Tetrahydromethylphthalic anhydride

Endpoint summary

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:

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:

24/48/72 h

Score:

3.5

Max. score:

8

Reversibility:

no data

Remarks on result:

other: time points: 24/72 h

Irritation parameter:

erythema score

Basis:

mean

Remarks:

of 6 animals

Time point:

24/48/72 h

Score:

2

Max. score:

4

Reversibility:

no data

Remarks on result:

other: time points: 24/72 h (intact skin)

Irritation parameter:

erythema score

Basis:

mean

Remarks:

of 6 animals

Time point:

24/48/72 h

Score:

1.58

Max. score:

4

Reversibility:

no data

Remarks on result:

other: time points: 24/72 h (abraded skin)

Irritation parameter:

edema score

Basis:

mean

Remarks:

of 6 animals

Time point:

24/48/72 h

Score:

1.92

Max. score:

4

Reversibility:

no data

Remarks on result:

other: time points: 24/72 h (intact skin)

Irritation parameter:

edema score

Basis:

mean

Remarks:

of 6 animals

Time point:

24/48/72 h

Score:

1.5

Max. score:

4

Reversibility:

no data

Remarks on result:

other: time points: 24/72 h (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:

GHS criteria not met

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:

guideline study with acceptable restrictions

Remarks:

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:

cornea opacity score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

not specified

Remarks on result:

not measured/tested

Irritation parameter:

iris score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

2

Reversibility:

not specified

Remarks on result:

not measured/tested

Irritation parameter:

conjunctivae score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

3

Reversibility:

not specified

Remarks on result:

not measured/tested

Irritation parameter:

chemosis score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

not specified

Remarks on result:

not measured/tested

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:

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:

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:

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:

10 d

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 0.1 mL of MTHPA, eye was closed immediately. Haze was observed after 1 minute. After 24 hours, bloodshot was 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, the 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, 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 as 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

Classification, Labelling, and Packaging Regulation (EC) No 1272/2008
The available experimental test data are reliable and suitable for classification purposes under Regulation (EC) No 1272/2008.

 

Skin: Based on available data on skin irritation, the test item is not classified according to Regulation (EC) No 1272/2008 (CLP), as amended for the eighteenth time in Regulation (EU) 2022/692.

 

Eye: Based on available data on eye irritation, the test item is  classified as eye irritation category 1 according to Regulation (EC) No 1272/2008 (CLP), as amended for the eighteenth time in Regulation (EU) 2022/692.