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Description of key information

Read-across_in vivo skin irritation study; rabbits, results: 5 - 10 Minutes contact of the rabbit skin to 3,5-xylenol can cause burns and skin necrosis indicating a skin corrosion potential of the substance.

Read-across_in vivo eye irritation study, rabbits, results: Contact of the rabbit eye to mixed xylenols can induce irritation of iris and conjunctivae. No corneal opacity was observed. Rating of conjunctival effects 4 hours after installation of the test substance resulted in a score of 14 and 4, respectively. After 24 hour, a conjunctival score level of 4 was noted in both animals. All effects were fully reversible within 92 hours.

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records
Reference
Endpoint:
skin irritation: in vivo
Type of information:
read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: test procedure in accordance with company standards
Justification for type of information:
1. HYPOTHESIS FOR THE CATEGORY APPROACH (ENDPOINT LEVEL)
No reproducible, significant variation in local effects on skin and eye between members of the category have been reported but rather strong irritation or even corrosive effects. Therefore, the general hypothesis for the category approach that xylenol isomers exert qualitatively and quantitatively similar toxicity effects applies for the endpoint "skin irritation / corrosion".

2. CATEGORY APPROACH JUSTIFICATION (ENDPOINT LEVEL)
Available data for two xylenol isomers and a mixture of isomers indicate a mostly strong reactivity with tissues of skin and eye. All 6 isomers as well as xylenol (mixed isomers) are classified as Skin Corr. 1B according to Annex VI of Regulation (EC) No 1272/2008 (CLP Regulation). See attached read-across justification for further information.
Qualifier:
no guideline available
Principles of method if other than guideline:
1 - 10 applications of diluted or undiluted material to the intact or abraded skin of rabbits
GLP compliance:
no
Species:
rabbit
Strain:
not specified
Type of coverage:
not specified
Preparation of test site:
abraded
Remarks:
or intact skin
Vehicle:
other: Dipropylene glycol methyl ether (Dowanol DPM)
Controls:
not specified
Amount / concentration applied:
undiluted, or 10% solution in Dowanol DPM
Duration of treatment / exposure:
1 or repeated applications
Observation period:
21 days
Number of animals:
not specified
Details on study design:
undiluted material: 1 application on intact and abraded belly skin, respectively
10% solution in Dowanol DPM: 10 applications on intact ear and belly skin; 3 applications on abraded belly skin

In addition patch tests with undiluted material and short exposure duration (0.5, 1, 5, and 10 min)
Irritation parameter:
other: hyperemia, edema, necrosis
Remarks:
based on clinical observation
Reversibility:
not fully reversible within: 21 days
Remarks on result:
probability of severe irritation
Irritation parameter:
erythema score
Remarks:
intact and abraded skin
Basis:
animal #1
Time point:
24/48/72 h
Score:
>= 2 - <= 3
Max. score:
4
Reversibility:
fully reversible within: 21 days
Remarks on result:
probability of severe irritation
Remarks:
interpretation of non-guideline gradings
Irritation parameter:
edema score
Remarks:
intact and abraded skin
Basis:
animal #1
Time point:
24/48/72 h
Score:
3
Max. score:
4
Reversibility:
fully reversible within: 21 days
Remarks on result:
probability of moderate irritation
Remarks:
interpretation of non-guidline gradings
Irritant / corrosive response data:
See Table 1 and 2 below.

Table 1: Skin irritation study with exposure of rabbit skin to 3,5-xylenol

Material

Condition

Number of applications

Site

Response

Undiluted

Intact

1

Belly

Slight hyperemia and edema with moderate necrosis. Skin healed with moderate scear in 21 days.

Undiluted

Abraded

1

Belly

Slight hyperemia and edema with moderate necrosis. Skin healed with moderate scear in 21 days.

10% solution in Dowanol DPM

Intact

10

Ear

No irritation observed

10% solution in Dowanol DPM

Intact

10

Bell

Very slight hyperemia and slight to moderate exfoliation. Skin normal in 21 days.

10% solution in Dowanol DPM

Abraded

3

Belly

Slight exfoliation only. Skin essentially normal in 21 days.

Table 2: Patch test with short exposure of rabbit skin to 3,5-xylenol

Material

Exposure duration (min)

Response

Undiluted

0.5

Essentially no irritation

Undiluted

1

Slight hyperemia

Undiluted

5

Slight hyperemia with moderate burn

Undiluted

10

Moderate hyperemia with moderate burn

Interpretation of results:
Category 1B (corrosive) based on GHS criteria
Remarks:
5 - 10 Minutes of skin contact may cause burns.
Conclusions:
5 - 10 Minutes contact of the rabbit skin to 3,5-xylenol can cause burns and skin necrosis indicating a skin corrosion potential of the substance.
Executive summary:

In a non-guideline in vivo skin irritation study a single application of undiluted 3,5-xylenol on intact or abraded belly skin of rabbits caused slight hyperemia and edema with moderate necrosis. The skin healed with moderate scear within 21 days. 10 Applications of a 10% solution in dipropylene glycol methyl ether (Dowanol DPM) did not induce irritation of the intact rabbit ear but evoked very slight hyperemia and slight to moderate exfoliation on intact belly skin. These effects were reversible within 21 days. Three applications of the diluted solution on abraded belly skin resulted in slight exfoliation only. The skin appeared to be essentially normal after 21 days. 5 - 10 Minutes contact of the rabbit skin to 3,5-xylenol can cause burns and skin necrosis indicating a skin corrosion potential of the substance.

