Registration Dossier

Administrative data

Description of key information

skin: OECD 404, rabbit, occlusive, 4h: irritating
eye: OECD 405, rabbit: severe eye damage

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records
Reference
Endpoint:
skin irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1994
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Version / remarks:
(1987)
Deviations:
yes
Remarks:
occlusive application of test material
Qualifier:
according to guideline
Guideline:
EU Method B.4 (Acute Toxicity: Dermal Irritation / Corrosion)
Version / remarks:
(1988)
Deviations:
yes
Remarks:
occlusive application of test material
Qualifier:
according to guideline
Guideline:
other: EPA Pesticide Assessment Guidelines, Section 81-5 (1984)
Deviations:
no
Qualifier:
according to guideline
Guideline:
other: MAFF Primary Dermal Irritation Study (1985)
Deviations:
no
GLP compliance:
yes
Species:
rabbit
Strain:
New Zealand White
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Hazleton Research Products, Inc., Kalamazoo, MI
- Age at study initiation: 16 weeks (animals were born on 6 Nov 1993 and dosed on 22 Feb 1994)
- Weight at study initiation: 2.12-2.52 kg
- Fasting period before study: no
- Housing: individually
- Diet: Purina Certified Rabbit Chow #5322 (Purina Mills Inc., St. Louis, MO), 4 oz/day (=113,398 g/day)
- Water: tap water, ad libitum
- Acclimation period: at least 1 week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19±3
- Humidity (%): 40-60
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 22 Feb 1994 To: 8 Mar 1994
Type of coverage:
occlusive
Preparation of test site:
shaved
Vehicle:
water
Controls:
not required
Amount / concentration applied:
TEST MATERIAL
- Amount applied: 0.5 g

VEHICLE
- Amount applied: 0.3 mL
- Purity: distilled
Duration of treatment / exposure:
4 h
Observation period:
14 days
Number of animals:
3 per sex
Details on study design:
TEST SITE
- Area of exposure: back
- Type of wrap if used: elastic rabbit jacket

REMOVAL OF TEST SUBSTANCE
- Washing (if done): with damp disposable towel
- Time after start of exposure: 4 h

SCORING SYSTEM: Draize Scoring System
Irritation parameter:
erythema score
Basis:
mean
Remarks:
of 6 animals
Time point:
other: 24+48+72 h
Score:
2.8
Max. score:
4
Reversibility:
not reversible
Irritation parameter:
edema score
Basis:
mean
Remarks:
of 6 animals
Time point:
other: 24+48+72 h
Score:
1.3
Max. score:
4
Reversibility:
fully reversible within: 7 days
Irritant / corrosive response data:
Very slight erythema was observed at the application site of 1/6 rabbits within 30 minutes and on 2/6 animals 24 hours after test material removal. Severe to slight eschar formation was observed on 4/6 rabbits within 30 minutes of test material removal and persisted through the remainder of the study. 4/6 animals had burns at the application site within 30 minutes of test substance removal. The burns resolved as scabs and then scars by study termination.
4/6 rabbits had very slight to severe oedema 30 minutes and 24 hours after test material removal. Slight to severe oedema was observed on 3/6 animals 48 and 72 h after removal of the test substance.
Other effects:
There were no effects on body weights noted throughout the study period.

Table 1: Individual Rabbit Skin Irritation Grades

Observation time following patch removal

Animal

Erythema

Oedema

 

 

Within 30 min

1

1

0

2

0

0

3

4 a

4

4

4 a

1

5

4 a

1

6

4 a

2

 

 

24 h

1

1

0

2

1

0

3

4 a

4

4

4 a

1

5

4 a

1

6

4 a

2

 

 

48 h

1

0

0

2

0

0

3

4 a

4

4

4 a

2

5

4 a

0

6

4 a

2

 

 

72 h

1

0

0

2

0

0

3

4 a

4

4

4 a

2

5

4 a

0

6

4 a

2

 

 

Day 7

1

0

0

2

0

0

3

4 b

0

4

4 b

0

5

4 b

0

6

4 b

0

 

 

Day 8

1

0

0

2

0

0

3

4 b

0

4

4 b

0

5

4 b

0

6

4 b

0

 

 

Day 9

1

0

0

2

0

0

3

4 b

0

4

4 b

0

5

4 b

0

6

4 b

0

 

 

Day 10

1

0

0

2

0

0

3

4 b

0

4

4 b

0

5

4 b

0

6

4 b

0

 

 

Day 11

1

0

0

2

0

0

3

4 c

0

4

4 c

0

5

4 c

0

6

4 c

0

 

