Registration Dossier

Diss Factsheets

Administrative data

Description of key information

Skin Irritation:

At all dose levels, the rabbits exhibited moderate to severe erythema with chemical burns and/or blanching, especially along the abrasions. The intensity of the reactions increased with the dose level. On days 7 and 14, desquamation and drying were also observed. Gross necropsy of the animals sacrificed at day 14 showed no remarkable abnormalities.

According to the Federal Hazardous Substances Act (FHSA) Guidelines for classification, Butane-1,2,3,4-tetracarboxylic acid was not determined to be a toxic substance via dermal route.

Hence, Butane-1,2,3,4-tetracarboxylic acid can be considered to be not a dermal irritant to rabbit skin.

Eye Irritation:

Vascularization was first observed at 96 hours and continued to develop through 14 days.The maximum average score of 85.3 was recorded at 72 hours for unwashed eyes.

Vascularization appeared in two of the three animals for the washed group at 96 hours and continued through 14 days.A maximum average score of 26.7 was recorded at 48 hours.

Since, the effects in the washed and unwashed eyes were not reversible even after 14 days of observation, Butane-1,2,3,4-tetracarboxylic acid can be considered to be an eye irritant capable of producing permanent damage to the eyes.

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:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Justification for type of information:
data is from safety assessment reports
Qualifier:
according to guideline
Guideline:
other: as mentioned below
Principles of method if other than guideline:
The dermal irritation potential of Butane-1,2,3,4-tetracarboxylic acid was assessed in rabbits as a part of acute dermal study
GLP compliance:
not specified
Specific details on test material used for the study:
Name of the test chemical: Butane-1,2,3,4-tetracarboxylic acidMolecular Formula: C8H10O8Molecular Weight: 234.159 g/molSmile Notation: OC(=O)C[C@H]([C@H](CC(=O)O)C(=O)O)C(=O)OInChI : 1S/C8H10O8/c9-5(10)1-3(7(13)14)4(8(15)16)2-6(11)12/h3-4H,1-2H2,(H,9,10)(H,11,12)(H,13,14)(H,15,16)/t3-,4+Substance type: organic Physical state: Solid
Species:
rabbit
Strain:
New Zealand White
Details on test animals or test system and environmental conditions:
sex: male and female
Type of coverage:
occlusive
Preparation of test site:
clipped
Remarks:
intact and abradded skin
Vehicle:
physiological saline
Controls:
not specified
Amount / concentration applied:
2.0 g/kg (n=4), 4.0 g/kg (n=4), and 8.0 g/kg (n=4), each as a 50% w/w suspension in isotonic saline
Duration of treatment / exposure:
24 hours
Observation period:
daliy for 14 days
Number of animals:
12 (6 males and 6 females)
Details on study design:
TEST SITE- Area of exposure: trunk - % coverage: no data available- Type of wrap if used: no dataREMOVAL OF TEST SUBSTANCE- Washing (if done): yes- Time after start of exposure: after 24 hours of exposureSCORING SYSTEM: no data
Other effects / acceptance of results:
no data available
Irritation parameter:
overall irritation score
Basis:
mean
Time point:
14 d
Reversibility:
fully reversible within: 14 days
Remarks on result:
no indication of irritation
Irritant / corrosive response data:
At all dose levels, the rabbits exhibited moderate to severe erythema with chemical burns and/or blanching, especially along the abrasions. The intensity of the reactions increased with the dose level. On days 7 and 14, desquamation and drying were also observed.
Other effects:
At each dose level, the signs of systemic toxicity were limited. At the highest level (8.00 g/kg body weight), one animal exhibited generalized weakness for 72 hours, and three animals were observed to be thin after 72 hours and until day 10 of the study. Wry neck was seen in two animals at the 2.00 g/kg body weight dose level. Two animals in this dose group also exhibited a generalized weakness for 24-48 hours. No other signs of systemic toxicity were observed. Final body weight data of surviving animals at day 14 revealed that three animals (two with intact skin, one with abraded skin) in the 2.00 g/kg dose group had significant (10% or greater) weight gains. At 4.00 g/kg, one (abraded skin) had a significant weight gain. Other surviving animals had weight gains or losses that were less than 10%.
Interpretation of results:
other: not irritating
Conclusions:
At all dose levels, the rabbits exhibited moderate to severe erythema with chemical burns and/or blanching, especially along the abrasions. The intensity of the reactions increased with the dose level. On days 7 and 14, desquamation and drying were also observed. Gross necropsy of the animals sacrificed at day 14 showed no remarkable abnormalities.According to the Federal Hazardous Substances Act (FHSA) Guidelines for classification, Butane-1,2,3,4-tetracarboxylic acid was not determined to be a toxic substance via dermal route.Hence, Butane-1,2,3,4-tetracarboxylic acid can be considered to be not a dermal irritant to rabbit skin.
Executive summary:

The dermal irritation potential of Butane-1,2,3,4-tetracarboxylic acid was assessed in rabbits as a part of acute dermal study.The concentrations for dermal application were 2.0 g/kg (n=4), 4.0 g/kg (n=4), and 8.0 g/kg (n=4), each as a 50% w/w suspension in isotonic saline. Prior to exposure, 12 New Zealand albino(6 male and 6 female) rabbits were prepared by clipping the skin of the trunk free of hair. One-half of the animals in each group (n=2) were further prepared by making epidermal abrasions over the area of exposure sufficiently deep enough to penetrate the stratum corneum, but not to disturb the derma. The test suspensions of BTCA were administered under binders fastened to each animal for a period of 24 hours. After 24 hours, the binders were removed, the amount of unabsorbed material was estimated, and the remaining suspension was wiped from the skin. The animals were observed for gross effects at regular intervals on the day of dosing and daily for 14 days, and any animals that perished were necropsied. When the observation period was completed, all surviving animals were weighed, sacrificed, and necropsied. At all dose levels, the rabbits exhibited moderate to severe erythema with chemical burns and/or blanching, especially along the abrasions. The intensity of the reactions increased with the dose level. On days 7 and 14, desquamation and drying were also observed. At each dose level, the signs of systemic toxicity were limited. At the highest level (8.00 g/kg body weight), one animal exhibited generalized weakness for 72 hours, and three animals were observed to be thin after 72 hours and until day 10 of the study. Wry neck was seen in two animals at the 2.00 g/kg body weight dose level. Two animals in this dose group also exhibited a generalized weakness for 24-48 hours. No other signs of systemic toxicity were observed. Final body weight data of surviving animals at day 14 revealed that three animals (two with intact skin, one with abraded skin) in the 2.00 g/kg dose group had significant (10% or greater) weight gains. At 4.00 g/kg, one (abraded skin) had a significant weight gain. Other surviving animals had weight gains or losses that were less than 10%.

According to the Federal Hazardous Substances Act (FHSA) Guidelines for classification,Butane-1,2,3,4-tetracarboxylic acid was not determined to be a toxic substance via dermal route.

Hence, Butane-1,2,3,4-tetracarboxylic acid can be considered to be not a dermal irritant to rabbit skin.

