Reaction mass of bis(oxiran-2-ylmethyl) terephthalate and tris(oxiran-2-ylmethyl) benzene-1,2,4-tricarboxylate

Endpoint summary

Description of key information

 A primary skin irritation study was performed on the main coumpound, bis(2,3-epoxypropyl)terephtalate  in rabbit and the substance was considered to be a slight skin irritant in the rabbit. An eye irritation test  was also performed in rabbits and the substance was considered to be corrosive to eye. No data are available for respiratory irritation.

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:

supporting study

Study period:

1976

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Non-GLP study that meets accepted scientific standard, well document and acceptable for assessment.

Qualifier:

no guideline followed

Principles of method if other than guideline:

The test was prformed according to the method given in the "Hazardous Substances Regulations" under the U.S. Federal Hazardous Labelling Act Sect. 191.11 (February 1965).

GLP compliance:

no

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

Healthy New Zealand White rabbits aged 12 - 16 weeks with average body weights of 2.93 kgs for the males and 2.80 kgs for the females, bred on the premises and maintained under semi-barrier system. The animals were acclimatized in the test area for one week prior to the start of the trial.
Experimental room was maintained at a temperature of 20C and a relative humidity of 50-70%. Light cycle of 10 Hours / 14 hours per day. A commercial irradiated diet was fed ad lib. and filtered sterile water was available at all times.

Type of coverage:

occlusive

Preparation of test site:

other: one site shaved and one site abraded

Vehicle:

other: 2% aqueous solution of carboxymethyl cellulose

Controls:

no

Amount / concentration applied:

1.0 mL of of the test substance in suspension at a concentration of 0.5g/mL was applied

Duration of treatment / exposure:

24 hours

Observation period:

72 hours

Number of animals:

3 males and 3 females

Details on study design:

TEST SITE
- Area of exposure: 2.5 cm square gau
- Type of wrap if used: The gauze was covered with aluminium foil secured with "seek" adhesive tape (Smith and Nephew, Hull, England). The test site was then covered by a 6" wide "coban" self adhesive bandage (3M Company, London).

REMOVAL OF TEST SUBSTANCE
- Washing (if done): No washing done
- Time after start of exposure: 24 hours

SCORING SYSTEM:
Erythema and eschar formation:
No erythema ......................................................................... .Grade 0
Slight eryhtema (barely perceptible) ..................................Grade 1
Well defined erythema............................................................Grade 2
Moderate to severe.................................................................Grade 3
Severe erythema (beet red) to slight eschar formation... Grade 4

Oedema formation:
No oedema.....................................................................................................................................Grade 0
Very slight oedema (barely perceptible)....................................................................................Grade 1
Slight oedema (edges or area well defined by definite raising)..............................................Grade 2
Moderate oedema (raised approximately 1 mm)......................................................................Grade 3
Severe oedema (raised more than 1mm and extending beyond the area of exposure).....Grade 4

Irritation parameter:

overall irritation score

Basis:

mean

Time point:

24/48 h

Score:

0.7

Max. score:

8

Reversibility:

fully reversible within: 72 hours

Remarks on result:

other: intact and abraded sites were taken into consideration

Irritation parameter:

erythema score

Basis:

animal: 3/6

Time point:

24 h

Remarks on result:

positive indication of irritation

Irritation parameter:

edema score

Basis:

animal: 2/6 intact and 5/6 abraded

Time point:

24 h

Remarks on result:

positive indication of irritation

Irritation parameter:

overall irritation score

Basis:

mean

Time point:

72 h

Reversibility:

fully reversible

Irritant / corrosive response data:

Slight erythema was seen on 3/6 intact and 6/6 abraded sites and very slight to slight oedema on 2/6 intact and 5/6 abraded sites.

Interpretation of results:

slightly irritating

Remarks:

Migrated information Criteria used for interpretation of results: expert judgment

Conclusions:

The substance is a slight primary skin irritant in the albino rabbit.

Executive summary:

The primary skin irritation potential of the substance was investigated by occlusive application to intact and abraded skin of six New Zealand White rabbits. The substance was applied at a concentration of 0.5 g/mL and a volume of 1.0 mL per application site. The duration of treatment was 24 hours. The scoring of the reaction 24 hours and 72 hours after treatment start.

The mean score was calculated across two scoring times (24 and 72 hours) for each animal for erythema and oedema.

The application of the test substance to the skin resulted in slight erythema on 3/6 intact and 6/6 abraded sites and very slight to slight oedema on 2/6 intact and 5/6 abraded sites.

The substance is considered to be a slight primary skin irritant in the albino rabbit.

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:

supporting study

Study period:

1976

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Non-GLP study that meets accepted scientific standard, well document and acceptable for assessment.

