Benzene-1,2,4-tricarboxylic acid 1,2-anhydride

Endpoint summary

Description of key information

Trimellitic anhydride was found to be a mild skin irritant in one study and was shown to be a severe eye irritant in two studies.  Findings in the acute inhalation toxicity studies also indicate that the substance is a respiratory irritant.

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

Study period:

1991-07-17 to 1991-07-31

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: The study methods are similar to the OECD guideline 404 and the study was conducted in accordance with the GLP principles (self-certified).

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

Deviations:

yes

Remarks:

: there is no information on the purity of the test material; the test material was not moistened however it was applied onto the pre-moistened test sites of the animals

GLP compliance:

yes

Remarks:

self-certified including GLP compliance statement

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

The animals were New Zealand White rabbits, 2-4 months of age, purchased from Johnson Rabbit Ranch. The rabbits arrived in three shipments with overall body weight ranges of 1.84-2.81 kg. The rabbits were held in quarantine for 3-6 weeks and examined to ensure their health and suitability as test subjects. Individuals were identified by metal ear tags and cage cards.
Each rabbit was provided with approximately 150 g of Purina Rabbit Chow HF #5326 daily. Reverse osmosis-purified water was supplied ad libitum. The rabbits were housed individually in stainless steel cages with Polyzorb cage liners placed below the mesh floor. The animal room average temperature and relative humidity were 22°C and 62%, respectively. Fluorescent lighting was provided on a 12 hour light/dark cycle.

Type of coverage:

semiocclusive

Preparation of test site:

shaved

Vehicle:

unchanged (no vehicle)

Controls:

no

Amount / concentration applied:

The test article was administered undiluted, individual doses were weighed onto aluminium foil to facilitate dosing. 0.5 g was applied uniformly to the pre-shaved moistened backs of the rabbits.

Duration of treatment / exposure:

4 hours

Observation period:

14 days

Number of animals:

Three males and three females

Details on study design:

Rabbits were selected at random for the study.
The test site was prepared by clipping the fur from an area of approximately 240 cm². Each rabbit's back was moistened with reverse-osmosis-purified water immediately prior to dosing. The test material was covered with a 2.5x2.5 cm adhesive dressing. The mid section of each rabbit was wrapped in a lint-free cloth towel and Elastoplast bandage. The dressings were removed four hours after application of the test material and the test sites were rinsed with light mineral oil and wiped with a paper towel to remove residual test material.
The rabbits were weighed immediately prior to dosing for calculation of doses. All animals were observed daily for signs of mortality and morbidity. Observations for signs of dermal irritation were made at 30-60 minutes after dressing removal, then at 24, 48 and 72 hours, 7 and 24 days later. The descriptive criteria and scores of Draize were used.
Rabbits were euthanised at study termination on day 15, necropsies were not performed.

Irritation parameter:

erythema score

Basis:

mean

Time point:

other: 24 hours

Score:

1

Reversibility:

fully reversible

Irritation parameter:

erythema score

Basis:

mean

Time point:

other: 48 hours

Score:

0.33

Reversibility:

fully reversible

Irritation parameter:

erythema score

Basis:

mean

Time point:

other: 72 hours

Score:

0.33

Reversibility:

fully reversible

Irritation parameter:

edema score

Basis:

mean

Time point:

other: 24 hours

Score:

1.17

Reversibility:

fully reversible

Irritation parameter:

edema score

Basis:

mean

Time point:

other: 48 hours

Score:

1

Reversibility:

fully reversible

Irritation parameter:

edema score

Basis:

mean

Time point:

other: 72 hours

Score:

0.83

Reversibility:

fully reversible

Irritation parameter:

erythema score

Basis:

mean

Time point:

other: 24-72 hours

Score:

0.39

Reversibility:

fully reversible

Irritation parameter:

edema score

Basis:

mean

Time point:

other: 24-72 hours

Score:

1

Reversibility:

fully reversible

Irritation parameter:

primary dermal irritation index (PDII)

Basis:

mean

Time point:

other: 24 and 72 hours

Score:

1.7

Reversibility:

fully reversible within: 14 days

Irritant / corrosive response data:

One animal displayed severe erythema 30-60 minutes after removal of dressing. At 24, 48 and 72 hour timepoint, pinpoint areas of eschar formation and scabbing were noted with a localised erythema score of 2. Superficial flaking was noted. No evidence of corrosivity was noted in any animal.

