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Description of key information

2-Phenoxyethanol is not irritating to rabbit skin, but irritating to the eyes and shows reversible signs of respiratory irritation.

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records

Referenceopen allclose all

Endpoint:
skin irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Deviations:
yes
Remarks:
The test substance was applied under occlusive conditions.
GLP compliance:
no
Remarks:
GLP was not compulsory at the time the study was performed.
Specific details on test material used for the study:
- Name of test material (as cited in study report): 2- phenoxyethanol (technical grade)
- Physical state: liquid
- Analytical purity: no data
- Lot/batch No.: substance number: 83/143
- Expiration date of the lot/batch: May 1984
Species:
rabbit
Strain:
Vienna White
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Firma Gaukler; Offenbach, Germany
- Weight at study initiation: 2.79 kg, 2.32 kg, 3.00 kg
- Housing: single in stainless-steel cages
- Diet (e.g. ad libitum): Ovator Solikanin 4mm, Muskator-Werke Düsseldorf
- Water (e.g. ad libitum): tap water
- Acclimation period: at least 8 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24
- Humidity (%): 30-70
- Photoperiod (hrs dark / hrs light): 12/12
Type of coverage:
occlusive
Preparation of test site:
shaved
Vehicle:
unchanged (no vehicle)
Controls:
not required
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): ca. 0.5 mL
- Concentration (if solution):
Duration of treatment / exposure:
4 h
Observation period:
72 h
Number of animals:
3 (two males and one female)
Details on study design:
TEST SITE
- Area of exposure: dorsal area of the trunk (2.5 x 2.5 cm)

REMOVAL OF TEST SUBSTANCE
- Washing (if done): with Lutrol/water (1:1) and water
- Time after start of exposure: 4 h

SCORING SYSTEM: according to OECD guideline 404
Irritation parameter:
erythema score
Basis:
mean
Time point:
other: 30-60 min
Score:
1
Reversibility:
fully reversible within: 24 h
Irritation parameter:
erythema score
Basis:
mean
Time point:
24/48/72 h
Score:
0
Irritation parameter:
edema score
Basis:
mean
Time point:
other: 30-60 min as well as 24, 48 and 72 h
Score:
0
Interpretation of results:
GHS criteria not met
Conclusions:
CLP: not classified
Endpoint:
skin irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
19 Jul 1983 - 01 Aug 1983
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Remarks:
non-GLP study
Qualifier:
according to guideline
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Deviations:
yes
Remarks:
- occlusive conditions were used
GLP compliance:
no
Specific details on test material used for the study:
- Name of test material (as cited in study report): Marlophen P 1
- Physical state: liquid
- Analytical purity: >99 %
- Lot/batch No.: 5
- Expiration date of the lot/batch: maximum of 12 months storage
- Other: clear
Species:
rabbit
Strain:
other: Russian white (Chbb-SPF)
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Weight at study initiation: 2400 - 3100 mg
- Housing: single animals in steel wire cages
- Diet (e.g. ad libitum): K4 diet for rabbits (Ssniff)
- Water (e.g. ad libitum): tap water
- Acclimation period: 14 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 ± 1
- Humidity (%): 60 ± 5
- Air changes (per hr): 15x
- Photoperiod (hrs dark / hrs light): 12/12
Type of coverage:
occlusive
Preparation of test site:
shaved
Vehicle:
unchanged (no vehicle)
Controls:
not specified
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.5 mL
Duration of treatment / exposure:
4 hours
Observation period:
24, 48, 72 hours and 6, 9, 10, 13 days after removal of the patch
Number of animals:
6 (3 male and 3 female)
Details on study design:
TEST SITE
- Area of exposure: 6 cm2
- % coverage:
- Type of wrap if used: Exposed animal skin was secured with linen (2.5 x 2.5 cm), polyethylene foil (6 x 6 cm) and an elastic bandage.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): test article residue was washed with aqua dest.
- Time after start of exposure: 4 hours

SCORING SYSTEM: OECD scoring system
Irritation parameter:
erythema score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0.3
Max. score:
4
Reversibility:
fully reversible within: 48 hours
Remarks on result:
other: female animal showing very slight erythema (barely perceptible) after 24 hours
Irritation parameter:
erythema score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0.3
Max. score:
4
Reversibility:
fully reversible within: 48 hours
Remarks on result:
other: female animal showing very slight erythema (barely perceptible) after 24 hours
Irritation parameter:
erythema score
Basis:
animal: #3,4,5,6
Time point:
24/48/72 h
Score:
0
Max. score:
4
Irritation parameter:
edema score
Basis:
mean
Time point:
24/48/72 h
Score:
0
Max. score:
4
Interpretation of results:
GHS criteria not met
Conclusions:
Marlophen P1 induced no signs of skin irritation in male and female rabbits.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Eye irritation

