Registration Dossier

Administrative data

Description of key information

Skin:
Tetrahydromethylphthalic anhydride (MTHPA) is not a dermal irritant according to CLP (1272/2008/EEC), but has to be classified R38 according to 67/548/EEC (erythema score 2.00, oedema score 1.92).
Eye:
MTHPA is seriously eye damaging when 0.1 ml are applied to the rabbits eye.

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:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP and guideline study
Reason / purpose for cross-reference:
reference to same study
Reason / purpose for cross-reference:
reference to other study
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 substances
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:
primary dermal irritation index (PDII)
Basis:
mean
Remarks:
of 6 animals
Time point:
other: 24/72 h
Score:
3.5
Max. score:
8
Reversibility:
no data
Irritation parameter:
erythema score
Basis:
mean
Remarks:
of 6 animals
Time point:
other: 24/72 h
Score:
2
Max. score:
4
Reversibility:
no data
Remarks on result:
other: intact skin
Irritation parameter:
erythema score
Basis:
mean
Remarks:
of 6 animals
Time point:
other: 24/72 h
Score:
1.58
Max. score:
4
Reversibility:
no data
Remarks on result:
other: abraded skin
Irritation parameter:
edema score
Basis:
mean
Remarks:
of 6 animals
Time point:
other: 24/72 h
Score:
1.92
Max. score:
4
Reversibility:
no data
Remarks on result:
other: intact skin
Irritation parameter:
edema score
Basis:
mean
Remarks:
of 6 animals
Time point:
other: 24/72 h
Score:
1.5
Max. score:
4
Reversibility:
no data
Remarks on result:
other: abraded skin
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:
not irritating
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Tetrahydromethylphthalic anhydride (MTHPA) is based on the available information (erythema score 2.00, oedema score 1.92) not a dermal irritant according to CLP (1272/2008/EEC).
In addition, the substance is also not classified according to ANNEX VI table 3.1 (GHS) and table 3.2 (DSD) of Regulation (EC) No 1272/2008 with regard to skin irritation.
The conditions of the available study are more stringed, in particular the 24 hour exposure period compared with 4 hours of current test methods (described in OECD TG 404), and are thus regarded as worst case scenario. In conclusion the substance is not classified skin irritating based on DSD and CLP.
Executive summary:

In a primary dermal irritation study, rabbits were dermally exposed to 0.5 ml of Methyl tetrahydrophthalic anhydride (MTHPA) for 72 hours to 1 inch x 1 inch of body surface area. Then animals were observed for 3 days. Irritation was scored by the method of patch test, code of Federal regulations, Title 16, Section 1500. 41 (Draize scaling).

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:
experimental study
Adequacy of study:
key study
Study period:
1969
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: This study is very old. Observation is poor. Number of animals is only two. But result is clear, and allows a final evaluation.
Reason / purpose for cross-reference:
reference to other study
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 poured 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:
overall irritation score
Basis:
mean
Time point:
other: 1 min
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:
cornea opacity score
Basis:
mean
Time point:
other: 1 min
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:
mean
Time point:
other: 24 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:
mean
Time point:
other: 24 H
Score:
0
Max. score:
3
Remarks on result:
other: Score is in accordance with OECD guideline 405.
Irritation parameter:
chemosis score
Basis:
mean
Time point:
other: 24 H
Score:
0
Max. score:
4
Remarks on result:
other: Score is in accordance with OECD guideline 405.
Irritation parameter:
chemosis score
Basis:
mean
Time point:
other: 10 days
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:
highly irritating
Remarks:
Migrated information Criteria used for interpretation of results: EU
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, bloodshots on iris 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, eye was only half-opened and bloodshot on iris were also observed. After 7-10 days, it recovered in normal condition. In conclusion, MTHPA was classified seriously eye damaging.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Respiratory irritation

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

Additional information

Skin:

In a primary dermal irritation study (key study, Liggett, 1980), rabbits were dermally exposed to 0.5 ml of Methyl tetrahydrophthalic anhydride (MTHPA) for 72 hours to 1 inch x 1 inch of body surface area. Then animals were observed for 3 days. Irritation was scored by the method of patch test, code of Federal regulations, Title 16, Section 1500. 41 (Draize scaling).

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.

In conclusion, MTHPA is not a dermal irritant according to CLP (1272/2008/EEC).

In a primary dermal irritation report (supporting study, Smyth, 1969), rabbits were dermally exposed to Methyl tetrahydrophthalic anhydride (MTHPA) on 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), 0.01 ml of Methyl tetrahydrophthalic anhydride (MTHPA) were 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, 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 0.1 mL 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.

In conclusion, MTHPA is classified 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.


Justification for selection of skin irritation / corrosion endpoint:
GLP and guideline study

Justification for selection of eye irritation endpoint:
This study is very old. Observation is poor. Number of animals is only two. But result is clear, and allows a final evaluation.

Effects on eye irritation: highly irritating

Justification for classification or non-classification

Skin:

Based on the results of the presented in the skin irritation studies the test substance is not classified according to Annex VI of CLP/GHS (1272/2008/EC). In accordance with the CLP regulation (1272/2008/EEC) tetrahydromethylphthalic anhydride (MTHPA) is also not classified and labelled regarding skin irritation laying down the provisions given in 67/548/EEC (DSD).

Eyes:

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