1,2,4-Benzenetricarboxylic acid, mixed lauryl and octyl triesters

Endpoint summary

Description of key information

The acute oral and dermal toxicity of 1,2,4 -benzenetricarboxylic acid, mixed dodecyl and octyl triesters has been determined in two OECD 423 and an OECD 402 study. The oral and dermal LD50 were determined as > 2000 mg/kg bw. An additional OECD 403 inhalation study conducted at the maxiumum attainable concentration determined the LC50 >2.24 mg/L.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Reference 1

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

1989

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Guideline:

OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)

GLP compliance:

yes (incl. QA statement)

Remarks:

Safety evaluation center, Shenyang Research Institute of Chemical Industry, China

Test type:

acute toxic class method

Limit test:

yes

Species:

rat

Strain:

Sprague-Dawley

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Beijing Vital River Laboratory Animal Technology Co., Ltd.
- Age at study initiation: 8-12 weeks
- Weight at study initiation: 193 - 212 g
- Fasting period before study: overnight
- Housing: Animals were raised in suspended, stainless, steel cages (32x28x20 cm) on cage racks (167x70x171 cm), 10 cages per layer, 4 layers per rack, animals were housed individually during the test
- Diet (e.g. ad libitum): sterilized diet with complete nutrition supplied by Beijing keaoxieli Feed Co., Ltd. (Product License No. SCXK (jing) 2012-0004, Batch No 15033213)
- Water (e.g. ad libitum): Water was purified by HT-R01000 purity system, ad libitum
- Acclimation period: 5 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21.1 - 24.1
- Humidity (%): 44 - 69
- Air changes (per hr): not mentioned
- Photoperiod (hrs dark / hrs light): 12/12


IN-LIFE DATES: From: 2015-04-30 To: 2015-05-21

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

Each animal was dosed once. The dosing volume was calculated according to the fasted body weight weighed before dosing. After the test item had been administered, food would be withheld for a further 3-4 hours.

DOSAGE PREPARATION (if unusual): test substance was applied undiluted

Doses:

2000 mg/kg body weight

No. of animals per sex per dose:

6

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
Mortality inspecition: twice daily during normal working day, once daily at weekends and public holidays
- Frequency of observations: Clinical observations were made once after 30 minutes and at 1, 2 and 4 hours after dosing and then once a day
Observations included skin, eyes and mucous membranes, and also respiratory, circulatory, autonomic and central nervous system, and somatomotor activity and behaviour pattern, attention had been directed to observations of tremors, convulsions, salivation, diarrhoea, lethargy, sleep and coma
-bodyweights were determined on the day of treatment, and 7 and 14 days thereafter or at death.
- Necropsy of survivors performed: yes, carefully eye examinations of the abdominal, thoracic organs and their contents of all animals
- Other examinations performed: no

Statistics:

The means of the body weights were calculated.

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

0/6

Clinical signs:

other: no clinical effects observed

Gross pathology:

no changes of organs macroscopically visible

Other findings:

none

Interpretation of results:

GHS criteria not met

Conclusions:

Based on the results the acute oral toxicity of the test item 1,2,4-Benzenetricarboxylic acid, mixed dodecyl and octyl triesters in rats was greater than 2000 mg/kg.

Executive summary:

The study was performed to assess the acute oral toxicity in Sprague Dawley rats according to OECD 423. 1,2,4-Benzenetricarboxylic acid, mixed dodecyl and octyl triesters is practically nontoxic after oral application to rats. There were not deaths and no abnormal findings. The LD50 under the conditions of this test is greater than 2000 mg/kg bw.

Reference 2

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

30.4.2015 - 21.5.2015

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)

GLP compliance:

yes (incl. QA statement)

Remarks:

Health Care Inspectorate of Health, Welfare and Sport, Den Haag, The Netherlands

Test type:

acute toxic class method

Limit test:

yes

Specific details on test material used for the study:

N/A

Species:

rat

Strain:

Sprague-Dawley

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Beijing Vital Rive Laboratory Animal Technology Co., Ltd., China
- Age at study initiation: 8-12 weeks
- Weight at study initiation: 193 - 212 g
- Fasting period before study: overnight
- Housing: Animals were raised in suspended, stainless steel cages (32x28x20cm) on cage racks (167x70x171 cm). There were 10 cages per layer, and 4 layers per rack. Animals were housed individually during the test.
- Diet (e.g. ad libitum): sterilized diet with complete nutrition supplied by Beijing keaoxieli Feed Co., Ltd.
- Water (e.g. ad libitum): was purified by HT-R01000 purity system, ad libitum
- Acclimation period: 5 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21.1 - 24.1
- Humidity (%): 44 - 69
- Air changes (per hr): not mentioned
- Photoperiod (hrs dark / hrs light): 12/12