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:
weight of evidence
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
secondary literature
Justification for type of information:
data is from NTRL reports
Qualifier:
according to guideline
Guideline:
other: Draize and Kelly Modified method
Principles of method if other than guideline:
To assess the ocular irritation potential of Butane-1,2,3,4-tetracarboxylic acid in rabbits according to Draize and Kelly Modified method
GLP compliance:
not specified
Specific details on test material used for the study:
Name of the test chemical: Butane-1,2,3,4-tetracarboxylic acidMolecular Formula: C8H10O8Molecular Weight: 234.159 g/molSmile Notation: OC(=O)C[C@H]([C@H](CC(=O)O)C(=O)O)C(=O)OInChI : 1S/C8H10O8/c9-5(10)1-3(7(13)14)4(8(15)16)2-6(11)12/h3-4H,1-2H2,(H,9,10)(H,11,12)(H,13,14)(H,15,16)/t3-,4+Substance type: organic Physical state: Solid
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
Sex: Male and femaleSource: No dataAge at study initiation: young adult stageWeight at study initiation: No dataFasting period before study: No dataHousing: metal cages elevated above droppingsDiet (e.g. ad libitum):Purina Rabbit Chow, ad libitumWater (e.g. ad libitum): Tap Water, ad libitumAcclimation period: No dataENVIRONMENTAL CONDITIONSTemperature (°C): No dataHumidity (%): No dataAir changes (per hr): No dataPhotoperiod (hrs dark / hrs light): No dataIN-LIFE DATES: From: To: No data
Vehicle:
unchanged (no vehicle)
Controls:
yes
Amount / concentration applied:
One-tenth mg of undiluted Powdered sample
Duration of treatment / exposure:
single exposure
Observation period (in vivo):
1,24,48, 72 hours and 7,10 and 14 days
Duration of post- treatment incubation (in vitro):
no data available
Number of animals or in vitro replicates:
9 rabbits
Details on study design:
TEST SITE- Area of exposure: conjunctival sacREMOVAL OF TEST SUBSTANCE- Washing (if done): yes, for 3 rabbits- Time after start of exposure: the treated eyes of 3 animals were washed with 120 ml. of lukewarm tap water (approximately at body temperature) at twenty seconds after instillation.Fluorescein test: The treated eyes of the nine animals were further examined by placing one drop of Fluorescein Sodium - 2% on the cornea. After fifteen seconds, the excess fluorescein was flushed out with sufficient isotonic saline.SCORING SYSTEM: The eyes were examined and the grade of ocular reaction was recorded at 1, 24, 48, 72 and 96 hours and 7, 10 and 14 days, using the scale for scoring ocular lesions as outlined by Lehman, A.J. et al., in Appraisal of the Safety of Chemicals in Foods, Drugs and Cosmetics, Association of Food and Drug Officials of the United States.Table 1: Scale for scoring of Ocular lesions**Cornea Grade (A)Opacity: degree of density (readings should be taken from most dense area)* No ulceration or opacity = 0 Scattered or diffuse areas of opacity (other than slight dulling of normal lustre); details of iris slightly obscured = 1 Easily discernible translucent area; details of iris slightly obscured = 2 Opalescent area; no details of iris visible; size of pupil barely discernible = 3 Opaque cornea; iris not discernible through the opacity = 4 (B)Area of cornea involvedOne quarter (or less) but not zero = 1Greater than one quarter, but less than half = 2Greater than half, but less than three quarters = 3Greater than three quarters, upto whole area = 4Score equals A*B*5 = Total maximum - 80Iris (A)ValuesNormal = 0 Markedly deepened rugae, congestion, swelling, moderate circumcorneal hyperaemia; or injection; iris reactive to light (a sluggish reaction is considered to be an effect = 1 Hemorrhage, gross destruction, or no reaction to light = 2Score Equals A*5 = Total maximum - 10Conjunctivae (A)Redness (refers to palpebral and bulbar conjunctivae; excluding cornea and iris) Vessels Normal = 0 Vessels definitely injected above normal = 1 Diffuse, crimson colour; individual vessels not easily discernible = 2 Diffuse beefy red = 3 (B)Chemosis Swelling (refers to lids and/or nictating membranes) Normal = 0 Any swelling above normal (includes nictating membrane)= 1 Obvious swelling, with partial eversion of lids = 2 Swelling, with lids about half closed = 3 Swelling, with lids more than half closed= 4(C)DischargeNo discharge = 0Any amount different from normal (does not include small amounts observed in inner canthus of normal animals) = 1Discharge with moistening of the lids and hairs just adjacent to lids = 3Discharge with moistening of the lids and hairs, and considerable area around the eye = 4Score Equals (A+B+C)*2 = Total maximum – 20The maximum total score is the sum of all scores obtained for the cornea, iris, conjunctivae.Overall Maximum Possible Score = 110** scale for scoring ocular lesions as outlined by Lehman, A.J. et al., in Appraisal of the Safety of Chemicals in Foods, Drugs and Cosmetics, Association of Food and Drug Officials of the United States.
Other effects / acceptance of results:
no data available
Irritation parameter:
overall irritation score
Basis:
mean
Time point:
72 h
Score:
85.3
Max. score:
110
Reversibility:
not fully reversible within: 14 days
Remarks on result:
probability of severe irritation
Remarks:
for unwashed eyes
Irritation parameter:
overall irritation score
Basis:
mean
Time point:
48 h
Score:
26.7
Max. score:
110
Reversibility:
not fully reversible within: 14 days
Remarks on result:
probability of severe irritation
Remarks:
for washed eyes
Irritant / corrosive response data:
The treated eyes were not washed following instillation of the test material, produced within 24 hours an ocular reaction in the form of a slight to moderate erythema of the bulbar and palpebral conjunctivae, a severe chemosis of the lids, a moderate to marked accumulation of watery-mucoid discharge and a moderate to marked corneal opacity involving one fourth to all of the corneal surface. At 48 hours the eyes reaction had become more pronounced with 5 of 6 test eyes developing iritis. The maximum reaction was observed at 72 hours and only slight improvement was observed through the 14 days. Vascularization was first observed at 96 hours and continued to develop through 14 days. The treated eyes washed at twenty seconds after instillation of the test material, produced within 24 hours an ocular reaction in the form of a slight to moderate erythema of the bulbar and palpebral conjunctivae, a moderate to severe chemosis of the lids, a slight to moderate accumulation of watery-mucoid discharge and a slight to moderate corneal opacity involving one-fourth to one-half of the corneal surface. At 48 hours the reaction of the conjunctivae became more intense where as the corneal reaction in one animal disappeared, was decreased in one other and became more intense in one animal. By 96 hours only slight improvement was noted. At 7 days, two animals showed only slight erythema as a reaction. The other continued to have corneal opacity. At the 14 day observation period, two animals were reaction free while the other exhibited erythema, chemosis and corneal opacity.

