Registration Dossier

Administrative data

Description of key information

Skin irritation: in vivo, New Zealand White rabbit (2), semi-occlusive, 500 mg over 24h onto inner ear (similar to OECD 404): not irritating

Skin irritation: in vivo, dry or suspended in oil or water for 24h on the inner rabbit ear (3) resp. human forearm (6), semi-occlusive: not irritating

Eye irritation: in vitro, 150 mg as 750 ml suspension in saline, 4h exposure (BCOP, OECD 437, GLP): IVIS = 5.31, no prediction can be made, precautionary classification as UN GHS Category 2

Eye irritation: in vivo, New Zealand White rabbit (2), 50 mg single instillation, no wash-out (similar to OECD 405): not irritating

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:
other: see 'Remark'
Remarks:
Conducted prior to GLP implementation similar to OECD 404 on the registered substance itself with some deficiencies in documentation and performance, i.e. only two animals were used instead of three, substance was applied on the ear, not the trunk, evaluation criteria not defined.
Reference:
Composition 0
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Deviations:
not applicable
GLP compliance:
no
Remarks:
test conducted prior to GLP implementation
Test material information:
Composition 1
Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
TEST ANIMALS
- Housing: individually
Type of coverage:
semiocclusive
Preparation of test site:
not specified
Vehicle:
unchanged (no vehicle)
Controls:
no
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 500 mg
Duration of treatment / exposure:
24 h
Observation period:
7 days
Number of animals:
2
Details on study design:
TEST SITE
- Area of exposure: inner face of the ear
- Type of wrap if used: band aid

REMOVAL OF TEST SUBSTANCE
- Washing (if done): with water and soap/vegetable oil
- Time after start of exposure: 24 h
Irritation parameter:
other: irritating properties
Basis:
mean
Remarks on result:
other: not irritating
Interpretation of results:
not irritating
Conclusions:
The study was conducted prior to GLP implementation similar to OECD 404 on the registered substance itself with some deficiencies in documentation and performance. Nevertheless, with the given properties of the test item, the methodological deficiencies are unlikely to have any influence on the results. The given information on test performance allows the conclusion that the method was scientifically reasonable performed. Also, the result (not irritating) is confirmed by the other available studies on skin and in vivo eye irritation, clearing any doubts regarding the reliability of the result. Hence, Phenol, 2,2'-methylenebis-(6-cyclohexyl-4-methyl) does not need to be regarded as dermal irritant.
Executive summary:

In a primary dermal irritation study similar to OECD 404, two New Zealand White rabbits were dermally exposed to 500 mg of unchanged Phenol, 2,2'-methylenebis-(6-cyclohexyl-4-methyl) for 24 hours to the inner side of the ear.  Animals then were observed for 7 days. In this study, Phenol, 2,2'-methylenebis-(6-cyclohexyl-4-methyl) is not a dermal irritant.

 

Endpoint:
skin irritation: in vivo
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
1959-03-16 - 1959-09-07
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Study conducted prior to GLP on the registered substance itself, no guideline followed as none was available in 1959 for rabbits resp. generally for humans, deficiencies in documentation and performance, i.e. substance (amount not defined) was applied on the rabbit ear, not the trunk, evaluation criteria not defined.
Reference:
Composition 0
Qualifier:
no guideline followed
Principles of method if other than guideline:
The test item was applied on a cotton ball either dry or suspended in oil or water for 24h on the inner rabbit ear resp. human forearm.
GLP compliance:
no
Remarks:
test conducted prior to GLP implementation
Test material information:
Composition 1
Species:
other: rabbit and human
Strain:
not specified
Details on test animals and environmental conditions:
no data
Type of coverage:
semiocclusive
Preparation of test site:
not specified
Vehicle:
other: unchanged, oil or water
Controls:
no
Amount / concentration applied:
no data
Duration of treatment / exposure:
24 h
Observation period:
no data
Number of animals:
3 rabbits, 6 humans
Details on study design:
TEST SITE
- Area of exposure: inner rabbit ear or human forearm
- Type of wrap if used: cotton ball with band aid
Irritation parameter:
other: irritating properties
Basis:
mean
Remarks on result:
other: not irritating in rabbits or humans
Interpretation of results:
not irritating
Conclusions:
The study was conducted prior to GLP implementation on the registered substance itself, no guideline followed as none was available in 1959 for rabbits resp. generally for humans, and there are some deficiencies in documentation and performance. Nevertheless, with the given properties of the test item, the methodological deficiencies are unlikely to have any influence on the results. The given information on test performance allows the conclusion that the method was scientifically reasonable performed. Furthermore, the study provides human data which can be considered as more relevant for human risk assessment than animal data. Also, the result (not irritating) is confirmed by the other available studies on skin and in vivo eye irritation, clearing any doubts regarding the reliability of the result. Hence, Phenol, 2,2'-methylenebis-(6-cyclohexyl-4-methyl) does not need to be regarded as dermal irritant.
Executive summary:

In a primary dermal irritation study three rabbits resp. six human volunteers were dermally exposed to either unchanged Phenol, 2,2'-methylenebis-(6-cyclohexyl-4-methyl) or the test item in oil or water for 24 hours to the inner side of the rabbit ear resp. human forearm. In this study, Phenol, 2,2'-methylenebis-(6-cyclohexyl-4-methyl) is not a dermal irritant.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Eye irritation

Link to relevant study records

Referenceopen allclose all

Endpoint:
eye irritation: in vitro / ex vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2015-10-22 - 2015-12-15
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Well-documented OECD GLP guideline study without deviations on the registered substance itself.
Reference:
Composition 0
Qualifier:
according to
Guideline:
OECD Guideline 437 (Bovine Corneal Opacity and Permeability Test Method for Identifying Ocular Corrosives and Severe Irritants)
Version / remarks:
OECD Guideline for Testing of Chemicals 437: Bovine Corneal Opacity and Permeability Test Method for Identifying i) Chemicals Inducing Serious Eye Damage and ii) Chemicals Not Requiring Classification for Eye Irritation or Serious Eye Damage (July, 2013).
Deviations:
no
GLP compliance:
yes (incl. certificate)
Remarks:
Hess. Ministerium für Umwelt, Klimaschutz, Landwirtschaft und Verbraucherschutz, Mainzer Straße 80, D65189 Wiesbaden
Test material information:
Composition 1
Species:
other: Freshly isolated bovine cornea (at least 9 month old donor cattle)
Strain:
not specified
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Source: Schlachthof Aschaffenburg, 63739 Aschaffenburg, Germany
- Age at study initiation: at least 9 month
Vehicle:
physiological saline
Controls:
yes, concurrent vehicle
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.75 ml (corresponds to approx. 150 mg)
- Concentration (if solution): 20% suspension

VEHICLE
- Amount(s) applied (volume or weight with unit): 0.75 ml suspension (corresponds to approx. 0.6 ml)
- Concentration (if solution): 0.9% (w/v) NaCl (saline)
Duration of treatment / exposure:
240 min
Observation period (in vivo):
no post-observation
Number of animals or in vitro replicates:
each 3 corneae for test group, positive and negative control
Details on study design:
REMOVAL OF TEST SUBSTANCE
- Washing (if done): rinsed with saline
- Time after start of exposure: 240 min

SCORING SYSTEM: IVIS = opacity value + (15 x OD490 value), In vitro Irritancy Score (according to OECD 437)
≤ 3 : No Category (according to GHS)
> 3; ≤ 55 : No prediction can be made
> 55 : Serious eye damage according to CLP/EPA/GHS (Cat 1)

