Registration Dossier

Administrative data

Description of key information

not irritant after 24 h occlusive conditions (IBR, 1983, according to Appraisal of the Safety of Chemicals in foods, drugs  and cosmetics, FDA Draize (1959), non-GLP)

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
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
test procedure in accordance with national standard methods with acceptable restrictions
Qualifier:
according to
Guideline:
other: according to Appraisal of the Safety of Chemicals in foods, drugs and cosmetics, FDA Draize (1959)
Principles of method if other than guideline:
Method: according to Appraisal of the Safety of Chemicals in foods, drugs and cosmetics, FDA Draize (1959)
Information about the method, described in the study report ( Draize test: skin irritation/corrosion), is given in the free text field "methods and materials".
GLP compliance:
no
Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: no data
- Age at study initiation: no data
- Weight at study initiation: 2.4 to 2.6 kg
- Housing: single housing
- Diet: ad libitum, standard diaet
- Water: ad libitum
- Acclimation period: no data


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 ± 1 °C
- Humidity (%): 45 - 55 %
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12 hrs dark / 12 hrs light
Type of coverage:
occlusive
Preparation of test site:
shaved
Vehicle:
unchanged (no vehicle)
Controls:
other: Untreated skin areas of the test animals serve as the control (shaved, scarified).
Amount / concentration applied:
undiluted 0.5 mL
Duration of treatment / exposure:
24 hour(s)
Observation period:
24h and 72h post application
Number of animals:
6
Details on study design:
TEST SITE
- Area of exposure: 2.5 x 2.5 cm
- % coverage: 100% the whole animal was covered with a gummed bandage
- Type of wrap if used: gummed bandage to wrap up the body of the test animal.
REMOVAL OF TEST SUBSTANCE
- Removal of the test substance by removal of the adhesive tape and the bandage, no wash off

SCORING SYSTEM:
Erythema and Eschar Formation
No erythema: 0
Very slight erythema (barely perceptible): 1
Well defined erythema: 2
Moderate to severe erythema: 3
Very severe erythema (beef redness) to eschar formation preventing grading of erythema: 4
Maximum possible: 4

Edema Formation
No edema: 0
Very slight edema (barely perceptible) : 1
Slight edema (edges of area well defined by definite raising):2
Moderate edema (raised approximately 1mm): 3
Severe edema (raised more than 1mm and extending beyond area of exposure):4
Maximum possible: 4
Irritation parameter:
erythema score
Basis:
mean
Time point:
other: 24 and 72 hours
Score:
0.08
Max. score:
4
Reversibility:
no data
Remarks on result:
other: No data in respect to reversibilty for times after exposure > 72h. Only data of shaved skin have been used, data of shaved and scarified skin have not been used.
Irritation parameter:
edema score
Basis:
mean
Time point:
other: 24 and 72 hours
Score:
0
Max. score:
4
Reversibility:
other: not relevant in absence of effects
Irritation parameter:
erythema score
Basis:
animal #1
Time point:
other: 24 and 72 h
Score:
0
Max. score:
4
Reversibility:
other: not relevant in absence of effects
Irritation parameter:
erythema score
Basis:
animal #2
Time point:
other: 24 and 72 h
Score:
0.5
Max. score:
4
Reversibility:
fully reversible within: 72 h
Irritation parameter:
erythema score
Basis:
animal #3
Time point:
other: 24 and 72 h
Score:
0
Max. score:
4
Reversibility:
other: not relevant in absence of effects
Irritation parameter:
erythema score
Basis:
animal #4
Time point:
other: 24 and 72 h
Score:
0
Max. score:
4
Reversibility:
other: not relevant in absence of effects
Irritation parameter:
erythema score
Basis:
animal #5
Time point:
other: 24 and 72 h
Score:
0
Max. score:
4
Reversibility:
other: not relevant in absence of effects
Irritation parameter:
erythema score
Basis:
animal #6
Time point:
other: 24 and 72 h
Score:
0
Max. score:
4
Reversibility:
other: not relevant in absence of effects
Irritant / corrosive response data:
The test substance caused exactly the same effects when applied to the scarified skin.