 

Day 14

1

0

0

2

0

0

3

4 d

0

4

4 d

0

5

4 d

0

6

4 c

0

 

 

Day 15

1

0

0

2

0

0

3

4 d

0

4

4 d

0

5

4 d

0

6

4 d

0

a = burns at application site; b = scabs at application site; c = scabs and scars at application site; d = scars at application site

Interpretation of results:
highly irritating
Remarks:
Migrated information Criteria used for interpretation of results: expert judgment
Conclusions:
The scores derived from this study indicate that the test item was corrosive to the rabbits' skin. However, the test was conducted under occlusive conditions, which is not in line with current guideline requirements and is considered to be more rigorous compared to the semi-occlusive patching used today. Thus, as recommended by ECHA (2012), having regard to the method of application, the test item is considered to be highly irritating.

Reference:
ECHA. (2012a). Guidance on the application of the CLP criteria. Guidance to Regulation (EC) No 1272/2008 on classification, labelling and packaging (CLP) of substances and mixtures. Version 3.0, November 2012.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Eye irritation

Link to relevant study records
Reference
Endpoint:
eye irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1981
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Non-GLP guideline study, however with some deviations. The lower end of the housing temperature range (16-18°C) was outside of the range (20°C +/- 3°C) specified in OECD Guideline 405; the observation period was 8 days whereas the guideline recommends 21 days to clarify reversibility; no data on the purity of the test item given.
Qualifier:
according to guideline
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Deviations:
yes
Remarks:
the lower end housing temperature range (16-18 °C) was outside the range specified in the guideline, observation time was 8 days instead of 21, no data on test material purity
GLP compliance:
no
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Source: Lippische Versuchstierzucht, Hagemann GmbH& Co. KG, Extertal, Germany
- Weight at study initiation: 2.7 kg
- Housing: in single cages
- Diet: "muemmel z" (ssniff/Soest), ad libitum
- Water: ad libitum
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 16 -18
- Humidity (%): 40
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12/12
Vehicle:
unchanged (no vehicle)
Controls:
other: the left eye remained untreated and served for control
Amount / concentration applied:
0.1 mL bulk volume instilled into the conjunctival sac of the lower eyelid of the right eye of each animal.
Duration of treatment / exposure:
single administration without washing
Observation period (in vivo):
8 days
Number of animals or in vitro replicates:
3 male animals
Details on study design:
REMOVAL OF TEST SUBSTANCE
- Washing: none

SCORING SYSTEM:
- Reading time points: 1 h, 24 h, 48 h, 72 h, day 8
- Scoring: Draize Scoring System