Table 2: Scores for ocular lesions at 1, 24, 48, 72, 96 hours and 7, 10 and 14 days of observation

Rabbit no

Structure

1 hour

24 hours

48 hours

72 hours

96 hours

7 days

10 days

14 days

Treated eyes were not washed following instillation of test compound:

1

Cornea

0

45

60

80

80

80

80

80

Iris

0

0

5

5

5

5*

5*

5*

Conjunctivae

10

14

20

20

18

14

14

16

2

Cornea

0

15

15

15

15

10

10

10

Iris

0

0

0

0

0

0

0

0

Conjunctivae

10

18

18

14

12

6

6

6

3

Cornea

0

30

30

60

60

60

40

40

Iris

0

0

5

5

5

0

0

0

Conjunctivae

8

16

18

20

18

12

14

10

4

Cornea

0

45

60

80

80

80

80

80

Iris

0

0

5

5

5

5*

5*

5*

Conjunctivae

10

16

20

18

20

16

18

16

5

Cornea

0

60

80

80

80

80

80

80

Iris

0

0

5

5

5

5*

5*

5*

Conjunctivae

10

16

20

20

20

16

12

14

6

Cornea

0

30

45

60

60

45

45

30

Iris

0

0

5

5

5

0

0

0

Conjunctivae

10

16

20

20

20

16

12

14

 

Average

9.3

53.8

71.8

85.3

84.3

75.0

72.0

69.2

 

Range

 

 

 

 

 

 

 

 

Cornea

0

15-60

15-80

15-80

15-80

10-80

10-80

10-80

Iris

0

0

0-5

0-5

0-5

0-5

0-5

0-5

Conjunctivae

8-10

14-18

18-20

14-20

12-20

6-16

6-18

6-18

Treated eyes were washed 20 seconds after instillation of test compound:

7

Cornea

0

5

0

0

0

0

0

0

Iris

0

0

0

0

0

0

0

0

Conjunctivae

12

8

10

8

6

2

0

0

8

Cornea

0

10

5

10

10

0

0

0

Iris

0

0

0

0

0

0

0

0

Conjunctivae

10

10

12

8

4

2

2

0

9

Cornea

0

20

30

30

30

20

20

20

Iris

0

0

5

5

5

0

0

0

Conjunctivae

8

16

18

14

14

8

4

4

 

Average

10.0

23.0

26.7

25.0

23.0

10.7

8.7

8.0

 

Range

 

 

 

 

 

 

 

 

Cornea

0

5-20

0-30

0-30

0-30

0-20

0-20

0-20

Iris

0

0

0-5

0-5

0-5

0

0

0

 

Conjunctivae

8-12

8-16

10-18

8-14

4-14

2-8

0-4

0-4

 

*These values are assumed since the density of the corneal opacity is great enough to obscure reading of the iris.