IN-LIFE DATES: From: 2015-04-30 To: 2015-05-21

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

Formulations were gavaged to animals' stomach using a standard gavage tube attached to a disposal syringe. Each animal was dosed once. The dosing volume was calculated according to the fasted body weight weighed before dosing. After the test item had been administered, food would be withheld for a furher 3-4 hours.
DOSAGE PREPARATION: test substance was applied undiluted

Doses:

2000 mg/kg body weight

No. of animals per sex per dose:

6

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: once in the first 30 minutes and at 1,2 and 4 hours after dosing and then once each day for up to 14 days. Observation included changes in skin and fur, eyes and mucous membranes, and also respiratory, circulatory, autonomic and central nervous systems, and somatomotor activity and behaviour pattern. Attention had been directed to observations of tremors, convulsions, salivation, diarrhoea, lethargy, sleep and coma; bodyweights were determined on day of dosing (day 0) 7 and 14 days thereafter or at death.
- Necropsy of survivors performed: yes, all animals under test, included carefully eye examinations of the abdominal, thoracic organs and their contents
- Other examinations performed: no

Statistics:

The means of the body weights were calculated.

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Mortality:

0/6

Clinical signs:

other: no clinical effects observed

Gross pathology:

no abnormalities were found at necropsy in all animals

Other findings:

none

N/A

Interpretation of results:

GHS criteria not met

Conclusions:

Based on the results, the oral LD50 in the rats for the test item was more than than 2000 mg/kg bw.

Executive summary:

The study was performed to assess the acute oral toxicity of 1,2,4 -Benzenetricarboxylic acid, mixed dodecyl and octyl ester in Sprague Dawley rats according to OECD 423. Based on the results, the oral LD50 in the rats for the test item was more than than 2000 mg/kg bw.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

July 08, 2015 - July 22, 2015

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

Version / remarks:

2009

Deviations:

yes

Remarks:

ange of humidity deviation was 71 to 72 % (instead of 30-70 %), no abnormality, therefore study results not affected. Airflow 3.4 m³/h (instead of 0-2.4 m³/h), but particle size distribution and concentration were met, has no impact on reliability

GLP compliance:

yes

Test type:

fixed concentration procedure

Limit test:

yes

Specific details on test material used for the study:

N/A

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Liaoning Changsheng Biology Technology Co., Ltd.
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: 9-10 weeks
- Weight at study initiation: 235 -347 g
- Housing: Animals were raised in suspended, stainless steel cages (32x28x20cm) on cage racks (16 7x70x171 cm). There were 10 cages per layer, and 4 layers per rack. Animals were housed individually during the test.
- Diet (e.g. ad libitum): sterilized diet with complete nutrition supplied by Beijing keaoxieli Feed Co., Ltd.
- Water (e.g. ad libitum): was purified by HT-R01000 purity system, ad libitum
- Acclimation period: not mentioned

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19.6-23.4 °C
- Humidity (%): 47-72 %
- Air changes (per hr): not mentioned
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: July 08, 2015 To: July 22, 2015

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

nose only

Vehicle:

air

Mass median aerodynamic diameter (MMAD):

ca. 2.5 µm

Geometric standard deviation (GSD):

1.98

Remark on MMAD/GSD:

inhalable fraction (% < 4 µm: 99.77-99.85 %)

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
The test item was aerosolized using a stainless steel aerosol generation system. There were many nebulizers at bottom of generation system, through which compressed air was supplied. Test item was infused into generation system through peristaltic pump, which provided a continuous supply of test item. Aerosol of test item was generated when test item met with compressed air through nebulizers. Target concentration was achieved by adjusting air flow rate and peristaltic pump infusion velocity.
Exposure Method:
Before exposure, the test animals were restrained in a tube. The exposure tubes were installed in the portholes of the inhalation chamber and the chamber was sealed up. HOPE-MED 8052 dynamic snout-only aerosol inhalation instrument was used. Filtered and compressed air (0.06 m³) was mixed with quantitative test item in exposure chamber. The moving speed of exposure airflow rate was adjusted as appropriate. The aerosol was continuously generated from generation system on the top of the chamber with an aerosol producer. The exhausted air was removed from the outlet at the bottom of the chamber to absorption unit. The content of CO2 was less than and equal to 1%.
Concentration trial:
Test item concentrations were determined prior to test animal exposure. The 4 hours exposures of the rats began once to successive concentrations measurements fell within 20 % of target concentration.
Monitoring Parameters of Exposure Chamber:
Airflow, chamber temperature, chamber, relatitive humidity, oxygen concentration (air flow rate: 3.4 m³/h), temperature: 19.6-19.8 °C, humidity 45.8-50.3 %, oxygen concentration: 21 %.
Actual concentration:
Actual concentration at the animals breathing zone was determined by using filter gravimetric analysis. Samples were collected by using fiber filter fixed in filter holder attached to ESA-3Z auto-sampling device, on which airflow time and volume were set.
- Method of particle size determination: Aerodynamic Particle Sizer (APS) 3321
Frequency of determination was 4 time and mean values of particle size was calculated as final results. Determination data was collected and analyzed by Aerosol Instrument Manager. Frequency of determination was about 1 time per hour.
- Exposure apparatus: nose-only inhalation chamber