TOOL USED TO ASSESS SCORE: fluorescein
Irritation parameter:
cornea opacity score
Basis:
animal #1
Remarks:
mean over the 3 following time points
Time point:
other: 24+48+72 h
Score:
1.66
Max. score:
4
Reversibility:
not reversible
Remarks:
within 8 days
Remarks on result:
other: corneal opacity graded 2 still was evident at day 8
Irritation parameter:
cornea opacity score
Basis:
animal #2
Remarks:
mean over the 3 following time points
Time point:
other: 24+48+72 h
Score:
1.66
Max. score:
4
Reversibility:
not reversible
Remarks:
within 8 days
Remarks on result:
other: corneal opacity graded 3 still was evident at day 8
Irritation parameter:
cornea opacity score
Basis:
animal #3
Remarks:
mean over the 3 following time points
Time point:
other: 24+48+72 h
Score:
2
Max. score:
4
Reversibility:
not reversible
Remarks:
within 8 days
Remarks on result:
other: corneal opacity graded 2 still was evident at day 8
Irritation parameter:
iris score
Basis:
animal #1
Remarks:
mean over the 3 following time points
Time point:
other: 24+48+72 h
Score:
1.33
Max. score:
2
Reversibility:
not reversible
Remarks:
within 8 days
Remarks on result:
other: iritis graded 2 still was evident at day 8
Irritation parameter:
iris score
Basis:
animal #2
Remarks:
mean over the 3 following time points
Time point:
other: 24+48+72 h
Score:
0.66
Max. score:
2
Reversibility:
not reversible
Remarks:
within 8 days
Remarks on result:
other: iritis graded 2 still was evident at day 8
Irritation parameter:
iris score
Basis:
animal #3
Remarks:
mean over the 3 following time points
Time point:
other: 24+48+72 h
Score:
0.66
Max. score:
2
Reversibility:
not reversible
Remarks:
within 8 days
Remarks on result:
other: iritis graded 2 still was evident at day 8
Irritation parameter:
conjunctivae score
Basis:
animal #1
Remarks:
mean over the 3 following time points
Time point:
other: 24+48+72 h
Score:
1.66
Max. score:
3
Reversibility:
not reversible
Remarks:
within 8 days
Remarks on result:
other: redness of the conjunctivae graded 1 still was evident at day 8
Irritation parameter:
conjunctivae score
Basis:
animal #2
Remarks:
mean over the 3 following time points
Time point:
other: 24+48+72 h
Score:
2
Max. score:
3
Reversibility:
not reversible
Remarks:
within 8 days
Remarks on result:
other: redness of the conjunctivae graded 1 still was evident at day 8
Irritation parameter:
conjunctivae score
Basis:
animal #3
Remarks:
mean over the 3 following time points
Time point:
other: 24+48+72 h
Score:
1.33
Max. score:
3
Reversibility:
not reversible
Remarks:
within 8 days
Remarks on result:
other: redness of the conjunctivae graded 1 still was evident at day 8
Irritation parameter:
chemosis score
Basis:
animal #1
Remarks:
mean over the 3 following time points
Time point:
other: 24+48+72 h
Score:
2.33
Max. score:
4
Reversibility:
not reversible
Remarks:
within 8 days
Remarks on result:
other: chemosis graded 1 still was evident at day 8
Irritation parameter:
chemosis score
Basis:
animal #2
Remarks:
mean over the 3 following time points
Time point:
other: 24+48+72 h
Score:
2.33
Max. score:
4
Reversibility:
not reversible
Remarks:
within 8 days
Remarks on result:
other: chemosis graded 1 still was evident at day 8
Irritation parameter:
chemosis score
Basis:
animal #3
Remarks:
mean over the 3 following time points
Time point:
other: 24+48+72 h
Score:
2
Max. score:
4
Reversibility:
not reversible
Remarks:
within 8 days
Remarks on result:
other: chemosis graded 1 still was evident at day 8
Irritation parameter:
other: discharge
Basis:
animal #1
Remarks:
mean over the 3 following time points
Time point:
other: 24+48+72 h
Score:
1.33
Max. score:
3
Reversibility:
fully reversible within: 72 h
Remarks on result:
other: eye discharge with moistening of the eyelids and hair (grade 2) was noticed at 24 and 48 h
Irritation parameter:
other: discharge
Basis:
animal #2
Remarks:
mean over the 3 following time points
Time point:
other: 24+48+72 h
Score:
1.66
Max. score:
3
Reversibility:
fully reversible within: 8 days
Remarks on result:
other: eye discharge with moistening of the eyelids and hair (grade 2) was noticed at 1, 24 and 48 h; discharge was slighter at 72 h and no more evident after 8 days.
Irritation parameter:
other: discharge
Basis:
animal #3
Remarks:
mean over the 3 following time points
Time point:
other: 24+48+72 h
Score:
2
Max. score:
3
Reversibility:
fully reversible within: 8 days
Remarks on result:
other: eye discharge with moistening of the eyelids and hair (grade 1 to 2) was noticed at 1, 24, 48 and 72 h; discharge was no more evident after 8 days.
Irritant / corrosive response data:
The single instillation of the test item in the eye of rabbit resulted in ocular irritation.
At reading time point 1 hour, corneal opacity of grade 1 to 2, conjunctival redness (grade 1) and chemosis (grade 1 to 2) were observed in all 3 animals; in two of them, discharge above normal also was reported (grade 1 to 2).
At reading time point 24 hour, corneal opacity of grade 1 to 2, conjunctival redness (grade 1 to 2) and chemosis (grade 2 to 3) were observed in all 3 animals; they all further showed discharge above normal (graded 2).
At reading time point 48 hour, corneal opacity of grade 2, conjunctival redness (grade 1 to 2) and chemosis (grade 2) were observed in all 3 animals, which all still showed discharge above normal (graded 2); in addition signs of iritis were noticed in all animals and were graded 1 to 2.
At reading time point 72 hour, corneal opacity of grade 2, conjunctival redness (grade 2) and chemosis (grade 2) were observed in all 3 animals; discharge still remained above normal in 2 cases (grade 2) whereas for the third animal, discharge had turned back to normal; signs of iritis still were evident in all animals (grade 1 to 2).
After 8 days, corneal opacity of grade 2 to 3, conjunctival redness (grade 1), chemosis (grade 1), and iritis (grade 2) still were evident in all 3 animals, indicating that the findings were not reversible within 8 days following treatment. No more discharge above normal was seen.