 

 

Interpretation of results:
Category 2 (irritating to eyes) based on GHS criteria
Conclusions:
Vascularization was first observed at 96 hours and continued to develop through 14 days.The maximum average score of 85.3 was recorded at 72 hours for unwashed eyes.Vascularization appeared in two of the three animals for the washed group at 96 hours and continued through 14 days.A maximum average score of 26.7 was recorded at 48 hours.Since, the effects in the washed and unwashed eyes were not reversible even after 14 days of observation, Butane-1,2,3,4-tetracarboxylic acid can be considered to be an eye irritant capable of producing permanent damage to the eyes.
Executive summary:

The ocular irritation potential of Butane-1,2,3,4-tetracarboxylic acid was assessed in rabbits according to Draize and Kelly Modified method.One-tenth mg of undiluted Powdered sample was placed in one eye of 9 New Zealand White rabbits by gently pulling the lower lid away from the eyeball to form a cup into which the test material was deposited. The lids were then gently held together for one second and the animal was released. The other eye was not treated and served as a control. Following instillation of the test material, the treated eyes of six animals remained unwashed. The treated eyes of the three remaining animals were each washed with 120 ml. of lukewarm tap water (approximately at body temperature) at twenty seconds after instillation of the test material. A one minute wash process was employed for eachanimal.All animals were immobilized in a suitable restrainer rack for one hour subsequent to treatment.The eyes were examined and the grade of ocular reaction was recorded at 1, 24, 48, 72 and 96 hours and 7, 10 and 14 days, using the scale for scoring ocular lesions as outlined by Lehman, A.J. et al., in Appraisal of the Safety of Chemicals in Foods, Drugs and Cosmetics, Association of Food and Drug Officials of the United States.

After examination of both eyes of each of the nine animals at twenty-four hours, the treated eyes of the first six rabbits were washed with sufficient clean isotonic saline at body temperature to remove any residual test sample. The treated eyes of each of the nine animals were further examined by placing one drop of Fluorescein Sodium - 2% on the cornea. After fifteen seconds, the excess fluorescein was flushed out with sufficient isotonic saline.The treated eyes were not washed following instillation of the test material, produced within 24 hours an ocular reaction in the form of a slight to moderate erythema of the bulbar and palpebral conjunctivae, a severe chemosis of the lids, a moderate to marked accumulation of watery-mucoid discharge and a moderate to marked corneal opacity involving one fourth to all of the corneal surface. At 48 hours the eyes reaction had become more pronounced with 5 of 6 test eyes developing iritis. The maximum reaction was observed at 72 hours and only slight improvement was observed through the 14 days. Vascularization was first observed at 96 hours and continued to develop through 14 days.The treated eyes washed at twenty seconds after instillation of the test material, produced within 24 hours an ocular reaction in the form of a slight to moderate erythema of the bulbar and palpebral conjunctivae, a moderate to severe chemosis of the lids, a slight to moderate accumulation of watery-mucoid discharge and a slight to moderate corneal opacity involving one-fourth to one-half of the corneal surface. At 48 hours the reaction of the conjunctivae became more intense where as the corneal reaction in one animal disappeared, was decreased in one other and became more intense in one animal. By 96 hours only slight improvement was noted. At 7 days, two animals showed only slight erythema as a reaction. The other continued to have corneal opacity. At the 14 day observation period, two animals were reaction free while the other exhibited erythema, chemosis and corneal opacity.The maximum average score of 85.3 was recorded at 72 hours for unwashed eyes.A maximum average score of 26.7 was recorded at 48 hours for the washed eyes.

Since, the effects in the washed and unwashed eyes were not reversible even after 14 days of observation,Butane-1,2,3,4-tetracarboxylic acid can be considered to be an eye irritant capable of producing permanent damage to the eyes

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Skin irritation:

In different studies,Butane-1, 2, 3, 4-tetracarboxylic acidhas been investigated for potential for dermal irritation to a greater or lesser extent. The studies are based on in vivo experiments in rabbits along with predicted data for target chemical, Butane-1,2,3,4-tetracarboxylic acid and its structurally similar read across substances, Dodecanedioic acid[CAS: 693-23-2] and Citric acid [CAS: 77-92-9].The predicted data using the OECD QSAR toolbox has also been compared with the experimental data.