Qualifier:

no guideline followed

Principles of method if other than guideline:

The test was performed according to the method given in the "Hazardous Substances Regulations" under the U.S. Federal Hazardous Labelling Act Sect. 191.12 (February 1965).

GLP compliance:

no

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

Healthy New Zealand White rabbits aged 12 - 16 weeks with average body weights of 2.93 kgs for the males and 2.80 kgs for the females, bred on the premises and maintained under semi-barrier system. The animals were acclimatized in the test area for one week prior to the start of the trial.
Experimental room was maintained at a temperature of 20C and a relative humidity of 50-70%. Light cycle of 10 Hours / 14 hours per day. A commercial irradiated diet was fed ad lib. and filtered sterile water was available at all times.

Vehicle:

unchanged (no vehicle)

Controls:

other: The right eye serve as control

Amount / concentration applied:

100 mg of the test material

Duration of treatment / exposure:

The eye lids were held closed for 1 second.
In three out of the six rabbits, after 30 seconds the test substance was, as far as possible, flushed out of the eyes with approx. 200 mL of warm water.

Observation period (in vivo):

The rabbits were examined 1, 24, 48 and 72 hours after application as well as 6 and 10 days.

Number of animals or in vitro replicates:

6 animals

Details on study design:

REMOVAL OF TEST SUBSTANCE
- Washing: in three animals the substance was flushed out with approx. 200 mL warm water
- Time after start of exposure: 30 seconds

SCORING SYSTEM:

CORNEA
Opacity: degree of density (area most dense taken for reading)

No ulceration or opacity.................................................................................................................... 0
Scattered or diffuse areas of opacity ,details of iris clearly visible..............................................1
Easily discernible translucent area, details of iris slightly obscured...........................................2
Oaplescent area, no details of iris visible, size of pupil barely discernible.................................3
Opaque cornea, iris invisible...............................................................................................................4


IRIS
Normal.....................................................................................................................................................0
Folds above normal, congestion, swelling, moderate circumcorneal injection,
any of these or combination of any thereof, iris still reacting to light
(sluggish reaction is positive) .............................................................................................................1
No reaction to light, hemorrhage, gross destruction (any or all of these)...................................2

CONHJUNCTIVAE
Redness (refers to palpebral and bulbar conjunctivae excluding cornea and iris)

vessels normal........................................................................................................................................0
vessels definitely injected above normal.............................................................................................1
More diffuse, deeper crimson red, individual vessels not easily discernible................................2
Diffuse beefy red.....................................................................................................................................3

Chemosis:

No swelling...............................................................................................................................................0
Any swelling above normal (including nictitating membranes).......................................................1
Obvious swelling with partial eversion of lids ....................................................................................2
Swelling with lids about half-closed.....................................................................................................3
Swelling with lids more than half-closed.............................................................................................4

Irritation parameter:

cornea opacity score

Basis:

mean

Time point:

24 h

Score:

25

Max. score:

80

Reversibility:

other: Animals sacrificed after 6 days

Irritation parameter:

cornea opacity score

Basis:

mean

Time point:

48 h

Score:

22

Max. score:

80

Reversibility:

other: Animlas sacrificed after 6 days

Irritation parameter:

cornea opacity score

Basis:

mean

Time point:

72 h

Score:

28

Max. score:

80

Reversibility:

other: Animals sacrificed after 6 days

Irritation parameter:

conjunctivae score

Basis:

mean

Time point:

24 h

Score:

2

Max. score:

3

Reversibility:

other: Animals sacrificed after 6 days

Irritation parameter:

chemosis score

Basis:

mean

Time point:

24 h

Score:

2

Max. score:

4

Reversibility:

other: Animals sacrificed after 6 days

Irritation parameter:

conjunctivae score

Basis:

mean

Time point:

48 h

Score:

2.66

Max. score:

3

Reversibility:

other: Animals sacrificed after 6 days

Irritation parameter:

chemosis score

Basis:

mean

Time point:

48 h

Score:

2

Max. score:

4

Reversibility:

other: Animals sacrificed after 6 days

Irritation parameter:

conjunctivae score

Basis:

mean

Time point:

72 h

Score:

3

Max. score:

3

Reversibility:

other: Animals sacrificed after 6 days

Irritation parameter:

chemosis score

Basis:

mean

Time point:

72 h

Score:

2

Max. score:

4

Reversibility:

other: Animals sacrificed after 6 days

Irritant / corrosive response data:

Conjunctiva. A uery slight to mild reaction was seen in all treated eyes one hour after the application of the substance. By 24 hours this had
increased in severity in the unwashed eyes but had remained the same in the washed ones. By 72 hours all unwashed eyes were showing necrotic
areas, whereas one washed eye was normal at this time and the other 2 returned to normal by 6 days. There was no change in the unwashed eyes
by 6 days when the animals were killed. If sufficient time had been allowed to elapse it is considered there might have been some residual
scarring of the conjunctivae.