Other effects:
none

Tab. 1: Results of the eye irritation study with Preventol o extra

Reading time point

1 h

24 h

48 h

72 h

8 days

Animal No.

1

2

3

1

2

3

1

2

3

1

2

3

1

2

3

Cornea score

1

1

2

1

1

2

2

2

2

2

2

2

2

3

2

Iris score

0

0

0

0

0

0

2

1

1

2

1

1

2

2

2

Conjunctivae score

1

1

1

1

2

1

2

2

1

2

2

2

1

1

1

Chemosis score

1

2

2

3

3

2

2

2

2

2

2

2

1

1

1

Discharge

0

2

1

2

2

2

2

2

2

0

1

2

0

0

0

Interpretation of results:
Category I
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
CLP: Eye damage 1, H318
DSD: Xi, R41
Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Skin irritation/corrosion:

A key study skin irritation in the rabbit was conducted with the test substance 2-phenylphenol (OPP) (Gilbert, K. S., 1994a and Bomhard, E. M. et al., 2002). The methods used in this study are in accordance with the guidelines of the US EPA Title 40 CRF Part 160 (1983), OECD-Guideline 404 and EEC Method No. B.4, however, treatment was conducted under occlusive conditions. Aliquots of 0.5 g OPP, moistened with 0.3 mL of distilled water, were applied for 4 h to the intact skin on the back of three male and three female New Zealand White rabbits, using a Hill Top Chamber which was held in place with an elastic rabbit jacket. Very slight erythema was observed at the application site of one rabbit within 30 minutes and on two animals 24 hours after test material removal. Severe to slight eschar formation was observed on four rabbits within 30 minutes of test material removal and persisted through the remainder of the study. Four animals had burns at the application site within 30 minutes of test substance removal. The burns resolved as scabs and then scars by study termination. Four of the six rabbits had very slight to severe oedema 30 minutes and 24 hours after test material removal. Slight to severe oedema was observed on 3 animals 48 and 72 h after removal of the test substance. The scores derived from this study indicate that the test item was corrosive to the rabbits' skin. However, the test was conducted under occlusive conditions, which is not in line with current guideline requirements and is considered to be more rigorous compared to the semi-occlusive patching used today. Thus, as recommended by ECHA (2012f), having regard to the method of application, the test item is considered to be highly irritating.

Data from further key studies are available, supporting strong irritative properties of the test item. After 4 h of exposure the test material induced skin reactions (erythema and oedema), which did not resolve within 7 days of exposure (Thyssen, J., 1982 and Bomhard, E. M. et al., 2002) and already after 30 min of occluded exposure slight transient skin reactions were noted (Suberg, H., 1983 and Bomhard, E. M. et al., 2002). However, treatment in these studies was always conducted under occlusive conditions.

A further key study is available, which was conducted according to OECD TG 404, but not in compliance with GLP (Schreiber, G., 1981a and Bomhard, E. M. et al., 2002). Three male New Zealand White albino rabbits were exposed semi-occlusively to 0.5 g of the test substance formulated as a paste in water for four hours. Thereafter, residual test substance was removed with water or olive oil. The skin reaction was evaluated at 1, 24, 48 and 72 hours, and 8 days after removal of the test patch. The Draize system was used for scoring the skin reactions. The mean erythema score of all 3 animals over 24, 48, and 72 was 1.3 with a maximum observed score of 2; the mean oedema score of all 3 animals over 24, 48, and 72 was 0.3 with a maximum observed score of 1. All skin reactions were fully reversible within the study period of 8 days. Based on the outcome of this study, the test item is concluded to be slightly irritating to the rabbits’ skin under the semi-occlusive conditions of this test.

Data from the key acute dermal toxicity study and the repeated dermal toxicity study support that the test item is only slightly irritating. In the acute dermal toxicity study (Bomhard, E., 1991 and Bomhard, E. M. et al., 2002) local skin changes in the form of slight reddening was observed in males and females on the day after application. This redness turned to incrustation on Day 5 and was more severe on females than on males. On Days 10 (males) and 14 (females) all skin reactions were resolved. In the repeated dermal toxicity study (Zempel, J. A. and Szabo, J. R., 1993 and Bomhard, E. M. et al., 2002) local irritation (erythema and scaling) of the application site was noted at 500 and 1000 mg/kg bw/day. Oedema formation was not observed in either sex at any dose level. Microscopical evaluation revealed hyperkeratosis and acanthosis in the treated skin of the 500 and 1000 mg/kg bw/day treated animals. However, this result does not indicate a full thickness destruction, which supports that OPP is irritating to the skin rather than corrosive.

