Registration Dossier

Acute oral toxicity:

Acute oral toxicity test form NTP report, 1991 and NTRL report (OTS02800059),1980 was performed in rats COX-SD strain for a period of 14 days. The rats have 198-293gm and metal wire bottomed cages were used for the housing of rats. The chemical was given orally in the form of gavage in distilled water. 5 animals per sex per dose were used in 800, 1260, 1590, 2000 and 3170 mg/kg bw concentrations. Observations for gross signs were performed at regular intervals on the day of dosage and 5 days per week and thereafter for fourteen days. Necropsy of survivors was also done at termination of the study.

Body weight were observed in animals some has constant weight and some has slight decrease in weight was observed. Moderate to severe congestion of the kidneys, adrenaIs , lungs, liver and intestines, scattered brownish lesions and/or erosion of the mucosa of the stomach (opaque portion), blanching of the mucosa of the stomach (opaque and translucent portions) and small intestine, paleness of the liver (underside of lobes) and brownish-gray coloration throughout the lungs.

The acute oral LD50 of BTCA, when administered to 5 male COX-SD rats was considered to be 1740 mg/kgbw, with a confidence interval of 1330 to 2280 mg/kg bw. The acute oral LD50 of BTCA, when administered to 5 female COX-SD rats was considered to be 1620 mg/kgbw.

Acute inhalation toxicity:

Ten albino rats (five male and five female, COX-SD strain), weighing 230 to 272 grams, were exposed by the route of inhalation to undiluted butane tetracarboxylic acid in the powder form at a delivery flow concentration of approximately 8.19 mg per liter of air at a flow rate of 2.5 liters per minute for a period of 60 minutes plus 23 minutes for equilibration. All of the animals survived the 60 minute exposure and the 14 day observation period which followed. Bady weight gain was observed.No sign of gross toxicity was observed in any animal after post exposure observation period. 3 of the 10 animals shows lung congestion and other animals were not remarkable.

On the basis of observation,the LD 50 value for butane tetracarboxylic acid was considered to be >8.19 mg/l of air concentations.

Acute dermal toxicity:

Acute dermal toxicity test was performed in New Zealand Albino rabbits. Twelve New Zealand Albino rabbits, six males and six females were used and treated for 24 hrs. The rabbits weight was 2.30 to 2.86 kg were housed in metal cages elevated above droppings. Rabbits were given Purina Rabbit Chow and water ad libitium. Those animals which were without observable skin defects or irritation were used for experiment. One-half of the animals in each group were further prepared by making epidermal abrasions every two or three centimeters longitudinally over the area of exposure. A plastic binder was used onto each animal and 50% w/w suspension in isotonic saline, was introduced under the plastic binder. After the experiment the binder was removed and skin reactions were observed.

Reference

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Data is from NTP and NTRL report.

Justification for type of information:

Data is from NTP and NTRL report.

Qualifier:

according to guideline

Guideline:

other: as mentioned below

Principles of method if other than guideline:

Acute oral toxicity was access in rats using Butane-1,2,3,4-tetracarboxylic acid.

GLP compliance:

not specified

Test type:

other: not specified

Limit test:

no

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:

rat

Strain:

other: COX-SD

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALSWeight at study initiation:198-293gmFasting period before study: yes, overnight fasting Housing: Metal wire bottomed cagesDiet (e.g. ad libitum): Purina Rodent Laboratory Chow, ad libitiumWater (e.g. ad libitum):Tap water, ad libitium IN-LIFE DATES: From: To: one group was dosed at 21/8/79 and second group 17/10/79 and sacrificed on 31/10/79

Route of administration:

oral: gavage

Vehicle:

other: Distilled water

Details on oral exposure:

VEHICLEConcentration in vehicle: 10%(w/w)MAXIMUM DOSE VOLUME APPLIED: 3170g/kgbw Rationale for the selection of the starting dose: Prior to the actual LD50 determination, exploratory doses were administered to eight rats to estimate the order of toxicity of the test material. Based on the results of the preliminary assay, groups of ten rats (five males and five females) were dosed at intervals spaced so as to provide a suitable dosage mortality curve for quantitative assessment of oral LD50

Doses:

800, 1260, 1590, 2000 and 3170mg/kgbw

No. of animals per sex per dose:

5 animals

Control animals:

not specified

Details on study design:

- Duration of observation period following administration: 14 days (or other?): 14 days- Frequency of observations and weighing: Observations for gross signs were performed at regular intervals on the day of dosage and 5 days per week and thereafter for fourteen days, Surviving animals were weighed seven days post-treatment.- Necropsy of survivors performed: Yes

Statistics:

LD50 with confidence limits and slope function with confidence limits (method of Litchfield and Wilcoxon)

Sex:

male/female

Dose descriptor:

LD50

Effect level:

1 720 mg/kg bw

Based on:

test mat.