Other effects:

No deaths occurred during the course of the study. The weight of the rabbits on the day of dosing ranged from 2.84 to 3.19 kg.

Summary of dermal irritation scores in rabbits for TMA

Time	Oedema						Erythema
	952	953	954	955	956	957	952	953	954	955	956	957
1 hour	2	1	2	2	2	2	2	2	4	2	2	3
24 hour	1	1	1	1	0	2	1	1	1	1	1	2
48 hours	0	0	1	0	0	1	1	1	1	0	1	2
72 hours	0	0	1	0	0	1	1	0	1	0	1	2
Mean	0.33	0.33	1	0.33	0	1.33	1	0.67	1	0.33	1	2
Mean 24 -72 hours	0.39						1

Interpretation of results:

not irritating

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

Trimellitic anhydride is not considered to be an irritant to the skin according to Directive 67/548/EEC and Regulation (EC) No 1272/2008.

Executive summary:

The skin irritation potential of trimellitic anhydride was evaluated in 3 male and 3 female New Zealand White rabbits. 0.5 g of the test material was applied to the shaved and pre-moistened backs of the rabbits, and covered with a semi-occlusive dressing for 4 hours. The dressings were removed at the end of the exposure period and the test sites rinsed with light mineral oil. Each application site was examined for dermal irritation and corrosivity 30 -60 minutes, 24, 48 and 72 hours and 7 and 14 days following removal of the wrappings. No deaths occurred during the course of the study. The test material was slightly irritating. All animals had recovered by the end of the observation period. No signs of dermal corrosivity were seen in any rabbit. Trimellitic anhydride is not considered as a skin irritant. On this basis, trimellitic anhydride does not warrant any classification according to Directive 67/548/EEC and Regulation (EC) No 1272/2008.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (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:

1991-07-09 to 1991-07-10

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Proprietary non-guideline study, the study was not conducted according to GLP

Qualifier:

no guideline followed

Principles of method if other than guideline:

There is no information on test material, on animals (such as housing conditions, strain, age, weight, source etc). There is no indication as to whether or not the test article was removed after instillation. It was not indicated as to whether or not the test article was ground as a fine dust when placed in the conjunctival sac.

GLP compliance:

no

Species:

rabbit

Strain:

not specified

Details on test animals or tissues and environmental conditions:

No further information available.

Vehicle:

unchanged (no vehicle)

Controls:

yes, concurrent no treatment

Amount / concentration applied:

0.1 g

Duration of treatment / exposure:

Single administration of test substance to eye

Observation period (in vivo):

The eye of the rabbit was examined at 1 and 24 hours after application

Number of animals or in vitro replicates:

1 male rabbit

Details on study design:

0.1 g of test material was applied to the right eye of 1 male rabbit, the left eye remained untreated to serve as a control. In the interests of animal welfare, only 1 male rabbit was used as it was assumed that trimellitic anhydride would be a severe eye irritant.
The eye irritation was scored according to the Draize method

Irritation parameter:

cornea opacity score

Basis:

animal #1

Time point:

other: 1 hour

Score:

4

Max. score:

4

Reversibility:

not reversible

Irritation parameter:

iris score

Basis:

animal #1

Time point:

other: 1 hour

Score:

2

Max. score:

2

Reversibility:

not reversible

Irritation parameter:

conjunctivae score

Basis:

animal #1

Time point:

other: 1 hour

Score:

2

Max. score:

3

Reversibility:

not reversible

Irritation parameter:

chemosis score

Basis:

animal #1

Time point:

other: 1 hour

Score:

3

Max. score:

4

Reversibility:

not reversible

Irritation parameter:

cornea opacity score

Basis:

animal #1

Time point:

other: 24 hour

Score:

4

Max. score:

4

Reversibility:

not reversible

Irritation parameter:

iris score

Basis:

animal #1

Time point:

other: 24 hour

Score:

2

Max. score:

2

Reversibility:

not reversible

Irritation parameter:

conjunctivae score

Basis:

animal #1

Time point:

other: 24 hour

Score:

3

Max. score:

3

Reversibility:

not reversible

Irritation parameter:

chemosis score

Basis:

animal #1

Time point:

other: 24 hour

Score:

4

Max. score:

4

Reversibility:

not reversible

Irritant / corrosive response data:

Signs of ocular irritation were maximum at 24 hours after application and the study was terminated immediately thereafter.