Data from a human patch test with 200 human volunteers revealed that OPP was not irritating to the skin when tested as a 5% solution in sesame oil (Hodge, H. C. et al., 1952 and Bomhard, E. M. et al., 2002).

In conclusion, the data available for skin irritation are not fully consistent, but taking into consideration all available data 2-phenylphenol (OPP) was irritating to the rabbits’ skin and therefore meets the criteria to be classified as Xi, R38 according to Directive 67/548/EEC and skin irritation Cat. 2, H315 according to Regulation (EC) No 1272/2008. This is in line with the harmonised classification notified in Annex I of Directive 67/548/EEC and Annex VI of Regulation (EC) No 1272/2008.

Eye irritation:

A key study eye irritation in the rabbit was conducted with the test substance 2-phenylphenol (OPP) (Schreiber, G., 1981b and Bomhard, E. M. et al., 2002). The method complied with the OECD Guideline 405 (1981). The test substance (100 µL bulk volume) was instilled into the conjunctival sac of the lower eyelid of three adult male New Zealand White albino rabbits. The test eye was not rinsed after administration. The left eye remained untreated for control purposes. The corneal status was assessed after 24 h by fluorescein test. Ocular reactions were scored at 1, 24, 48 and 72 h, and 8 days after test substance administration. The Draize scoring system was used for scoring eventual lesions. OPP produced ocular irritation characterised by corneal and iridial involvement and conjunctival irritation. Positive irritation reactions were observed in all animals beginning one hour post instillation and were not resolved at the end of study on day 8. The authors report a slow repair after 8 days; however, no scores are given for that.

Further key data are available, supporting corrosive properties of 2-phenylphenol (OPP) (Thyssen, J., 1978). Strong irreversible effects on cornea, iris, and conjunctivae (reddening and chemosis) were further reported by Norris, J. M. (1971) and Bomhard, E. M. et al. (2002).

In conclusion, 2-phenylphenol (OPP) induced irreversible damage to the rabbits’ eye. The effects observed are above the hazard notified by the harmonised classification (Xi, R36 according to Annex I of Directive 67/548/EEC and Eye irritation Cat 2, H319 according to Annex VI of Regulation (EC) No 1272/2008). Based on the data available to the registrant, OPP meets the criteria to be classified as Xi, R41 according to Directive 67/548/EEC and Eye damage Cat 1, H318 according to Regulation (EC) No 1272/2008.

Respiratory irritation

In the acute inhalation toxicity studies clinical symptoms indicating respiratory irritation were not observed. No further data are available for respiratory irritation. Because of its proven irritant effects on mucosa of the eye, it cannot be excluded that OPP is irritating to the airways when inhaled in high concentrations (e. g. pure substance dust). Therefore, the harmonised classification as irritating to the respiratory tract (Xi, R37) according to Directive 67/548/EEC and (STOT SE Cat 3, H335) according to Regulation (EC) No 1272/2008 is not unplausible, even if clinical symptoms were not recorded in the acute inhalation toxicity studies.

References:

ECHA. (2012f). Guidance on the application of the CLP criteria. Guidance to Regulation (EC) No 1272/2008 on classification, labelling and packaging (CLP) of substances and mixtures.European Chemicals Agency, Helsinki.


Justification for selection of skin irritation / corrosion endpoint:
The most reliable study (guideline study in compliance with GLP, reliability 1) with the worst outcome was selected as key study and therefore chosen for the hazard assessment.

Justification for selection of eye irritation endpoint:
The most reliable study (guideline study, but not in compliance with GLP, reliability 2) with the worst outcome was selected as key study and therefore chosen for the hazard assessment.

Effects on skin irritation/corrosion: irritating

Effects on eye irritation: corrosive

Effects on respiratory irritation: irritating

Justification for classification or non-classification

Based on the available data for the registered substance, 2-phenylphenol meets the criteria to be classified as Xi, R38 according to Directive 67/548/EEC and skin irritation Cat. 2, H315 according to Regulation (EC) No 1272/2008.

Based on the available data for the registered substance, 2-phenylphenol meets the criteria to be classified as Xi, R41 according to Directive 67/548/EEC and Eye damage Cat 1, H318 according to Regulation (EC) No 1272/2008.

Based on the harmonised classification notified in Annex I of Directive 67/548/EEC and Annex VI of Regulation (EC) No 1272/2008 he registered substance, 2-phenylphenol is classified as irritating to the respiratory tract (Xi, R37) according to Directive 67/548/EEC and (STOT SE Cat 3, H335) according to Regulation (EC) No 1272/2008.