95% CL:

> 1 420 - < 2 080

Mortality:

Cumulative Mortality dataDosage Level mg/kgbw% Mortality80001260101590202000803170100

Clinical signs:

other: Slight to severe hypoactivity,hypersalivation, diarrhea. unkempt pelage, piloerection, malaise and proneness were seen.

Gross pathology:

Moderate to severe congestion of the kidneys, adrenaIs , lungs, liver and intestines, scattered brownish lesions and/or erosion of the mucosa of the stomach (opaque portion), blanching of the mucosa of the stomach (opaque and translucent portions) and small intestine, paleness of the liver (underside of lobes) and brownish-gray coloration throughout the lungs.

Interpretation of results:

Category 4 based on GHS criteria

Conclusions:

The acute oral LD50 of BTCA , when administered to 5 male COX-SD rats was considered to be 1740mg/kgbw, with a confidence interval of 1330 to 2280mg/kgbwThe acute oral LD50 of BTCA , when administered to 5 female COX-SD rats was considered to be 1620mg/kgbw.

Executive summary:

Acute oral toxicity test was performed in rats COX-SD strain for a period of 14 days. The rats have 198-293gm and metal wire bottomed cages were used for the housing of rats. The chemical was given orally in the form of gavage in distilled water. 5 animals per sex per dose were used in 800, 1260, 1590, 2000 and 3170 mg/kg bw concentrations. Observations for gross signs were performed at regular intervals on the day of dosage and 5 days per week and thereafter for fourteen days. Necropsy of survivors was also done at termination of the study.

Body weight were observed in animals some has constant weight and some has slight decrease in weight was observed.

Moderate to severe congestion of the kidneys, adrenaIs , lungs, liver and intestines, scattered brownish lesions and/or erosion of the mucosa of the stomach (opaque portion), blanching of the mucosa of the stomach (opaque and translucent portions) and small intestine, paleness of the liver (underside of lobes) and brownish-gray coloration throughout the lungs.

The acute oral LD50 of BTCA , when administered to 5 male COX-SD rats was considered to be 1740 mg/kgbw, with a confidence interval of 1330 to 2280 mg/kg bw.The acute oral LD50 of BTCA , when administered to 5 female COX-SD rats was considered to be 1620 mg/kgbw.

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

1 620 mg/kg bw

Quality of whole database:

Data is from NTRL and NTP reports.

Reference

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Data is from NTP and NTRL report.

Justification for type of information:

Data is from NTP and NTRL report.

Qualifier:

according to guideline

Guideline:

other: as mentioned below

Principles of method if other than guideline:

To access the effect of Butane-1,2,3,4-tetracarboxylic acid in rats.

GLP compliance:

not specified

Test type:

other: not specified

Limit test:

no

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:

rat

Strain:

other: COX-SD

Sex:

male/female

Details on test animals or test system and environmental conditions:

Source: No dataAge at study initiation: No dataWeight at study initiation:198-293gmFasting period before study: yes, overnight fasting Housing: Metal wire bottomed cagesDiet (e.g. ad libitum): Purina Rodent Laboratory Chow, ad libitiumWater (e.g. ad libitum):Tap water, ad libitium Acclimation period: No data

Route of administration:

inhalation

Type of inhalation exposure:

not specified

Vehicle:

other: dust

Details on inhalation exposure:

- Weight at study initiation:Animal NoSexInitial weight(g)1M2562M2563M2464M2575M2726F2427F2418F2519F23010F251- Fasting period before study: No- Housing: Metal Wire Bottomed cages- Diet (e.g. ad libitum): Purina Rodent Laboratory Chow(pellitized),ad libitium- Water (e.g. ad libitum):tap water, ad libitum- Acclimation period: Not dataENVIRONMENTAL CONDITIONS- Temperature (°C): Not data- Humidity (%): Not data- Air changes (per hr):Not data- Photoperiod (hrs dark / hrs light): Not data

Analytical verification of test atmosphere concentrations:

not specified

Duration of exposure:

1 h

Remarks on duration:

60 minutes (plus a 23 minute equilibration period).

