Registration Dossier

Administrative data

Description of key information

Skin: Irritating but not classified according to CLP (1272/2008/EEC) and 67/548/EEC
Eye: Highly irritating and classified as Seriously eye damaging according to CLP (1272/2008/EEC) and 67/548/EEC

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 from supporting substance (structural analogue or surrogate)
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
Justification for type of information:
1. HYPOTHESIS FOR THE ANALOGUE APPROACH
Structural similarities of the target substance to the source substances include the (bi)cyclic ring structure with a carboxylic acid anhydride group as the single reactive moiety. For the target substance the bicyclic ring structures contains a double bond at a specific location within the ring and also contains a substituted methyl group at a specific location on the ring structure whereas for the source substance neither the position of the double bond nor the methyl group are specified.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
The target substance is a specific isomer of the source substance, tetrahydromethylphthalic anhydride (MTHPA), in which neither the location of the double bond nor the methyl substitution are defined. MTHPA, has a stated composition comprising the target substance 1,2,3,6-tetrahydro-3-methylphthalic anhydride (CAS No. 5333-84-6, EC No. 226-247-6) together with tetrahydro-4-methylphthalic anhydride (CAS No. 34090-76-1, EC No. 251-823-9), 1,2,3,6-tetrahydro-4-methylphthalic anhydride (CAS No. 3425-89-6, CAS No. 222-323-8) and 3-cyclohexene-1,2-dicarboxylic anhydride, 4-methyl-
(CAS No. 19438-64-3).

3. ANALOGUE APPROACH JUSTIFICATION
The registered substance is a specific isomer of the tested substance. The mechanism of action for irritation is hydrolysis of the anhydride to the diacid with pH being the driver for local irritation and the substances are thus expected to exhibit the same characteristics. Both the registered substance and the tested substance share a common harmonised classifiication (Index No. 607-240-00-0).
Reason / purpose for cross-reference:
read-across source
Qualifier:
according to guideline
Guideline:
other: Code of federal regulations, Title 16, Section 1500.41 (USA)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Species:
rabbit
Strain:
not specified
Details on test animals or test system and environmental conditions:
no details given
Type of coverage:
occlusive
Preparation of test site:
not specified
Vehicle:
unchanged (no vehicle)
Controls:
no
Amount / concentration applied:
no details given
Duration of treatment / exposure:
24 h treatment, patch test, 0.5 ml of test substance
Observation period:
24 hours and 72 hours
Number of animals:
6
Details on study design:
TEST SITE
- Area of exposure: 1 inch x 1 inch
- Type of wrap if used: rubberized cloth
SCORING SYSTEM:
erythema and eschar formation
0: no erythema, 1: very slight erythema (barely perceptible), 2: Well-defined erythema, 3: moderate to severe erythema,
4: severe erythema (beet redness) to slight eschar formation (injuries in depth)
oedema formation
0: no oedema, 1: very slight oedema (barely perceptible), 2: slight oedema (edges of area well-defined by definite raising),
3: moderate oedema (raised approximately 1 millimeter),
4: severe oedema (raised more than 1 millimeter and extending beyond the area of exposure)
Irritation parameter:
erythema score
Basis:
animal #1
Time point:
24/48/72 h
Score:
2
Max. score:
4
Reversibility:
not fully reversible within: 72 h
Remarks on result:
other: intact skin
Remarks:
FHSA test method
Irritation parameter:
erythema score
Basis:
animal #2
Time point:
24/48/72 h
Score:
2
Max. score:
4
Reversibility:
not fully reversible within: 72 h
Remarks on result:
other: intact skin
Remarks:
FHSA test method
Irritation parameter:
erythema score
Basis:
animal #3
Time point:
24/48/72 h
Score:
2.5
Max. score:
4
Reversibility:
not fully reversible within: 72 h
Remarks on result:
other: intact skin
Remarks:
FHSA test method
Irritation parameter:
erythema score
Basis:
animal #4
Time point:
24/48/72 h
Score:
2
Max. score:
4
Reversibility:
not fully reversible within: 72 h
Remarks on result:
other: intact skin
Remarks:
FHSA test method
Irritation parameter:
erythema score
Basis:
animal #5
Time point:
24/48/72 h
Score:
2
Max. score:
4
Reversibility:
not fully reversible within: 72 h
Remarks on result:
other: intact skin
Remarks:
FHSA test method
Irritation parameter:
erythema score
Basis:
animal #6
Time point:
24/48/72 h
Score:
1.5
Max. score:
4
Reversibility:
not fully reversible within: 72 h
Remarks on result:
other: intact skin
Remarks:
FHSA test method
Irritation parameter:
edema score
Basis:
animal #1
Time point:
24/48/72 h
Score:
2
Max. score:
4
Reversibility:
not fully reversible within: 72 h
Remarks on result:
other: intact skin
Remarks:
FHSA test method
Irritation parameter:
edema score
Basis:
animal #2
Time point:
24/48/72 h
Score:
2
Max. score:
4
Reversibility:
not fully reversible within: 72 h
Remarks on result:
other: intact skin
Remarks:
FHSA test method
Irritation parameter:
edema score
Basis:
animal #3
Time point:
24/48/72 h
Score:
2.5
Max. score:
4
Reversibility:
not fully reversible within: 72 h
Remarks on result:
other: intact skin
Remarks:
FHSA test method
Irritation parameter:
edema score
Basis:
animal #4
Time point:
24/48/72 h
Score:
2
Max. score:
4
Reversibility:
not fully reversible within: 72 h
Remarks on result:
other: intact skin
Remarks:
FHSA test method
Irritation parameter:
edema score
Basis:
animal #5
Time point:
24/48/72 h
Score:
2
Max. score:
4
Reversibility:
not fully reversible within: 72 h
Remarks on result:
other: intact skin
Remarks:
FHSA test method
Irritation parameter:
edema score
Basis:
animal #6
Time point:
24/48/72 h
Score:
1
Max. score:
4
Reversibility:
fully reversible within: 72 h
Remarks on result:
other: intact skin
Remarks:
FHSA test method
Irritant / corrosive response data:
no details given
Other effects:
no details given