The dermal irritation potential of Butane-1, 2, 3, 4-tetracarboxylic acid was assessed [EXECUTIVE SUMMARY OF SAFETY AND TOXICITY INFORMATION, NATIONAL TOXICOLOGY PROGRAM, last updated 1991] in rabbits as a part of acute dermal study. The concentrations for dermal application were 2.0 g/kg (n=4), 4.0 g/kg (n=4), and 8.0 g/kg (n=4), each as a 50% w/w suspension in isotonic saline. Prior to exposure, 12 New Zealand albino(6 male and 6 female) rabbits were prepared by clipping the skin of the trunk free of hair. One-half of the animals in each group (n=2) were further prepared by making epidermal abrasions over the area of exposure sufficiently deep enough to penetrate the stratum corneum, but not to disturb the derma. The test suspensions of BTCA were administered under binders fastened to each animal for a period of 24 hours. After 24 hours, the binders were removed, the amount of unabsorbed material was estimated, and the remaining suspension was wiped from the skin. The animals were observed for gross effects at regular intervals on the day of dosing and daily for 14 days, and any animals that perished were necropsied. When the observation period was completed, all surviving animals were weighed, sacrificed, and necropsied. At all dose levels, the rabbits exhibited moderate to severe erythema with chemical burns and/or blanching, especially along the abrasions. The intensity of the reactions increased with the dose level. On days 7 and 14, desquamation and drying were also observed. At each dose level, the signs of systemic toxicity were limited. At the highest level (8.00 g/kg body weight), one animal exhibited generalized weakness for 72 hours, and three animals were observed to be thin after 72 hours and until day 10 of the study. Wry neck was seen in two animals at the 2.00 g/kg body weight dose level. Two animals in this dose group also exhibited a generalized weakness for 24-48 hours. No other signs of systemic toxicity were observed. Final body weight data of surviving animals at day 14 revealed that three animals (two with intact skin, one with abraded skin) in the 2.00 g/kg dose group had significant (10% or greater) weight gains. At 4.00 g/kg, one (abraded skin) had a significant weight gain. Other surviving animals had weight gains or losses that were less than 10%.

According to the Federal Hazardous Substances Act (FHSA) Guidelines for classification, Butane-1,2,3,4-tetracarboxylic acid was not determined to be a toxic substance via dermal route.

Hence, Butane-1,2,3,4-tetracarboxylic acid can be considered to be not a dermal irritant to rabbit skin.

In an another study summarized in OTS – 0280 – 0059 – IN, NTRL, last updated 1979;Butane-1,2,3,4-tetracarboxylic acid was applied in the form of a 50% w/v suspension in isotonic saline for twenty-four hours to the intact and abraded skin of six New Zealand White rabbits.

The backs of the animals were clipped and made free of hair. Two sets of abrasions (minor incisions through the stratum corneum, but not deep enough to disturb the derma) were made approximately ten centimeters apart on the right side of the back of each animal, while the skin of the left side remained intact. The animals were immobilized in a restrainer rack and 0.5 g.of the test material in the form of a 50% w/v suspension in isotonic saline was under each of four one-inch square gauze patches to the prepared areas (2 intact and 2 abraded) of the back of each rabbit. After the patches had been secured by adhesive tape, the entire trunk of each animal was enclosed in a plastic binder to keep the material in position and in contact with the skin for twenty-four hours. The treated sites were wiped free of the test material after 24 hours of exposure. The reactions (Erythema and edema) observed and evaluated under the scoring method of Draize, Woodard and Calvery. The skin was examined further at forty-eight, seventy-two and ninety-six hours and at 5, 6 and 7 days to evaluated the degree of erythema and edema at the treated sites. A barely perceptible to slight skin response was observed in the form of a barely perceptible to moderate erythema (1 animal) and a slight edema (1 animal). Steady reduction of the response was noted throughout 7 days the animals were observed. None of the usual sequelae to irritation, such as desquamation and drying, were observed during the course of the study.