TOOL USED TO ASSESS SCORE: opacitometer (OP_KiT opacitometer (Electro Design, 63-Riom, France)) / fluorescein + spectrophotometer (Versamax® Molecular Devices)
Irritation parameter:
in vitro irritation score
Remarks:
test item
Run / experiment:
mean, 240 min
Value:
5.31
Vehicle controls valid:
yes
Negative controls valid:
yes
Remarks:
yes, vehicle
Positive controls valid:
yes
Remarks on result:
other: test item
Irritation parameter:
in vitro irritation score
Remarks:
negative control
Run / experiment:
mean, 240 min
Value:
1.14
Vehicle controls valid:
not applicable
Negative controls valid:
not applicable
Positive controls valid:
yes
Remarks on result:
no indication of irritation
Remarks:
negative control, not categorized
Irritation parameter:
in vitro irritation score
Remarks:
positive control
Run / experiment:
mean, 240 min
Value:
127.14
Vehicle controls valid:
yes
Negative controls valid:
yes
Positive controls valid:
not applicable
Remarks on result:
positive indication of irritation
Remarks:
positive control, Category 1
Irritant / corrosive response data:
With the negative control (saline) neither an increase of opacity nor permeability of the corneae could be observed (mean IVIS = 1.14).
The positive control (10% (w/v) Benzalkonium chloride in saline) showed clear opacity of the corneae (mean IVIS = 127.14) corresponding to a classification as serious eye damaging (CLP/EPA/GHS (Cat 1)).
Relative to the negative control, the test item caused a slight increase of the corneal opacity. Permeability did not occur. The calculated mean IVIS was 5.31 (threshold for serious eye damage: IVIS ≥ 55). According to OECD 437 no prediction for the damage hazard of the test item to the eye can be made.
Interpretation of results:
other: not serious eye damaging (CLP/EPA/GHS (Cat 1) but a prediction for the damage hazard cannot be made (GHS)
Remarks:
Criteria used for interpretation of results: OECD GHS
Conclusions:
Testing was performed via a GLP OECD 437 guideline study on the registered substance itself. The present in vitro method is recommended in a tiered testing approach and the validity criteria are met, making the results sufficiently reliable to assess the corrosivity of 2,2'-Methylen-bis-(4-methyl-6-cyclohexylphenol) to the eye. The present in vitro method allows the identification of corrosive chemical substances and mixtures or of substances which do not require classification.
According to OECD Guideline no. 437 (Jul. 2013), a substance with an IVIS > 3 and ≤ 55 induces effects on the cornea, that cannot be classified in an UN GHS Category for eye damage.
Hence, no conclusion can be drawn whether the substance needs to be classified as eye irritant, for a clear distinction an in vivo study would be required based on the current state of the art.
According to the OECD 437guideline, “Test chemicals inducing serious eye damage are classified as UN GHS Category 1. Chemicals not classified for eye irritation or serious eye damage are defined as those that do not meet the requirements for classification as UN GHS Category 1 or 2 (2A or 2B), i.e. they are referred to as UN GHS No Category“.
Based on the tonnage-driven data requirements under REACH (Annex VIII), the present result “inconclusive” may not serve as a stand-alone result. As, according to the present results, no prediction can be made with regard to the classification of 2,2'-Methylen-bis-(4-methyl-6-cyclohexylphenol), but it is evident that the substance does not need to be classified as UN GHS Category 1, it will be classified in a precautionary approach as UN GHS Category 2, as no additional testing is intended due to animal welfare.
Executive summary:

This in vitro study according to OECD guideline 437 under GLP was performed to assess the corneal damage potential of 2,2'-Methylen-bis-(4-methyl-6-cyclohexylphenol) by means of the BCOP assay using fresh bovine corneae.

After a first opacity measurement of the fresh bovine corneae (t0), the 20% (w/v) suspension in saline (0.9% (w/v) NaCl in deionised water) of the test item, the positive, and the negative controls were applied to corneae fixed in an incubation chamber in horizontal position and incubated for 240 minutes at 32 ± 1 °C. The posterior chamber contained incubation medium. After the incubation phase the test item, the positive, and the negative controls were each rinsed from the corneae and opacity was measured again (t240).