Rabbit no.

Reaction

24 hours

72 hours

LEFT

intact

RIGHT

abraded

LEFT

intact

RIGHT

abraded

1

Erythema

2

2

2

2

Oedema

2

2

2

2

2

Erythema

2

2

2

2

Oedema

2

2

2

2

3

Erythema

2

2

3

1

Oedema

2

2

3

1

4

Erythema

2

2

2

1

Oedema

2

2

2

1

5

Erythema

2

2

2

0

Oedema

2

2

2

0

6

Erythema

2

2

1

1

Oedema

2

2

0

0

Interpretation of results:
GHS criteria not met
Conclusions:
A mean erythema score (24/72 h) calculated over all 6 animals for intact skin of 2 and for abraded skin of 1.58 was observed. The oedema score was determined to be 1.92 for intact skin and 1.50 for abraded skin.
Taking the test conditions into account, in particular the 24 hour exposure period compared with 4 hours of current test methods (described in OECD TG 404, MTHPA has not to be classified and labelled as dermal irritant according to CLP (1272/2008/EEC), and according to 67/548/EEC (DSD).
Executive summary:

In a primary dermal irritation study, rabbits were dermally exposed to 0.5 ml of Methyl tetrahydrophthalic anhydride (MTHPA) for 24 hours. Irritation was assessed after 24 and 72 hours and reaction scored according to the Draize scale.

A mean erythema score (24/72 h) calculated over all 6 animals for intact skin of 2 and for abraded skin of 1.58 was observed. The oedema score was determined to be 1.92 for intact skin and 1.50 for abraded skin.