By the 7 day observation, all reaction had disappeared except for a slight erythema along the abrasions of one animal. No essential difference was observed in the reaction of the intact and abraded areas. The reaction at the front and rear sites were of similar intensity. The Primary Irritation Index was 0.9.

Based on the scores and observations, Butane-1, 2, 3, 4-tetracarboxylic acid can be considered not irritating to rabbit skin.

Skin irritation effects were also estimated by four different models i.e, Battery, Leadscope, SciQSAR and CASE Ultra used within Danish QSAR database for Butane-1, 2, 3, 4-tetracarboxylic acid. Based on estimation, no severe skin irritation effects were known when Butane-1, 2, 3, 4-tetracarboxylic acid was exposed to rabbit skin.

In a prediction done by SSS (2017) using the OECD QSAR toolbox with log kow as the primary descriptor, the ocular irritation potential was estimated for Butane-1, 2, 3, 4-tetracarboxylic acid. Butane-1, 2, 3, 4-tetracarboxylic acid was estimated to be not irritating to eyes of New Zealand White rabbits.

The estimated and experimental results indicate the possibility of Butane-1, 2, 3, 4-tetracarboxylic acid being not irritating to skin.

These results are supported by the experimental study summarized in Int J Toxicol; 2012 Jul-Aug; 31(4 Suppl):5S-76S; for the structurally similar read across substance,Dodecanedioic acid[CAS: 693-23-2]. The study was performed according to FHSA Guidelines.0.5 g of dodecanedioic acid was applied to the rabbit skin and observed for signs of irritation (duration not mentioned). Application of 0.5 g of dodecanedioic acid to rabbit skin was not irritating to skin.

Hence, dodecanedioic acid can be considered as not irritating to skin.

These results are further supported by the experimental study summarized in Cosmetic Ingredient Review, 2012; for the structurally similar read across substance, Citric acid [CAS: 77-92-9].The study was performed according to Draize test.0.5 ml of 30% aqueous solution of citric acid was applied for 4 hours to the intact and abraded skin of 3 New Zealand White rabbits under occlusive conditions. The rabbits were observed for signs and scored.

The Primary Irritation Index (PII) for citric acid was 84, after 4 hours of exposure to rabbit skin. Citric acid can be considered to be not irritating to New Zealand White rabbit skin.

Based on the available data for the target as well as it read across substances;and applying the weight of evidence approach, it can be concluded that Butane-1, 2, 3, 4-tetracarboxylic acid was not irritating to skin.Comparing the above annotations with the criteria of CLP regulation, test chemical can be classified under the category “Not Classified”.

Eye irritation:

In different studies,Butane-1, 2, 3, 4-tetracarboxylic acidhas been investigated for potential for ocular irritation to a greater or lesser extent. The studies are based on in vivo experiments in rabbits along with predicted data for target chemicalButane-1,2,3,4-tetracarboxylic acidand its structurally similar read across substances,Dodecanedioic acid[CAS: 693-23-2] and Citric acid [CAS: 77-92-9].The predicted data using the OECD QSAR toolbox has also been compared with the experimental data.