This result can be transferred to the target test item 2,5-xylenol based on high structural similarities in the read-across category of xylenol isomers (see 'Read-across statement' in section 13.2).

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (corrosive)

Eye irritation

Link to relevant study records
Reference
Endpoint:
eye irritation: in vivo
Type of information:
read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Study period:
Study initiated: 2/23/81. Study terminated: 3/02/81
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Justification for type of information:
1. HYPOTHESIS FOR THE CATEGORY APPROACH (ENDPOINT LEVEL)
No reproducible, significant variation in local effects on skin and eye between members of the category have been reported but rather strong irritation or even corrosive effects. Therefore, the general hypothesis for the category approach that xylenol isomers exert qualitatively and quantitatively similar toxicity effects applies for the endpoint "eye irritation".

2. CATEGORY APPROACH JUSTIFICATION (ENDPOINT LEVEL)
Available data for two xylenol isomers and a mixture of isomers indicate a mostly strong reactivity with tissues of skin and eye. All 6 isomers as well as xylenol (mixed isomers) are classified as Skin Corr. 1B with hazard statement H314 (Causes severe skin burns and eye damage) according to Annex VI of Regulation (EC) No 1272/2008 (CLP Regulation). See attached read-across justification for further information.
Qualifier:
no guideline available
Principles of method if other than guideline:
Range-finding eye irritation test in two rabbits (Draize test) with rating of irritation effects according to a classification system outlined in Dow Chemical Protocol 78P-103.
GLP compliance:
no
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
Male animals
Vehicle:
unchanged (no vehicle)
Controls:
not specified
Amount / concentration applied:
0.1 ml (undiluted)
Duration of treatment / exposure:
7 days (eyes were not washed)
Observation period (in vivo):
7 days
Number of animals or in vitro replicates:
2
Details on study design:
0.1 ml of the test substance, as received, was introduced into the conjunctival sac. Eyes were not washed. Rating for irritation effects on cornea, iris and conjunctivae was performed 4, 24, 48, 72, and 96 hours, as well as 7 days after instillation of the test material according to a classification system outlined in Dow Chemical Protocol 78P-103.
Irritation parameter:
cornea opacity score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0
Max. score:
0
Reversibility:
fully reversible
Remarks on result:
no indication of irritation
Irritation parameter:
cornea opacity score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0
Max. score:
0
Reversibility:
fully reversible
Remarks on result:
no indication of irritation
Irritation parameter:
iris score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0
Max. score:
0
Reversibility:
fully reversible
Remarks on result:
no indication of irritation
Irritation parameter:
iris score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0
Max. score:
2.5
Reversibility:
fully reversible
Remarks:
max score after 4 hours
Remarks on result:
no indication of irritation
Irritation parameter:
conjunctivae score
Remarks:
mean
Basis:
animal #1
Time point:
24/48/72 h
Score:
1.3
Max. score:
4
Reversibility:
fully reversible within: 48 h
Remarks on result:
probability of mild irritation
Irritation parameter:
conjunctivae score
Remarks:
mean
Basis:
animal #2
Time point:
24/48/72 h
Score:
2.6
Max. score:
14
Reversibility:
fully reversible within: 96 h
Remarks:
max score after 4 hours
Remarks on result:
probability of moderate irritation
Irritation parameter:
chemosis score
Basis:
animal #1
Time point:
24/48/72 h
Remarks on result:
not measured/tested
Irritation parameter:
chemosis score
Basis:
animal #2
Time point:
24/48/72 h
Remarks on result:
not measured/tested

Time

Structure

Score

Rabbit 1

Rabbit 2

Mean

4 h

Cornea

Iris

Conjunctivae

0

0

4

0

2.5

14

0

1.3

9

24 h

Cornea

Iris

Conjunctivae

0

0

4

0

0

4

0

0

4

48 h

Cornea

Iris

Conjunctivae

0

0

0

0

0

2

0

0

1

72 h

Cornea

Iris

Conjunctivae

0

0

0

0

0

2

0

0

1

96 h

Cornea

Iris

Conjunctivae

0

0

0

0

0

0

0

0

0

7 d

Cornea

Iris

Conjunctivae

0

0

0

0

0

0

0

0

0

Interpretation of results:
Category 2 (irritating to eyes) based on GHS criteria
Conclusions:
Based on the duration of the ocular effects only, the mixture of xylenol isomers was considered by the authors as "moderately" irritating to the eyes of rabbits (i.e., all ocular effects were reversible within 7 days, but not within 24 hr after dosing).
Executive summary:

The effect of a mixture of xylenol isomers on the eye was investigated in New Zealand White rabbits (SS_in vivo_Range finder study on eye irritation_rabbit_1982_Target). 0.1 ml of the mixture of xylenol isomers, as received, was introduced into the conjunctival sac. Eyes were not washed. Rating for irritation effects on cornea, iris and conjunctivae was performed 4, 24, 48, 72, and 96 hours, as well as 7 days after instillation of the test material according to a classification system outlined in Dow Chemical Protocol 78P-103. Irritation of iris and conjunctivae but no corneal opacity was observed. Rating of conjunctival effects 4 hours after installation of the test substance resulted in a score of 14 and 4, respectively. After 24 hours, a conjunctival score level of 4 was noted in both animals. All effects were fully reversible within 92 hours. Range-finding irritation data indicate this substance is "moderately" irritating to the eyes of rabbits.

This result can be transferred to the target test item 2,5-xylenol based on high structural similarities in the read-across category of xylenol isomers (see 'Read-across statement' in section 13.2).

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irreversible damage)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Skin irritation/corrosion - Read-across

In the key non-guideline in vivo skin irritation study a single application of undiluted 3,5-xylenol on intact or abraded belly skin of rabbits caused slight hyperemia and edema with moderate necrosis (KS_in vivo_Skin irritation study_rabbit_1961_Target). The skin healed with moderate scear within 21 days. 10 Applications of a 10% solution in dipropylene glycol methyl ether (Dowanol DPM) did not induce irritation of the intact rabbit ear but evoked very slight hyperemia and slight to moderate exfoliation on intact belly skin. These effects were reversible within 21 days. 3 applications of the diluted solution on abraded belly skin resulted in slight exfoliation only. The skin appeared to be essentially normal after 21 days. 5 - 10 Minutes contact of the rabbit skin to 3,5-xylenol can cause burns and skin necrosis indicating a skin corrosion potential of the substance.

In an in vivo supporting range finding study (non-guideline) using xylenol, mixed isomers, two New Zealand White rabbits were dermally exposed to a limit dose of 5000 mg per kg body weight (SS_in vivo_range finder study on eye irritation_rabbit_1982_Target). The closely clipped skin was treated under occlusive coverage during 24 hours with consecutive washing of the exposed skin area with lukewarm water. The animals were clinically observed for a post-expose period of 14 days. Local skin irritation with severe erythema, severe edema, followed by desiccation, eschar formation and peeling of eschar was noted. The skin reactions noted during this study indicate the substance is "severely" irritating to rabbit skin.

These results can be transferred to the target test item 2,5-xylenol based on high structural similarities in the read-across category of xylenol isomers (see 'Read-across statement' in section 13.2).

Eye irritation/corrosion - Read-across

In the key in vivo eye irritation study, 0.1 ml of a mixture of xylenol isomers, as received, was introduced into the conjunctival sac of two New Zealand White rabbits (KS_in vivo_Range finder study on eye irritation_rabbit_1982_Target). Eyes were not washed. Rating for irritation effects on cornea, iris and conjunctivae was performed 4, 24, 48, 72, and 96 hours, as well as 7 days after instillation of the test material according to a classification system outlined in Dow Chemical Protocol 78P-103. Irritation of iris and conjunctivae but no corneal opacity was observed. Rating of conjunctival effects 4 hours after installation of the test substance resulted in a score of 14 and 4, respectively. After 24 hour, a conjunctival score level of 4 was noted in both animals. All effects were fully reversible within 92 hours. Range-finding irritation data indicate this substance is "moderately" irritating to the eyes of rabbits.

In the supporting in vivo eye irritation study (non-guideline) contact of the rabbit eye to undiluted 3,5-xylenol caused extensive conjunctivitis with moderate conjunctival injury and iritis not subsided in one week (SS_in vivo_Eye irritation study_rabbit_1961_Target). This may be associated with some loss of sight. The effects were reversible within 7 days if eyes were washed with water after instillation of the test material into the conjunctival sac. Application of the diluted substance (10% in propylene glycol) produced extensive conjunctivitis with moderate corneal injury and iritis, which were not subsided in one week, whether eyes were rinsed with water or not. Contact of the rabbit eye to undiluted 3,5-xylenol can induce conjunctivitis, corneal injury and iritis, which are not reversible within 7 days, indicating a potential for severe eye damage.

These results can be transferred to the target test item 2,5-xylenol based on high structural similarities in the read-across category of xylenol isomers (see 'Read-across statement' in section 13.2).

Justification for classification or non-classification

Based on findings from an in vivo skin irritation/corrosion study using the isomer analogue 3,5-xylenol, the target substance is classified as Skin Corr.1B (H314) in accordance with the harmonised classification as agreed in Annex VI of Regulation (EC) No 1272/2008 (CLP Regulation). Classification as skin corrosive as well as study results, which showed irreversible eye effects after instillation of the isomer analogue, lead in addition to classification for serious eye damage/eye irritation (Cat. 1, H318).