Link to relevant study records
Reference
Endpoint:
eye irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Qualifier:
according to guideline
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Deviations:
yes
Remarks:
the test was terminated at post-application day 15, when effects were not completely reversed
GLP compliance:
no
Remarks:
GLP was not compulsory at the time the study was performed
Specific details on test material used for the study:
- Name of test material (as cited in study report): 2-Phenoxyethanol (technical grade)
- Analytical purity: no data
- Lot/batch No.: substance number: 83/143
- Expiration date of the lot/batch: May 1984
Species:
rabbit
Strain:
Vienna White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Source: Firma Gaukler; Offenbach, Germany
- Age at study initiation:
- Weight at study initiation: 2.51 kg, 2.37 kg, 2.61 kg
- Housing: single housing in stainless-steel cages
- Diet (e.g. ad libitum): Ovator Solikanin 4 mm, Muskator-Werke Duesseldorf, Germany
- Water (e.g. ad libitum): drinking water
- Acclimation period: at least 8 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24
- Humidity (%): 30-70
- Photoperiod (hrs dark / hrs light): 12/12
Vehicle:
unchanged (no vehicle)
Controls:
not required
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.1 mL
Duration of treatment / exposure:
The substance remained in the eye, therefore 15 days.
Observation period (in vivo):
15 days
Number of animals or in vitro replicates:
3
Details on study design:
SCORING SYSTEM: according to OECD and Draize

Corneal Opacity (maximum possible: 4)
0 = no finding
1 = slight opacity
2 = well-defined opacity
3 = severe opacity
4 = very severe opacity

Involved corneal area
1 = > 0 - < ¼
2 = >= 1/4 - < ½
3 = >= ½ - < ¾
4 = >= 3/4

Iris (maximum possible: 2)
0 = no finding
1 = ciliary injection
2 = iritis

Conjunctival redness (maximum possible: 3)
0 = no finding
1 = slight redness
2 = well-defined redness
3 = severe redness

Conjunctival swelling (maximum possible: 4)
0 = no finding
1 = slight swelling
2 = well-defined swelling
3 = severe swelling
4 = very severe swelling

Secretion (maximum possible: 3)
0 = no finding
1 = slight increase
2 = well-defined increase
3 = severe increase

Calculation of the irritation index:
For each animal and each reading time point, the irritation index (I) was calculated according to following formula:
I = A + B + C
A = 5 x opacity x involved corneal area
B = 5 x iris
C = 2 x (conjunctival redness + swelling + secretion)