Duration of exposure:

4 h

Remarks on duration:

N/A

Concentrations:

2.24 mg/L

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Individual weights of animals were determined at grouping, before dosing (day 0), on day 1, 3, 7 and 14.
observations during exposure: only once during the exposure, at immediately and 1 hour after dosing and then once daily for up to 14 days.
Observations of moribund and death was conducted daily at morning and afternoon, on weekends, holiday and necropsy only at the morning.
Observation included changes in fur, eyes and mucous membranes, and also respiratory system, circulating system, rhythm of breathing, changes patterns of inspiration and exhalation. Particular attention had been directed to observations of tremors, convulsions, salivation, diarrhoea, lethargy, sleep and coma.
Observation times were determined by the nature and time of onset of clinical signs and length of the recovery period. Any evidence of overt toxicity observed at each observation time was recorded.
- Necropsy of survivors performed: yes, all surviving animals were dissected at the end of the study by anesthetizing with aether inhalation and killed by exsanguination. Special attention was taken on the irritation of nose, pharynx and larynx, trachea, lung and eyes. The necropsy included following examinations such as the external features of the carcass, external body orifices, the abdominal, thoracic and their contents of all animals, and the location, size, hardness and the color. The necropsy examination findings were recorded. Histopathology examination was not conducted unless abnormal gross necropsy findings were observed.

Statistics:

N/A

Preliminary study:

N/A

Key result

Sex:

male

Dose descriptor:

LC50

Effect level:

>= 2.24 mg/L air (analytical)

Based on:

test mat.

95% CL:

0.033

Exp. duration:

4 h

Key result

Sex:

female

Dose descriptor:

LC50

Effect level:

>= 2.24 mg/L air (analytical)

Based on:

test mat.

95% CL:

0.033

Exp. duration:

4 h

Mortality:

none

Body weight:

were decreased at day 1, began to increase at day 3

Gross pathology:

No abnormalities were found at necropsy for all test animals. Histopathological examiniation was not conducted.

Other findings:

N/A

N/A

Interpretation of results:

GHS criteria not met

Conclusions:

Under the condition of this study, the single exposure acute inhalation LC50 of the test substance is greater than 2.240 mg/L in male and female rats.

Executive summary:

The study was performed to assess the acute inhalation toxicity of 1,2,4 -Benzenetricarboxylic acid, mixed dodecyl and octyl triesters in Sprague Dawley rats according to OECD 403. The study was conducted at the single maximum generated concentration of 2000 mg/m3. A group of 10 animals (5 males and 5 females) were exposed for 4 hours using a snout-only exposure system. Concentration and particle size distribution were measured. Clinical observations were performed daily throughout the exposure period of 14 days. Body weights were periodically collected. At the end of the test, a gross necropsy was performed for all surviving animals.

Actual mean concentration was 2240 +-33 mg/m3. MMAD and GSC for four determinations were 2.50 µm and 1.98, respectively. The inhalable fraction (% < 4 µm) was more than 99 %. There were no deaths during the test. No abnormalities were noted for all test animals during exposure. Mean bodyweights showed to be decreased at day 1. Mean bodyweights began to increase beginning at day 3. No abnormality was found at necropsy.

The acute inhalation median lethal concentration (LC50, 4 h) of the test item in Sprague Dawley rat was as follows: Male rats: > 2240 +- 33 mg/m³. Female rats > 2240 +- 33 mg/m³.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LC50

Value:

> 2.24 mg/L air

Physical form:

inhalation: aerosol

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Study period:

4.2.2015-13.8.2015

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Remarks:

Health Care Inspectorate of Health, Welfare and Sport, Den Haag, The Netherlands

Test type:

standard acute method

Limit test:

yes

Specific details on test material used for the study:

N/A

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Beijing Vital Rive Laboratory Animal Technology Co., Ltd., China
- Age at study initiation: 8-12 weeks
- Weight at study initiation: 245-268 g (males), 224-243 g (females)
- Housing: Animals were raised in suspended, stainless steel cages (32x28x20cm) on cage racks (16 7x70x171 cm). There were 10 cages per layer, and 4 layers per rack. Animals were housed individually during the test.
- Diet (e.g. ad libitum): sterilized diet with complete nutrition supplied by Beijing keaoxieli Feed Co., Ltd.
- Water (e.g. ad libitum): drinking water ad libitum
- Acclimation period: at least 5 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21.1 ± 24
- Humidity (%): 44-69
- Air changes (per hr): not mentioned
- Photoperiod (hrs dark / hrs light): 12/12