Other effects:

No other effects reported.

Table 1: Summary of eye irritation scores in one male rabbit

Time	Cornea		Iris	Conjunctiva
	Density of opacity	Area of opacity		Erythema	Chemosis	Discharge
1 hour	4	4	2	2	3	2
24 hour	4	4	2	3	4	3

Interpretation of results:

highly irritating

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

Trimellitic acid (TMA) is considered a severe eye irritant. TMA is classified as irritating with the symbol Xi and is assigned the risk phrase R41 " Risk of serious damage to eyes" according to Regulation (EC) No 1272/2008. It is classified as Category 1 for serious eye damage with the signal word "Danger" and is assigned the hazard statement H318 "causes serious eye damage" according to Regulation (EC) No 1272/2008

Executive summary:

The study investigated the eye irritant effects of the test material in 1 male rabbit. 0.1 g of trimellitic anhydride was administered to the right eye of one male rabbit. The left eye served as the untreated control. The treated eye was examined at 1 and 24 hours after application of the test material. The control eye was used for comparison.

Signs of ocular irritation were maximum at 24 hours after application and the study was terminated immediately thereafter. On this basis, trimellitic anhydride is considered a severe eye irritant. TMA is classified as irritating with the symbol Xi and is assigned the risk phrase R41 " Risk of serious damage to eyes" according to 67/548/EEC. It is classified as Category 1 for serious eye damage with the signal word "Danger" and is assigned the hazard statement H318 "causes serious eye damage" according to Regulation (EC) No 1272/2008

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (irritating)

Additional information

Skin Irritation/Corrosion

Hatoum & Johnson (1991) applied trimellitic anhydride to the shaved, pre-moistened backs of three male and three female New Zealand albino rabbits. The dose level applied was 0.5 g. The duration of exposure was 4 hours. The irritation score ranged from 4.3/8.0 at 30 - 60 minutes following unwrapping of dressing and 0.0/8.0 at 14 days. The Primary Dermal Irritation Score for trimellitic anhydride was 1.7. No signs of dermal corrosivity were seen in any test animal during the study.

Eye Irritation

Hatoum & Johnson (1991) administered a dose of 0.1 g of trimellitic anhydride to the right eye of one rabbit. 24 hours following administration of the test substance, signs of ocular irritation were maximum, with a Draize score of 110.0/110.0. The study was terminated immediately following this observation and no additional animals were dosed. Trimellitic anhydride was considered to be a severe eye irritant.

In a previous study, Stachowiak & Mastri (1975) administered 100 mg of undiluted trimellitic anhydride to the eyes of 6 albino rabbits. Following a week-long observation period, the corrosivity score was 105.6 / 110.0, indicating the test substance is corrosive to rabbit eyes.

Justification for selection of skin irritation / corrosion endpoint:
Single study available

Justification for selection of eye irritation endpoint:
Best documented of the available studies

Effects on skin irritation/corrosion: slightly irritating

Effects on eye irritation: highly irritating

Effects on respiratory irritation: irritating

Justification for classification or non-classification

No classification is required for skin irritation based on the results of the dermal irritation study.

The two eye irritation studies show severe effects. Trimellitic anhydride is therefore classified according to DSD as irritating with the symbol Xi and is assigned the risk phrase R41 " Risk of serious damage to eyes". It is classified as Category 1 for serious eye damage with the signal word "Danger" and is assigned the hazard statement H318 "causes serious eye damage" according to Regulation (EC) No 1272/2008.

Findings in the acute inhalation toxicity studies also indicate that the substance is a respiratory irritant and should therefore be classified as such.