The ocular irritation potential of Butane-1, 2, 3, 4-tetracarboxylic acid was assessed (OTS – 0280 – 0059 – IN, NTRL, last updated 1979) in rabbits according to Draize and Kelly Modified method. One-tenth mg of undiluted powdered sample was placed in one eye of 9 New Zealand White rabbits by gently pulling the lower lid away from the eyeball to form a cup into which the test material was deposited. The lids were then gently held together for one second and the animal was released. The other eye was not treated and served as a control. Following instillation of the test material, the treated eyes of six animals remained unwashed. The treated eyes of the three remaining animals were each washed with 120 ml. of lukewarm tap water (approximately at body temperature) at twenty seconds after instillation of the test material. A one minute wash process was employed for each animal. All animals were immobilized in a suitable restrainer rack for one hour subsequent to treatment. The eyes were examined and the grade of ocular reaction was recorded at 1, 24, 48, 72 and 96 hours and 7, 10 and 14 days, using the scale for scoring ocular lesions as outlined by Lehman, A.J. et al., in Appraisal of the Safety of Chemicals in Foods, Drugs and Cosmetics, Association of Food and Drug Officials of the United States. After examination of both eyes of each of the nine animals at twenty-four hours, the treated eyes of the first six rabbits were washed with sufficient clean isotonic saline at body temperature to remove any residual test sample. The treated eyes of each of the nine animals were further examined by placing one drop of Fluorescein Sodium - 2% on the cornea. After fifteen seconds, the excess fluorescein was flushed out with sufficient isotonic saline.The treated eyes were not washed following instillation of the test material, produced within 24 hours an ocular reaction in the form of a slight to moderate erythema of the bulbar and palpebral conjunctivae, a severe chemosis of the lids, a moderate to marked accumulation of watery-mucoid discharge and a moderate to marked corneal opacity involving one fourth to all of the corneal surface. At 48 hours the eyes reaction had become more pronounced with 5 of 6 test eyes developing iritis. The maximum reaction was observed at 72 hours and only slight improvement was observed through the 14 days. Vascularization was first observed at 96 hours and continued to develop through 14 days.The treated eyes washed at twenty seconds after instillation of the test material, produced within 24 hours an ocular reaction in the form of a slight to moderate erythema of the bulbar and palpebral conjunctivae, a moderate to severe chemosis of the lids, a slight to moderate accumulation of watery-mucoid discharge and a slight to moderate corneal opacity involving one-fourth to one-half of the corneal surface. At 48 hours the reaction of the conjunctivae became more intense where as the corneal reaction in one animal disappeared, was decreased in one other and became more intense in one animal. By 96 hours only slight improvement was noted. At 7 days, two animals showed only slight erythema as a reaction. The other continued to have corneal opacity. At the 14 day observation period, two animals were reaction free while the other exhibited erythema, chemosis and corneal opacity. The maximum average score of 85.3 was recorded at 72 hours for unwashed eyes. A maximum average score of 26.7 was recorded at 48 hours for the washed eyes.

Since, the effects in the washed and unwashed eyes were not reversible even after 14 days of observation, Butane-1, 2, 3, 4-tetracarboxylic acid can be considered to be an eye irritant capable of producing permanent damage to the eyes

In a prediction done by SSS (2017) using the OECD QSAR toolbox with log kow as the primary descriptor, the ocular irritation potential was estimated for Butane-1, 2, 3, 4-tetracarboxylic acid. Butane-1, 2, 3, 4-tetracarboxylic acid was estimated to be irritating to eyes of New Zealand White rabbits.

The experimental and estimated results indicate the possibility of Butane-1, 2, 3, 4-tetracarboxylic acid being irritating to eyes.

These results are supported by the experimental study summarized in Int J Toxicol; 2012 Jul-Aug; 31(4 Suppl):5S-76S; for the structurally similar read across substance,Dodecanedioic acid[CAS: 693-23-2]. Dodecanedioic acid was instilled in to the rabbit eyes and observed for signs of irritation (dose and duration not mentioned). The Primary Irritation Index(PII) for dodecanedioic acid was 11.6/110.

Hence, dodecanedioic acid can be considered as slightly irritating to eyes.

These results are further supported by the experimental study summarized in Cosmetic Ingredient Review, 2012; for the structurally similar read across substance, Citric acid [CAS: 77-92 -9].The study was performed according to Draize test. 0.1 ml of 30% aqueous solution of citric acid was instilled into eyes of 3 New Zealand White rabbits under occlusive conditions. The rabbits were observed for signs and scored (duration not mentioned).

The Primary Irritation Index (PII) for citric acid was 16.0, after exposure to rabbit eyes.

Citric acid can be considered to be mild to moderately irritating to New Zealand White rabbit eyes.

Based on the available data for the target as well as it read across substances;and applying the weight of evidence approach, it can be concluded that Butane-1, 2, 3, 4-tetracarboxylic acid was irritating to eyes.Comparing the above annotations with the criteria of CLP regulation, test chemical can be classified under the category “Category 2”.

Justification for classification or non-classification

Based on the available information,Butane-1, 2, 3, 4-tetracarboxylic acid is not likely to cause any irritation to skin, but causes severe irritation to eyes. Hence,Butane-1, 2, 3, 4-tetracarboxylic acid can be classified under the category “Not Classified” for skin and “Category 2”as per CLP regulation.