Concentrations:

1.7 grams of the substance

No. of animals per sex per dose:

5 animals per sex

Control animals:

not specified

Details on study design:

- Duration of observation period following administration: 14 days (or other?): 14 day observation period- Frequency of observations and weighing: 1 day, 7 day and 14 day- Necropsy of survivors performed: yes- Other examinations performed: clinical signs, body weight, organ weights, histopathology, other: body weight and lung observations

Sex:

male/female

Dose descriptor:

LC0

Effect level:

8.19 other: mg

Based on:

test mat.

Exp. duration:

1 h

Remarks on result:

other: LC 0 value was observed

Mortality:

No mortality was observed

Clinical signs:

other: No data available

Body weight:

Body weight showed weight gain within the expected limits.

Gross pathology:

moderate congestion of the lungs in three of the ten animals were observed. It is not possible to assign acause effect relation to the lung congestion, but this type of congestion is often observed as a sacrifice artifact in rats.

Interpretation of results:

other:

Conclusions:

At a flow concentration of approximately 8.19 mg per liter of air and flow rate of 2.5 liters per minute for a period of 60 minutes plus 23 minutes equilibration time, all of the test animals survived. The LD50 for butane tetracarboxylic acid >8.19 mg/lt of air.

Executive summary:

Ten albino rats (five male and five female, COX-SD strain), weighing 230 to 272 grams, were exposed by the route of inhalation to undiluted butane tetracarboxylic acid in the powder form at a delivery flow concentration of approximately 8.19 mg per liter of air at a flow rate of 2.5 liters per minute for a period of 60 minutes plus 23 minutes for equilibration. All of the animals survived the 60 minute exposure and the 14 day observation period which followed. Body weight gain was observed.No sign of gross toxicity was observed in any animal after post exposure observation period. 3 of the 10 animals shows lung congestion and other animals were not remarkable.

On the basis of observation,the LD 50 value for butane tetracarboxylic acid was considered to be >8.19 mg/l of air concentations.

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LC50

Value:

8 190 mg/m³ air

Quality of whole database:

Data is from NTP and NTRL report.

Reference

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Data is from NTP and NTRL report

Justification for type of information:

Data is from NTP and NTRL report

Qualifier:

according to guideline

Guideline:

other: as mentioned below

Principles of method if other than guideline:

Acute dermal toxicity test was access in rabbits using Butane-1,2,3,4-tetracarboxylic acid.

GLP compliance:

no

Test type:

other: not specified

Limit test:

no

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:

other: New Zealand Albino

Sex:

male/female

Details on test animals or test system and environmental conditions:

- Weight at study initiation: 2.30 to 2.86 kg - Fasting period before study: Not fasted- Housing: Metal cages elevated above droppings- Diet (e.g. ad libitum): Purina Rabbit Chow, ad libitium- Water (e.g. ad libitum): Tap water, ad libitum

Type of coverage:

other: intact and abraded skin

Vehicle:

other: 50%(w/w) isotonic saline

Details on dermal exposure:

No data available

Duration of exposure:

Single exposure for a period of 24 hours

Doses:

2000, 4000,8000 mg/kgbw

No. of animals per sex per dose:

Twelve rabbits, 6 animals per sexGroup NumberNumber of AnimalsSkin Preparation12Intact12Abraded22Intact22Abraded32Intact32Abraded

Control animals:

not specified

Details on study design:

- Duration of observation period following administration: 14 days (or other?): 14 days- Necropsy of survivors performed: Yes- Other examinations performed: clinical signs, body weight, organ weights, histopathology, other: body weight, clinical signs

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 8 000 mg/kg bw

Based on:

test mat.

Remarks on result:

other: 50 % mortality was observed

Mortality:

No mortality at highest dose level

Clinical signs:

other: Few systemic signs of toxicity were observed at any dose level.

Gross pathology:

Gross necropsy of animal which succumbed showed the skin to have severe erythema of sides and ventrum with severe congestion appearance of chemical burns. The stomach was blanched with the mucosal surface. The small intestines showed severe scattered congestion.

Other findings:

At all dose levels there was moderate to severe erythema with chemical burns and/or blanching especially along abrasions The intensity increased with the dose level.This was followed at 7 and 14 days with desquamation and drying.

Interpretation of results:

other: not classified

Conclusions:

The lethal dose concentration causing 50% mortality skin exposure of 1,2,3,4 butane tetracarboxylic acid to New Zealand Albino rabbits was considered to be 8000mg/kgbw.