Overall primary irritation score (PDII): 0.8 of 8 scores FDA (Draize), 1959,  

re-evaluated according to OECD 404

Reevaluation of the test results according to OECD404/GHS: only records for the shaved skin (not scarified) were considered  Erythema/ 24h     Erythema/72h  Oedema/24h  Oedema/72h
 animal 1  0  0  0  0
 animal 2  1  0  0  0
 animal 3  0  0  0  0
 animal 4  0  0  0  0
 animal 5  0  0  0  0
 animal 6  0  0  0  
 average (single scores: animal 1-6)  0,17 0,0  0,0  0,0
 Primary irritation index I = Mean erythema score  (Erythema; 24h, 72h);  out of 4 scores  0,08  Primary irritation index II =  Mean oedema score (Oedema; 24h, 72h);   out of 4 scores  0,0  0,0
 Overall average PDII out of 8 scores; For evaluation according to GHS classification system:  0,08    

Remarks concerning the study result: The study for acute skin irritation/  
corrosion was performed before OECD 404 came into force. For this reason the 
test values were reevaluated according to OECD criteria and test scores 
(erythema, oedema) obtained for the scarified skin were regarded as irrelevant.

  
Classification criteria according to the different classification systems:

EU-GHS:

Category 1: Corrosive subcategories

Corrosive in >= 1 of 3 animals
(applies to authorities not using subcategories): Corrosive
(only applies to some authorities)

Subcategory    Exposure                       Observation
------------------------------------------------------------
1A             <= 3 minutes                   <= 1 hour
1B             > 3 minutes to <= 1 hour       <= 14 days
1C             > 1 hour to <= 4 hours         <= 14 days
------------------------------------------------------------

A: Single harmonized corrosion category, using the results of animal testing.
A: Corrosive is a test substance that produces destruction of skin tissue, namely, 
visible necrosis through the epidermis and into the dermis, in at least 1 of 3 
tested animals after exposure up to 4 hours duration. Corrosive reactions are 
typified by ulcers, bleeding, bloody scrabs and, by the end of observation at 14 
days, by discoloration due to bleaching of the skin, complete areas of alopecia 
and scars. Histopathologic determinations should be consided evaluate questionable 
lesions.

Substances and/or mixtures are considered corrosive (Skin categorry 1) if it has
a pH of 2 or less or a pH of 11.5 or greater. If consideration of alkali/acid 
reserve suggests the substance or prepatration may not be corrosive despite the 
low or high pH value, then further testing needs to be carried out to confirm 
this, preferably by use of an appropriate validated in vitro test.

Category 2:

(1) Mean value of >= 2.3 to < 4.0 for erythem/eschar or for oedema in at least 2 
    of 3 animals from gradings at 24, 48 and 72 hours after patch removal or, if 
    reactions are delayed, from grades on 3 consecutive days after the onset of 
    skin reactions, or
(2) Inflammation that persits to the end of the observation period normally 14
    days in at least 2 animals, particularly taking into account alopecia 
    (limited area), hyperkeratosis, hyperplasia, and scalling, or
(3) In some cases where there is pronounced variability of response amoung 
    animals, with very definite positive effects related to chemical exposure
    in a single animal but less than the criteria above.

UN-GHS (additional category 3):

Category 3: Mild irritant (Applies to only some authorities for e.g. UN-GHS)

Mean value of >= 1.5 to < 2.3 for erythem/eschar or for oedema from gradings
in at least 2 of 3 tested animals from grades at 24, 48 and 72 hours or, if
reactions are delayed, from grades on 3 consecutive days after the onset of
skin reactions (when not included in the irritant category above).

According to the results of this dermal irritation study 1,6-Hexanedioldimethacrylate
has to be classified as follows:

According to GefStoffV:(non-irritant, but 24 hour exposition, no wash off the test substance)
According to EU-GHS (CLP): Hazard category: None (effects < 2.3 both erythem 
                        and oedema)
According to UN-GHS: Hazard category: None (effects < 1.5 both erythem and oedema, 24 hour exposition, no wash off the test substance)











   
    
    
    
    
    
    
    
    
    
    
    
    
    
    
    

ems:

Classification criteria according to the different classification systems:

   

Classification criteria according to the different classification systems:

Classification criteria according to the different classification systems:

 

EU-GHS:

Category 1: Corrosive subcategories

  

Corrosive in >= 1 of 3 animals

(applies to authorities not using subcategories): Corrosive

(only applies to some authorities)

Subcat. Exposure                          Observation

1A    <= 3 minutes                      <= 1 hour

1B     > 3 minutes -- <= 1 hour  <= 14 days

1C     > 1 hour -- <= 4 hours      <= 14 days

A single harmonized corrosion category is provided in Table 3.2.1, using the results of animal

testing. A corrosive is a test material that produces destruction of skin tissue, namely, visible necrosis

through the epidermis and into the dermis, in at least 1 of 3 tested animals after exposure up to a 4 hour

duration. Corrosive reactions are typified by ulcers, bleeding, bloody scabs and, by the end of observation at

14 days, by discoloration due to blanching of the skin, complete areas of alopecia and scars. Histopathology

should be considered to discern questionable lesions.