After the opacity measurements permeability of the corneae was determined by measuring spectrophotometrically the transfer of sodium fluorescein after incubation in a horizontal position for 90 minutes at 32 ± 1 °C.

With the negative control (physiological saline) neither an increase of opacity nor permeability of the corneae could be observed.

The positive control (10% (w/v) Benzalkonium chloride in saline) showed distinct opacity of the corneae corresponding to a classification as serious eye damage (CLP/EPA/GHS (Cat 1)).

Relative to the negative control, 2,2'-Methylen-bis-(4-methyl-6-cyclohexylphenol) caused a slight increase of the corneal opacity, permeability effects were not observed compared with the values caused by the negative control. The calculated mean in vitro irritancy score was 5.31. According to OECD 437, the test item is not classified as serious eye damaging (CLP/EPA/GHS (Cat 1) but the test item’s hazard for eye damaging cannot be predicted. So, due to animal welfare, the substance will be classified as UN GHS Category 2.

Endpoint:
eye irritation: in vivo
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Conducted prior to GLP implementation similar to OECD 405 on the registered substance itself with some deficiencies in documentation and performance, i.e. evaluation criteria not defined.
Reference:
Composition 0
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Deviations:
not applicable
GLP compliance:
no
Remarks:
test conducted prior to GLP implementation
Test material information:
Composition 1
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Housing: individually
Vehicle:
unchanged (no vehicle)
Controls:
no
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 50 mg
Duration of treatment / exposure:
single instillation, no wash-out
Observation period (in vivo):
7 days
Number of animals or in vitro replicates:
2
Details on study design:
Single instillation into the conjuctival sac, no wash-out
Irritation parameter:
other: irritating properties
Basis:
mean
Remarks on result:
other: not irritating
Interpretation of results:
not irritating
Conclusions:
The study was conducted prior to GLP implementation similar to OECD 405 on the registered substance itself with some deficiencies in documentation and performance. Nevertheless, with the given properties of the test item, the methodological deficiencies are unlikely to have any influence on the results. The given information on test performance allows the conclusion that the method was scientifically reasonable performed. Hence, Phenol, 2,2'-methylenebis-(6-cyclohexyl-4-methyl) does not need to be regarded as eye irritant.
Executive summary:

In a primary eye irritation study similar to OECD 404, 50 mg of unchanged Phenol, 2,2'-methylenebis-(6-cyclohexyl-4-methyl) was instilled into the conjunctival sac of two New Zealand White rabbits, eyes were not washed out.  Animals then were observed for 7 days. 

No signs of irritation were denoted. In this study, Phenol, 2,2'-methylenebis-(6-cyclohexyl-4-methyl) is not an eye irritant.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Justification for classification or non-classification

Regulation 1272/2008 encourages to evaluate all available data relevant for irritation prior to conduct testing in order to classify a substance. The available in vivo studies conducted scientifically reasonable similar and prior to adoption of the OECD 404 guideline revealed that the substance does not need to be regarded as a skin irritant. They pose a solid database and allow the conclusion that also a study conducted acc. to the recent guideline would not have revealed a different result, and so, no classification as irritating to the skin is required.

The available in vivo study conducted similar to the recent OECD 405 revealed also that the substance does not need to be classified as irritating to the eye, but this result resp. the poorer details given was considered to need confirmation by an in vitro study. The conducted BCOP study acc. OECD TG 437 revealed an IVIS of 5.31, so no prediction can be made on the necessity for classification. For a clear distinction an in vivo study would be required based on the current state of the art. Based on the tonnage-driven data requirements under REACH (Annex VIII), the present result “inconclusive” may not serve as a stand-alone result. As, according to the present results, no prediction can be made with regard to the classification of 2,2'-Methylen-bis-(4-methyl-6-cyclohexylphenol), but it is evident that the substance does not need to be classified as UN GHS Category 1, it will be classified in a precautionary approach as UN GHS Category 2, as no additional testing is intended due to animal welfare.