Executive summary:

Acute dermal toxicity test was performed in New Zealand Albino rabbits. Twelve New Zealand Albino rabbits, six males and six females were used and treated for 24 hrs. The rabbits weight was 2.30 to 2.86 kg were housed in metal cages elevated above droppings. Rabbits were given Purina Rabbit Chow and water ad libitium. Those animals which were without observable skin defects or irritation were used for experiment. One-half of the animals in each group were further prepared by making epidermal abrasions every two or three centimeters longitudinally over the area of exposure. A plastic binder was used onto each animal and 50% w/w suspension in isotonic saline, was introduced under the plastic binder. After the experiment the binder was removed and skin reactions were observed.

No mortality at highest dose level was observed. Few systemic signs of toxicity were observed at any dose level. At all dose levels there was moderate to severe erythema with chemical burns and/or blanching especially along abrasions. The intensity increased with the dose level. This was followed at 7 and 14 days with desquamation and drying. Gross necropsy of animal which succumbed showed the skin to have severe erythema of sides and ventrum with severe congestion appearance of chemical burns. The stomach was blanched with the mucosal surface. The small intestines showed severe scattered congestion.

As per the all observation, the LD 50 value for acute dermal toxicity for Butane-1,2,3,4-tetracarboxylic acid was considered to be 8000mg/kg bw. Based on that, Butane-1, 2, 3, 4-tetracarboxylic acid was considered to be non-toxic to rabbits and classified as “not classified “as per the CLP regulations.

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

8 000 mg/kg bw

Quality of whole database:

Data is from NTP and NTRL report.

Acute oral toxicity:

In different studies, Butane-1,2,3,4-tetracarboxylic acid (1703-58-8) has been investigated for potential of acute oral toxicity to a greater or lesser extent. The studies are based on in vivo experiments in rats for target chemical Butane-1,2,3,4-tetracarboxylic acid (1703-58-8)and structurally similar read across chemical are as follows:

Acute oral toxicity test form NTP report, 1991 and NTRL report (OTS02800059),1980 was performed in rats COX-SD strain for a period of 14 days. The rats have 198-293gm and metal wire bottomed cages were used for the housing of rats. The chemical was given orally in the form of gavage in distilled water. 5 animals per sex per dose were used in 800, 1260, 1590, 2000 and 3170 mg/kg bw concentrations. Observations for gross signs were performed at regular intervals on the day of dosage and 5 days per week and thereafter for fourteen days. Necropsy of survivors was also done at termination of the study.

Body weight were observed in animals some has constant weight and some has slight decrease in weight was observed. Moderate to severe congestion of the kidneys, adrenaIs , lungs, liver and intestines, scattered brownish lesions and/or erosion of the mucosa of the stomach (opaque portion), blanching of the mucosa of the stomach (opaque and translucent portions) and small intestine, paleness of the liver (underside of lobes) and brownish-gray coloration throughout the lungs.

The acute oral LD50 of BTCA, when administered to 5 male COX-SD rats was considered to be 1740 mg/kgbw, with a confidence interval of 1330 to 2280 mg/kg bw. The acute oral LD50 of BTCA, when administered to 5 female COX-SD rats was considered to be 1620 mg/kgbw.

An acute oral toxicity test was performed in rats on read across chemical malonic acid from NTP Chemical Repository, 1991. After the experiment, LD 50 value for malonic acid (60-00-4) was considered to be 1310 mg/kg.

Another read across chemical Edetic acid from Iuclid dataset, 2000, an acute oral toxicity test was performed on rats. 46.6 w/v aqueous solutions were administered. Dyspnoea, apathy, wobbling, trembling, clonic Cramps, exsiccosis, salivary flow Section, Heart acute dilation and congestion hyperaemia; Liver mottled surface, Stomach diffuse rehydration of the Mucous membranes, Bowel diffuse curdling of the mucosa symptoms were seen.

Based on the clinical signs the LD 50 value for Edetic acid (60-00-4) was considered to be 1700 mg/kg. On the basis of value the edetic acid was considered to be toxic to rats and can be classified in “acute category 4” as per the CLP regulations.

Thus, based on the above studies on Butane-1, 2, 3, 4-tetracarboxylic acid (1703-58-8), it can be concluded that LD50 value is lesser than 2000 mg/kg bw. Thus, comparing this value with the criteria of CLP regulation, Butane-1,2,3,4-tetracarboxylic acid (1703-58-8) can be considered to be “classified in acute category 4” for acute oral toxicity.