The primary irritation index (PI) was the sum of all irritation indices for all animals and all reading time points (24, 48 and 72 h), subdivided by 3 x the number of animals.
Irritation parameter:
cornea opacity score
Basis:
mean
Time point:
other: 1 h
Score:
0
Reversibility:
not fully reversible within: 15 days
Remarks on result:
other: occurence of effects after 24 h
Irritation parameter:
cornea opacity score
Basis:
animal #1
Time point:
24/48/72 h
Score:
1
Reversibility:
not reversible
Irritation parameter:
cornea opacity score
Basis:
animal #2
Time point:
24/48/72 h
Score:
1
Reversibility:
fully reversible within: 15 days
Irritation parameter:
cornea opacity score
Basis:
animal #3
Time point:
24/48/72 h
Score:
1.7
Reversibility:
fully reversible within: 15 days
Irritation parameter:
iris score
Basis:
mean
Time point:
other: 1 h
Score:
0
Reversibility:
fully reversible within: 15 days
Remarks on result:
other: occurence of effects after 24 h
Irritation parameter:
iris score
Basis:
animal #1
Time point:
24/48/72 h
Score:
1.3
Reversibility:
fully reversible within: 15 days
Irritation parameter:
iris score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0.7
Reversibility:
fully reversible within: 72 h
Irritation parameter:
iris score
Basis:
animal #3
Time point:
24/48/72 h
Score:
1
Reversibility:
fully reversible within: 8 days
Irritation parameter:
conjunctivae score
Basis:
mean
Time point:
other: 1 h
Score:
2
Reversibility:
fully reversible within: 8 days
Irritation parameter:
conjunctivae score
Basis:
animal #1
Time point:
24/48/72 h
Score:
2
Reversibility:
fully reversible within: 8 days
Irritation parameter:
conjunctivae score
Basis:
animal #2
Time point:
24/48/72 h
Score:
1
Reversibility:
fully reversible within: 72 h
Irritation parameter:
conjunctivae score
Basis:
animal #3
Time point:
24/48/72 h
Score:
2
Reversibility:
fully reversible within: 8 days
Irritation parameter:
chemosis score
Basis:
mean
Time point:
other: 1 h
Score:
2
Reversibility:
fully reversible within: 8 days
Irritation parameter:
chemosis score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0.3
Reversibility:
fully reversible within: 48 h
Irritation parameter:
chemosis score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0.3
Reversibility:
fully reversible within: 48 h
Irritation parameter:
chemosis score
Basis:
animal #3
Time point:
24/48/72 h
Score:
1.3
Reversibility:
fully reversible within: 8 days
Other effects:
Additional symptoms such as narrowness of pupil, scarred retraction of eyelid, marginal corneal vascularisation and suppuration were also considered.
No clinical signs observed.
Interpretation of results:
Category 1 (irreversible effects on the eye) based on GHS criteria
Conclusions:
A tendency to reversibility was observed but after the exposure period (15 days), one animal still displayed slight corneal opacity affecting less than ¼ of the corneal area of the treated eye. In the CLH report on the Proposal for Harmonised Classification and Labelling for Phenoxyethanol (June 2018), an additional study in rabbits acc. to OECD 405 was cited, that also showed persistent corneal opacity in 1/6 animals on observation day 21 after phenoxyethanol administration. Here, it was proposed to classify for irreversible effects to the eye, category 1, on the basis that at least one animal had effects to the cornea that were not fully reversed within the observation period of 21 days.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Additional information

Skin irritation:


A mild primary irritation was observed in one rabbit 1 hour after application, which was reversible within 24 hours (BASF AG, 1983). Although the test conditions were not in full accordance with OECD guideline 404, the results should be considered representative for the toxicological properties of 2-phenoxyethanol. 2-Phenoxyethanol was not an irritant to rabbit skin.


According to OECD 404, the skin irritation potential of 2-phenoxyethanol was determined (Sasol, 1983). The test substance was applied to the intact skin of rabbits for 4 hours under occlusive conditions. After removal of the test substance, no oedema, but very slight erythema were noted in 2 of 6 animals. All erythema were reversible within 48 hours. Under the test conditions, 2-Phenoxyethanol was not irritating to the skin.


 


Eye irritation


In the key study for eye irritation, the single application of 0.1 mL unchanged test material in the eye of each of 3 rabbits clearly induced signs of irritation in all 3 animals; the signs were of maximal severity between 48 and 72 hours following application (BASF AG, 1983; 82/143). Thereafter, a tendency to reversibility was observed and after 15 days, only one animal still displayed slight corneal opacity affecting less than ¼ of the corneal area of the treated eye. The test substance 2-phenoxyethanol is therefore considered an eye irritant.


A tendency to reversibility was observed but after the exposure period (15 days), one animal still displayed slight corneal opacity affecting less than ¼ of the corneal area of the treated eye.


 


In the CLH report on the Proposal for Harmonised Classification and Labelling for Phenoxyethanol (June 2018), the supporting study in rabbits acc. to OECD 405 was included as additional evidence, showing persistent corneal opacity in 1/6 animals on observation day 21 after phenoxyethanol administration (Sasol 1983; 0118).  


The results of the two guideline eye irritation studies in rabbits showed a score (average 24, 48, 72 h) of ≥ 1 for corneal opacity (in 6/6 rabbits and 3/3 rabbits respectively), meeting the criteria for classification for this endpoint. One of the 3 tested animals continued to have corneal opacity to the end of the study period of 15 days (shorter than the usual observation period of 21 days) and the effect was reported as mild and affecting less than one quarter of the corneal area.


The supporting study showed corneal opacity not fully resolved by the end of the 21 day study period 1 of the 6 tested animals. Therefore, in accordance with the classification criteria for category 1, it is proposed to classify for irreversible effects to the eye, category 1, on the basis that at least one animal had effects to the cornea that were not fully reversed within an observation period of 21 days.