IN-LIFE DATES: From: 2015-04-30 To: 2015-05-19

Type of coverage:

semiocclusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

TEST SITE
Approximately 24 hours before the test, fur was removed from the dorsal area of the trunk of the test animals by shaving. Care was taken to avoid abrading the skin, which could alter its permeability.
Each animal was dosed once and only animals with healthy and intact skin were used.
The gauze with the test item was placed uniformly over the treatment area and semi-occluded with a piece of self-adhesive bandage. Shortly after dosing the dressing should be examined to ensure that the animals cannot ingest the test item.
- Area of exposure: dorsal surfaces of the trunk (clear area 40 cm²)

REMOVAL OF TEST SUBSTANCE
- Washing (if done): yes, at the end of exposure period for approximately 24 hours, residual test item was removed by cotton wool soaked in water.


TEST MATERIAL
- Amount(s) applied (volume or weight with unit): Because the test item was liquid, before administration calculate the theoretical test item used for each animal in accordance with the design of dose and animal body weight. The mean density was 941 mg/L.

Duration of exposure:

24 hours

Doses:

2000 mg/kg bw

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: once in the first 30 minutes and at 1,2 and 4 hours after dosing and then once each day for up to 14 days. Observation included changes in skin and fur, eyes and mucous membranes, and also respiratory, circulatory, autonomic and central nervous systems , and somatomotor activity and behaviour pattern. Attention had been directed to observations of tr emors, convulsions, salivation, diarrhoea, lethargy, sleep and coma; bodyweights were determined on day of dosing (day 0) 7 and 14 days thereafter or at death.
- Skin irritation: Adverse skin reactions at the site of application were recorded daily following the removal of the dressings.
- Necropsy of survivors performed: yes, all animals under test, included carefully eye examinations of the abdominal, thoracic organs and their contents

Statistics:

not performed

Preliminary study:

N/A

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Key result

Sex:

male

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

no mortality occurred

Clinical signs:

other: no clinical signs were observed

Gross pathology:

No abnormalities found.

Other findings:

No signs of dermal irritation.

N/A

Interpretation of results:

GHS criteria not met

Conclusions:

Based on the results, the acute dermal LD50 in rats for 1,2,4-Benzenetricarboxylic Acid, mixed dodecyl and octyl triesters for male rats was > 2000 mg/kg and for female rats also > 2000 mg/kg.

Executive summary:

The study was performed to assess the acute dermal toxicity of 1,2,4 -Benzenetricarboxylic acid, mixed dodecyl and octyl triesters in Sprague Dawley rats according to OECD 402. At test at one dose level of 2000 mg/kg bw was carried out in a group of 10 animals (5 males and 5 females). Clinical observations were made during the first 30 minutes, and at 1,2, and 4 hours after dosing and then once each day for up to 14 days. Individual weights of animals were determined at grouping, day 0 (day of dosing), on day 7 and 14. At the end of the test, a gross necroscopy was performed on all animals under test. There were not deaths of moribund during the test. There were no abnormal findings in all animals after dosing from the first day until the end of the test. There were no signs of dermal irritation. One animal showed a small decrease in body weight during the second week.

Based on the results, the acute dermal LD50 in rats for 1,2,4-Benzenetricarboxylic Acid, mixed dodecyl and octyl triesters for male rats was > 2000 mg/kg and for female rats also > 2000 mg/kg.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Additional information

The acute toxicity of 1,2,4 -benzenetricarboxylic acid, mixed dodecyl and octyl triesters has been determined in two OECD 423 acute oral study, an OECD 402 acute dermal and OECD 403 acute inhalation study in rats.

 

An acute dermal toxicity study of 1,2,4-Benzenetricarboxylic acid, mixed dodecyl and octyl triesters shows also a low dermal toxicity. No mortalities nor clinical effects were observed at the limit dose of 2000 mg/kg.

 

An acute inhalation study was conducted in male and female rats at the maximum attainable concentration of 2.24 mg/L (MMAD; ca 2.5 um and geometric standard deviation 1.98). Animals were exposed nose only to aerosolised test material for a 4 hour period. There was no mortality and the LD50 determined to be 2.24 mg/L in male and female rats.

 

Based on the available data it can be concluded that 1,2,4-Benzenetricarboxylic acid, mixed dodecyl and octyl triesters is of very low acute oral, dermal and inhalation toxicity.

Justification for classification or non-classification

No classification for acute oral and dermal toxicity is indicated according to the general classification and labeling requirements for dangerous substances and preparations (67/544 EEC) or the classification, labeling and packaging (CLP) regulation (EC 1272/2208).