Taking the test conditions into account, in particular the 24 hour exposure period compared with 4 hours of current test methods (described in OECD TG 404), MTHPA has not to be classified and labelled as dermal irritant according to CLP (1272/2008/EEC), and according to 67/548/EEC (DSD).

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:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
1969
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Justification for type of information:
1. HYPOTHESIS FOR THE ANALOGUE APPROACH
Structural similarities of the target substance to the source substances include the (bi)cyclic ring structure with a carboxylic acid anhydride group as the single reactive moiety. For the target substance the bicyclic ring structures contains a double bond at a specific location within the ring and also contains a substituted methyl group at a specific location on the ring structure whereas for the source substance neither the position of the double bond nor the methyl group are specified.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
The target substance is a specific isomer of the source substance, tetrahydromethylphthalic anhydride (MTHPA), in which neither the location of the double bond nor the methyl substitution are defined. MTHPA, has a stated composition comprising the target substance 1,2,3,6-tetrahydro-3-methylphthalic anhydride (CAS No. 5333-84-6, EC No. 226-247-6) together with tetrahydro-4-methylphthalic anhydride (CAS No. 34090-76-1, EC No. 251-823-9), 1,2,3,6-tetrahydro-4-methylphthalic anhydride (CAS No. 3425-89-6, CAS No. 222-323-8) and 3-cyclohexene-1,2-dicarboxylic anhydride, 4-methyl-
(CAS No. 19438-64-3).

3. ANALOGUE APPROACH JUSTIFICATION
The registered substance is a specific isomer of the tested substance. The mechanism of action for irritation is hydrolysis of the anhydride to the diacid with pH being the driver for local irritation and the substances are thus expected to exhibit the same characteristics. Both the registered substance and the tested substance share a common harmonised classifiication (Index No. 607-240-00-0).
Reason / purpose for cross-reference:
read-across source
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Principles of method if other than guideline:
No information on guideline available.
GLP compliance:
no
Species:
rabbit
Strain:
Belgian Hare
Details on test animals or tissues and environmental conditions:
no details given
Vehicle:
unchanged (no vehicle)
Controls:
other: one eye for test other eye for vehicle control for each animal.
Amount / concentration applied:
0.1ml of the liquid was applied (undiluted and 10 times diluted with olive oil) to one eye for each animal.
The other eye was treated with 0.1 ml olive oil and served as reference.
Duration of treatment / exposure:
no details given
Observation period (in vivo):
10 days
Number of animals or in vitro replicates:
Two rabbits (undiluted and ten times diluted solution)
Details on study design:
not rinsed
Irritation parameter:
cornea opacity score
Basis:
animal #1
Time point:
24/48/72 h
Score:
3
Max. score:
4
Reversibility:
not fully reversible within: 10 days
Remarks on result:
other: Score is in accordance with OECD guideline 405.
Irritation parameter:
iris score
Basis:
animal #1
Time point:
24/48/72 h
Score:
1
Max. score:
2
Reversibility:
not fully reversible within: 10 days
Remarks on result:
other: Score is in accordance with OECD guideline 405.
Irritation parameter:
conjunctivae score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0
Max. score:
3
Remarks on result:
other: Score is in accordance with OECD guideline 405.
Irritation parameter:
chemosis score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0
Max. score:
4
Remarks on result:
other: Score is in accordance with OECD guideline 405.
Irritation parameter:
chemosis score
Basis:
animal #1
Time point:
24/48/72 h
Score:
1
Max. score:
4
Reversibility:
not fully reversible within: 10 days
Remarks on result:
other: Score is in accordance with OECD guideline 405.
Irritant / corrosive response data:
In case of 0.1ml of MTHPA, eye was closed immediately. Haze was observed after 1 minute. After 24 hours, bloodshot were observed. Blindness
or bleeding were not observed. After 10 days, the eye was able to be half-opened. Then reaction of light was recovered in normal condition.
In case of 0.1ml MTHPA diluted 1:10 in olive oil, eye was closed after 1 minutes. After 24 hours, eye was only half-opened and bloodshot were also observed. After 7-10 days, it recovered in normal condition.
Other effects:
no details given
Interpretation of results:
Category 1 (irreversible effects on the eye) based on GHS criteria
Conclusions:
Tetrahydromethylphthalic anhydride (MTHPA) is seriously eye damaging applied to the rabbits eye.
Executive summary:

In a primary eye irritation study, 0.1 ml of methyl tetrahydrophthalic anhydride (MTHPA) was instilled into the conjunctival sac of Belgian Hare. Animals then were observed for 10 days. In case of 0.1 mL of MTHPA, eye was closed immediately. Haze was observed after 1 minute. After 24 hours, iris injection and circumcorneal injection were observed. Blindness or bleeding were not observed. After 10 days, the eye was able to be half-opened. Eyes recovered to normal condition within 14 days. In case of 0.1 mL MTHPA diluted 1:10 in olive oil, eye was closed after 1 minutes. After 24 hours, the eye was only half-opened and bloodshot. After 7-10 days, it recovered in normal condition. In conclusion, MTHPA was classified seriously eye damaging.

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

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Various studies have been undertaken on tetrahydromethylphthalic anhydride (MTHPA). This is a structural analogue of 3 -MTHPA D4 in which the methyl substitution is not defined or fixed in a specific position on the carbon cyclic structure, as opposed to 3 -MTHPA D4 where the methyl substitution is fixed at the 3C position. 3 -MTHPA D4 is regarded as a specific isomer of MTHPA.

Skin:

In a primary dermal irritation study (key study, Liggett, 1980), rabbits were dermally exposed to 0.5 ml of a structural analogue of the substance, methyl tetrahydrophthalic anhydride (MTHPA), for 72 hours. A mean erythema score (24/72 h) calculated over all 6 animals for intact skin of 2 and for abraded skin of 1.58 was observed. The oedema score was determined to be 1.92 for intact skin and 1.50 for abraded skin. Taking the test conditions into account, in particular the 24 hour exposure period compared with 4 hours of current test methods (described in OECD TG 404), MTHPA has not to be classified and labelled as a dermal irritant according to CLP (1272/2008/EEC), and according to 67/548/EEC (DSD). In a primary dermal irritation report (supporting study, Smyth, 1969), rabbits were dermally exposed to Methyl tetrahydrophthalic anhydride (MTHPA) on the belly. In this report, MTHPA is not a dermal irritant. The irritant score of MTHPA is 1 of 6, which means minimal irritating to the skin.

 

Eye:

In a primary eye irritation study (key study, Irie, 1969), 0.1 ml of a structural analogue of the substance, methyl tetrahydrophthalic anhydride (MTHPA), was instilled into the conjunctival sac of Belgian Hare. Animals then were observed for 10 days. The response to treatment requires MTHPA to be classified as seriously eye damaging according to CLP (1272/2008/EC).

In a supporting primary eye irritation study (Smyth, 1969), MTHPA was instilled into the conjunctival sac of rabbits eyes. An irritation score of 9 (maximum score 10) was determined. Thus, MTHPA was considered to be seriously eye damaging.


Effects on eye irritation: highly irritating

Effect level: empty Endpoint conclusion: Adverse effect observed

Justification for classification or non-classification

Skin:

Based on the results of the presented in the skin irritation studies the test substance was not classified and labelled according to Regulation 1272/2008/EC (CLP) nand Directive 67/548/EEC (DSD).

Eyes:

Based on the results of the available eye irritation studies, tetrahydromethylphthalic anhydride (MTHPA) was classified as eye damaging category 1 with labelling of H318: causes serious eye damage according to CLP (1272/2008/EC) and as seriously eye damaging (Xi, R41) according to 67/548/EEC.