 


Respiratory irritation


The inhalation toxicity observed for the registered substance in a subacute (14 day) aerosol inhalation toxicity study in rats (performed according to OECD TG 412 and GLP) was used to assess the irritative potential towards the respiratory tract (BASF AG, 2007; 36I0498/01187). For further information see “7.5.2 Repeated dose toxicity: inhalation”. In this study, the respiratory tract, with substance-related lesions to the nasal cavity and larynx, and the lungs were the target organs. The upper respiratory tract showed degeneration, metaplasia and inflammatory cell infiltration. The respiratory epithelium of the nose appeared to be the most sensitive region, especially in the anterior septum area. The epithelial lining of other sites, e.g. respiratory epithelium of lungs, transitional epithelium larynx was also affected but appeared to be less sensitive. The base of the epiglottis was covered by metaplastic squamous epithelium in high concentration males and females and one female of the mid-dose group. The morphological changes occurring at the mid and top test concentrations were considered indicative of respiratory irritation. No adverse effects were seen at the lowest exposure level.


 


In the CLH report on the Proposal for Harmonised Classification and Labelling for Phenoxyethanol (June 2018), the relevance of these effects for the classification concerning  specific target organ toxicity-single exposure (STOT-SE) was discussed:


In the acute and repeated dose studies available for the registered substance, there was no evidence of specific target organ toxicity relevant for classification in categories 1 or 2. Classification with STOT-SE 3 is reserved for substances/mixtures causing “transient effects” following a single exposure, specifically respiratory tract irritation (RTI) and narcotic effects.


The 14 day inhalation rat study available was designed with particular emphasis on potential effects to the respiratory tract. Signs of degeneration and metaplasia were noted in the nasal cavity and squamous metaplasia was observed in the larynx of mid and top dosed animals. The European Society of Toxicologic Pathology held an expert workshop on the toxicologic significance of squamous metaplasia of the larynx in rodents and its relevance to humans (Kaufmann et al., 2009), during which it was concluded that focal epithelial changes of the larynx epithelium occurring predominantly at the base of the epiglottis should be described as epithelial alterations rather than laryngeal squamous metaplasia. It is recognised that, in rodents, the epithelium lining at the base of the epiglottis is the area most susceptible to changes induced by respiratory irritants (Renne et al., 1993), and that most squamous metaplasia of the larynx is a reversible response to chronic irritation.


There were no such findings reported in the acute inhalation study (see 7.2.2 Acute toxicity: inhalation), however the dose used was similar to the lowest dose used in the 14-day study, at which no treatment-related effects were observed.


According to the guidance, there are currently no validated animal tests that deal specifically with RTI, however useful information may be obtained from single and repeated inhalation toxicity tests. Clinical observations such as hyperemia, edema, minimal inflammation, thickened mucous layer which are reversible and may be reflective of the characteristic clinical symptoms of RTI. This special classification would occur only when more severe organ effects including in the respiratory system are not observed.


The findings observed in the 14-day inhalation study are indicative of reversible signs of respiratory irritation. Although there are no sufficient data following a single dose, the study period was short, only 14 days, and the exposure levels used were low. Therefore, the minimal to mild metaplasia observed in the nasal cavity and larynx of rats are considered indicative of short-term adaptive changes to the irritant potential of the registered substance. Supporting this perspective is the ability of this substance to cause irritation to the eyes. Classification for STOT-SE 3, respiratory tract irritation, is warranted.

Justification for classification or non-classification

Skin irritation:


not irritating to skin.


CLP: not classified


 


Eye Irritation:


In line with the CLH report on the Proposal for Harmonised Classification and Labelling for Phenoxyethanol (June 2018), it is appropriate to classify for irreversible effects to the eye, category 1, on the basis that at least one animal had effects to the cornea that were not fully reversed within the observation period of 21 days.


CLP: Cat. 1


 


Respiratory irritation


In line with the CLH report on the Proposal for Harmonised Classification and Labelling for Phenoxyethanol (June 2018), the findings observed in the 14-day inhalation study are indicative of reversible signs of respiratory irritation. The minimal to mild metaplasia observed in the nasal cavity and larynx of rats are considered indicative of short-term adaptive changes to the irritant potential of the registered substance. This Classification for STOT-SE 3, respiratory tract irritation, is warranted.


CLP: STOT-Single Exp. Cat. 3, May cause respiratory irritation