Cornea. Slight opacity with damage to the surface epithelium was seen in all treated eyes at one hour. This was still present at 24 hours inthe
3 unwashed eyes and 2/3 washed eyes. ' These 2 washed eyes had returned to normal by 48 hours and 10 days whereas 2/3 of the unwashed eyes
showed ulceration from 72 hours onwards. By 6 days there was slight pannus formation in the 3 unwashed eyes. It is considered that if sufficiënt
time had been allowed to elapse there might have been some residual . scarring of the cornea in the unwashed eyes.

Iris. Increased folding was seen in one unwashed eye at one hour and in 3 unwashed eyes and 2 washed eyes at 24 hours. The washed eyes
had returned to normal by 48 hours, but the unwashed eyes were still showing a reaction when the rabbits were killed at 6 days.

Washing the eyes reduced the severity of the reactions to a very great extent in that only slight reaction was present at 24 hours and all eyes
had returned to normal by 10 days.

Because of the severity of the reactions the 3 rabbits with unwashed eyes were killed after 6 days.

Interpretation of results:

corrosive

Remarks:

Migrated information Criteria used for interpretation of results: expert judgment

Conclusions:

Based on the above mentioned data and as the animals were sacrificed for animal welfare reasons the test material is considered to be corrosive.

Executive summary:

100 mg of the test material was instilled into the conjunctval sac of the left eye of six healthy new zealand white rabbits. The right eye served as control. After 30 seconds the substance was flushed out of the eyes of three rabbits with approx 200 mL water.

The rabbits were examined after 1, 24, 48, 72 hours as well as 6 and 10 days after treatment.

Washing the eyes reduced the severity of the reactions to a very great extent in that only slight reaction was present at 24 hours and all eyes had returned to normal by 10 days.

Because of the severity of the reactions the 3 rabbits with unwashed eyes were killed after 6 days.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Both bis(2,3 -epoxypropyl) terephthalate and tris(oxiranylmethyl) benzene-1,2,4 -tricarboxylate which are the main compounds of the substance were tested in vivo for skin and eye irritation in rabbits.

On bis(2,3-epoxypropyl) terephthalate one primary skin irritation study was conducted in rabbits and showed slight irritating effects.

The application of the test substance to the skin resulted in slight erythema on 3/6 intact and 6/6 abraded sites and very slight to slight oedema on 2/6 intact and 5/6 abraded sites. The substance is considered to be a slight primary skin irritant in the albino rabbit.

One eye irritation study was performed in rabbits. Due to the severity of the effects observed the three animals were sacrificed for animal welfare reasons after 6 days. The substance cause irreversible damage to the eyes.

On tri(oxiranylmethyl) benzene-1,2,4 -tricarboxylate one in vivo skin irritation study and one in vivo eye irritation study were performed in New Zealand White rabbits. In both studies tris(oxiranylmethyl)benzene-1,2,4-tricarboxylate showed irritating potential. However, the effects were not sufficient for classification as irritant to the skin. The effects were fully reversible within 10 days in the skin irritation study and within 14 days in the eye irritation study.

Justification for selection of skin irritation / corrosion endpoint:
Main compound of Reaction mass of bis(oxiran-2-ylmethyl) terephthalate and tris(oxiran-2-ylmethyl) benzene-1,2,4-tricarboxylate

Justification for selection of eye irritation endpoint:
Main compound of Reaction mass of bis(oxiran-2-ylmethyl) terephthalate and tris(oxiran-2-ylmethyl) benzene-1,2,4-tricarboxylate

Effects on skin irritation/corrosion: slightly irritating

Effects on eye irritation: corrosive

Justification for classification or non-classification

Based on the above stated assessment of the skin irritation potential of bis(2,3 -epoxypropyl)terephthalate which is the main compound, the substance does have to be classified as R36: Irritating to skin according to Council Directive 2001/59/EC and Category 2 (H315 Causes skin irritation) according to CLP (Regulation (EC) No 1272/2008 Of the European parliament and of the Council.

Base on the above assessment of the eye irritation potential of bis(2,3 -epoxypropyl)terephthalate which is the main compound, the substance does have to be classified as R41 Risk of serious damage to eyes according to Council Directive 2001/59/EC and Category 1 ( H318: Causes serious eye damage)according to CLP (Regulation (EC) No 1272/2008 Of the European parliament and of the Council.