 

A mixture is considered corrosive (Skin Category 1) if it has a pH of 2 or less or a pH of 11.5 or greater. If

consideration of alkali/acid reserve suggests the substance or preparation may not be corrosive despite the low or high pH value, then further testing needs to be carried out to confirm this, preferably by use of an appropriate validated in vitro test.

Interpretation of results:
GHS criteria not met
Conclusions:
1,6-Hexanedioldimethacrylate was not irritating in a primary skin irritation study in rabbits (24-hour occlusive application, no wash of the test substance). The slight erythema formation after 24 hours in one animal was reversible after 72 hours observation. Only data of shaved skin have been used, data of shaved and scarified skin have not been used. According to the results of this dermal irritation study 1,6-Hexanedioldimethacrylate has to be classified as follows:
According to EU-GHS (CLP): Hazard category: None (effects < 2.3 both erythem and oedema)
According to UN-GHS: Hazard category: None (effects < 1.5, 24 hour application, no wash off the test substance) not irritating
Executive summary:

In a primary dermal irritation study New Zealand White rabbits were dermally exposed (intact and scarified skin) to 0.5 mL undiluted 1,6 -Hexanedioldimethacrylate for 24 hours. Animals then were observed for 3 days. Irritation was scored by the method of Draize et al, 1959. The mean erythema score (average value of  the single scores (animals 1-6; erythema; intact skin, 24h and 72h)  was determined to be 0.08 out of 4 and the mean edema score was 0.0 out of 4.   

Remarks concerning the study result: The study for acute skin irritation/corrosion was performed before OECD 404  came into force. For this reason the test values were reevaluated according to OECD criteria and test scores  (erythema, oedema) obtained for the scarified skin were regarded as irrelevant. According to the results of this dermal irritation study 1,6 -Hexanedioldimethacrylate has to be classified as follows: According to GefStoffV: non-irritant, but 24 hour application, no wash off the test substance) According to EU-GHS (CLP): Hazard category: None (effects < 2.3 both erythem and oedema) According to UN-GHS: Hazard category: None ( effects < 1.5 both erythem and oedema, 24 hour application, no wash off the test substance) not irritating NOTE: Any of data in this dataset are disseminated by the European Union on a right-to-know basis and this is not a publication in the same sense as a book or an article in a journal. The right of ownership in any part of this information is reserved by the data owner(s). The use of this information for any other, e.g. commercial purpose is strictly reserved to the data owners and those persons or legal entities having paid the respective access fee for the intended purpose.

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

Eye irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Skin irritation

In a primary dermal irritation study, New Zealand White rabbits were dermally exposed to 0.5 mL undiluted 1,6 -Hexanedioldimethacrylate for 24 hours. Animals then were observed for 3 days. Irritation was initially scored by the method of Draize et al, 1959 and reevaluated according to OECD 404.The mean erythema score (average value of  the single scores (animals 1-6; erythema; intact skin, 24h and 72h)  was determined to be 0.08 out of 4 and the mean edema score was 0.0 out of 4. 

Eye irritation

No study is available for

1,6 -Hexanedioldimethacrylate. However, in the Category of multifunctional methacrylates, all tested category members showed a consistent scheme of maximum slight effects below GHS classification tresholds. Details on the category assessment according to the RAAF guidance (ECHA 2017) are discussed in the attached category document. Thus, a maximum slight eye irritation is assumed for

1,6 -Hexanedioldimethacrylate.

For formal reasons, a valid eye irritation study is attached from the category member 1,4 Butandiol dimethacrylate (1,4 -BDDMA). Here,

0.1 mL of 1,4-BDDMA was instilled into the conjunctival sac of the left eye of 6 New Zealand White rabbits without removing the test substance in a primary eye irritation study similar toUS FHSA Federal regulation: 16 CFR 1500.42 (similar to OECD guideline 405). Animals then were observed for 7 days. Irritation was scored by the method of Draize.

Transient conjunctival irritating effects were seen 1, 2 and 8 hours after application. All effects were completely reversible at the 24 h scoring. From 24 h onward all scores were zero.

In this study, 1,4-BDDMA is not an eye irritant.


Justification for classification or non-classification

Based on results of a valid skin irritation study,

1,6 -Hexanedioldimethacrylate is classified as not a skin irritant according to Annex I of CLP/EU-GHS (1272/2008/EC) and UN-GHS.

Based on the consistent results of a valid skin irritation studies with substances of the mutlifunctional category,

1,6 -Hexanedioldimethacrylate is classified as not an eye irritant according toAnnex I of CLP/EU-GHS (1272/2008/EC) and UN-GHS.