and as Xi, R43 according to the dangerous substance directive 67/548/EEC.

Justification for selection of skin sensitisation endpoint:
The key study was selected.

Respiratory sensitisation

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

Preventol KMX has to be classified according to the dangerous substance directive 67/548/EEC as skin sensitizing Xi, R43 and according to CLP 1272/2008/EC as skin sensitizing category 1B, H317.