Acute inhalation toxicity:

In different studies, Butane-1,2,3,4-tetracarboxylic acid (1703-58-8) has been investigated for potential of acute inhalation toxicity to a greater or lesser extent. The studies are based on in vivo experiments in rats for target chemical Butane-1,2,3,4-tetracarboxylic acid (1703-58-8)and structurally similar read across chemical are as follows:

From the NTP report, 1991 and NTRL report (OTS02800059),1980 ten albino rats (five male and five female, COX-SD strain), weighing 230 to 272 grams, were exposed by the route of inhalation to undiluted butane tetracarboxylic acid in the powder form at a delivery flow concentration of approximately 8.19 mg per liter of air at a flow rate of 2.5 liters per minute for a period of 60 minutes plus 23 minutes for equilibration. All of the animals survived the 60 minute exposure and the 14 day observation period which followed. Body weight gain was observed. No sign of gross toxicity was observed in any animal after post exposure observation period. 3 of the 10 animal’s shows lung congestion and other animals were not remarkable.

On the basis of observation, the LD 50 value for butane tetracarboxylic acid was considered to be >8.19 mg/l of air concentations.

For the read across chemical 2,2',2''-nitrilotriacetic acid from Gestis database,2016, acute inhalation toxicity was performed in rats for 4 hrs at 5000 mg/m3 of 2, 2’, 2’’-nitrilotriacetic acid concentration. No clinical signs were seen and no mortality was observed. Based on the observation the LD 50 for acute inhalation test for 2,2',2''-nitrilotriacetic acid (139-13-9) was considered to be >5000 mg/m3(5 mg/l).

Thus, based on the above weight of evidence studies on Butane-1, 2, 3, 4-tetracarboxylic acid (1703-58-8) and read across. Comparing this value with the criteria of CLP regulation, Butane-1,2,3,4-tetracarboxylic acid (1703-58-8) can be considered to be “not classified” for acute inhalation toxicity.

Acute dermal toxicity:

Acute dermal toxicity test was performed in New Zealand Albino rabbits. Twelve New Zealand Albino rabbits, six males and six females were used and treated for 24 hrs. The rabbits weight was 2.30 to 2.86 kg were housed in metal cages elevated above droppings. Rabbits were given Purina Rabbit Chow and water ad libitium. Those animals which were without observable skin defects or irritation were used for experiment. One-half of the animals in each group were further prepared by making epidermal abrasions every two or three centimeters longitudinally over the area of exposure. A plastic binder was used onto each animal and 50% w/w suspension in isotonic saline, was introduced under the plastic binder. After the experiment the binder was removed and skin reactions were observed.

No mortality at highest dose level was observed. Few systemic signs of toxicity were observed at any dose level. At all dose levels there was moderate to severe erythema with chemical burns and/or blanching especially along abrasions. The intensity increased with the dose level. This was followed at 7 and 14 days with desquamation and drying. Gross necropsy of animal which succumbed showed the skin to have severe erythema of sides and ventrum with severe congestion appearance of chemical burns. The stomach was blanched with the mucosal surface. The small intestines showed severe scattered congestion.

As per the all observation, the LD 50 value for acute dermal toxicity for Butane-1,2,3,4-tetracarboxylic acid was considered to be 8000mg/kg bw. Based on that, Butane-1, 2, 3, 4-tetracarboxylic acid was considered to be non-toxic to rabbits and classified as “not classified “as per the CLP regulations.

Acute oral toxicity:

Based on the above studies on Butane-1, 2, 3, 4-tetracarboxylic acid (1703-58-8), it can be concluded that LD50 value is lesser than 2000 mg/kg bw. Thus, comparing this value with the criteria of CLP regulation, Butane-1,2,3,4-tetracarboxylic acid (1703-58-8) can be considered to be “classified in acute category 4” for acute oral toxicity.

Acute inhalation toxicity:

Based on the above weight of evidence studies on Butane-1, 2, 3, 4-tetracarboxylic acid (1703-58-8) and read across. Comparing this value with the criteria of CLP regulation, Butane-1,2,3,4-tetracarboxylic acid (1703-58-8) can be considered to be “not classified” for acute inhalation toxicity.

Acute dermal toxicity:

The LD 50 value for acute dermal toxicity for Butane-1,2,3,4-tetracarboxylic acid was considered to be 8000mg/kg bw. Based on that, Butane-1, 2, 3, 4-tetracarboxylic acid was considered to be non-toxic to rabbits and classified as “not classified “as per the CLP regulations.