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Administrative data

Description of key information

The acute oral and dermal toxicity of 1,2,4 -benzenetricarboxylic acid, mixed decyl and octyl triesters has been determined in two OECD 401 and two OECD 402 studies. The oral and dermal LD50 were determined as > 2000 mg/kg bw.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Referenceopen allclose all

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
not mentioned
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Comparable to guideline study with acceptable restrictions
Qualifier:
no guideline followed
Principles of method if other than guideline:
Principle of method equivalent to OECD guideline 401
GLP compliance:
no
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Willi Gassner (WIGA) Versuchtierzuchtanstalt, Sulzfeld, Germany
- Age at study initiation: not mentioned
- Weight at study initiation: 147-196 g (mean body weights of application groups)
- Fasting period before study: from the evening before the application day
- Housing: up to 5 animals in Makrolon cages
- Diet (e.g. ad libitum): conventional diet for rats and mice ad libitum
- Water (e.g. ad libitum): tap water ad libitum
- Acclimation period: from 3 (minimum) to 7 days (maximum)


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ±1
- Humidity (%): 55 ± 10
- Air changes (per hr): not mentioned
- Photoperiod (hrs dark / hrs light): 12 / 12


IN-LIFE DATES: not mentioned
Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
Administration of undiluted test substance as single doses
Doses:
10.0 , 13.3, 17.8, 23.7 and 31.6 mL/kg body weight
No. of animals per sex per dose:
5 animals in the 10.0 mL/kg dose group, in all other dose groups 10 animals each
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: observations up to 6 hours (at 10, 18, 33 minutes and 1.0, 1.8, 3.3 and 6.0 hours) after dosing and subsequently daily; weighing before treatment and 7 and 14 days after application
- Necropsy of survivors performed: yes
- Other examinations performed: Deaths and overt signs of toxicity, individual bodyweights
Statistics:
probit analysis according to Finney, D.J., Cambridge 1952; Chi square test, alpha = 0.05, according to Weber, E., Jena 1964
Sex:
male
Dose descriptor:
LD50
Effect level:
ca. 24.9 mL/kg bw
95% CL:
ca. 21.5 - ca. 28.8
Mortality:
- Number of deaths at each dose: 0/5 (10.0 mL/kg bw), 0/10 (13.3 mL/kg bw), 3/10 (17.8 mL/kg bw), 3/10 (23.7 mL/kg bw) and 8/10 (31.6 mL/kg bw)
- Time of death: 17.8 mL/kg bw:: 2 deaths on day 6, 1 death on day 7; 23.7 mL/kg: 1 death on day 3, 2 deaths on day 6; 31.6 mL/kg bw: 1 death on day 3, 1 death on day 6, 5 deaths on day 7 ans 1 death on day 9
Clinical signs:
other: in all dose groups animals showed reduced spontaneous activity, narrow palpebral fissures, soft faeces, reduced quantity of faeces and in some animals severe emaciation
Gross pathology:
no findings
Other findings:
none

Table: Mortality data

 concentration

[mL/kg]

 Mortality

[#dead/total]

 Time range of death

[days]

 Number of evident toxicity

[#/total]

 10.0  0/5  -  5/5
 13.3  0/10  -  10/10
 17.8  3/10  6 - 7  10/10
 23.7  3/10  3 - 6  10/10
 31.6  8/10  3 - 9  10/10

 

 

Interpretation of results:
GHS criteria not met
Conclusions:
In the study performed the dosis letalis media (LD50 oral) to male rats of WITAMOL 218 Nr. 770928 was found to be 24.9 mL/kg bodyweight with a 95% confidence limit of 21.5 - 28.8.
Executive summary:

The test substance "WITAMOL 218 Nr. 770928" was evaluated for the LD50 oral to male rats as single intragastric application. The test substance was administered undiluted in the following dose levels: 10.0, 13.3, 17.8, 23.7 and 31.6 mL/kg bodyweight. 10 animals per dose level were treated with test substance with an exception in the 10.0 mL/kg dose level, where only 5 animals were used.

The observation of clinical signs and recording of mortality were carried out up to 14 days after application. Gross necropsy was conducted at animals found dead and at termination of the observation period in all dose groups.

Body weight gains were inconsistent throughout the study. In the first week after application the body weights of the 23.7- and 31.6 mL/kg-group were equal, while the mean body weights of the animals of the 17.8 mL/kg-group were reduced.

In all dose groups animals showed signs of toxicity. Mainly reduced spontaneous activity, soft faeces and reduced quantity of faeces were recorded. From day 12 on the majority of the surviving animals were free of symptoms. Gross necropsy revealed no observalble abnormalities.

In the study performed the dosis letalis media (LD50 oral) to male rats of "WITAMOL 218 Nr. 770928" was found to be 24.9 mL/kg bodyweight with a 95% confidence limit of 21.5 - 28.8.

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
from 1989-04-19 to 1989-05-03
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Guideline study without detailed documentation
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
GLP compliance:
no
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Winkelmann, Borchen, Germany
- Age at study initiation: young healthy adults, no further details mentioned
- Weight at study initiation: 113 g (mean)
- Fasting period before study: 16 hours
- Housing: 1 - 5 animals in Makrolon cages, type III
- Diet (e.g. ad libitum): R10 Complete feed for rats ad libitum, supplied by Ssniff Spezialfutter GmbH, Soest, Germany
- Water (e.g. ad libitum): Drinking water ad libitum
- Acclimation period: 5 - 8 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 ± 1
- Humidity (%): 60 ± 5
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12


IN-LIFE DATES: From: 1989-04-19 To: 1989-05-03
Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
MAXIMUM DOSE VOLUME APPLIED: 3.06 cm³/kg

DOSAGE PREPARATION (if unusual): test substance was applied undiluted
Doses:
3000 mg/kg body weight
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: Examination of clinical signs up to 6 hours after the treatment and daily observations thereafter; bodyweights were determined before treatment, and 1, 7 and 14 days after treatment.
- Necropsy of survivors performed: yes
- Other examinations performed: no
Statistics:
The means of the body weights were calculated.
The LD50 was determined according to Litchfield and Wilcoxon and reported with 95% confidence limits (J. Pharmacol. Exp. Ther. 96, 1949, 99)
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 3 000 mg/kg bw
Mortality:
0/10
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:
In the study performed the LD50 to rats of 1,2,4-Benzenetricarboxylic acid, mixed decyl and octyl triesters was found to be > 3000 mg/kg bodyweight.
Executive summary:

A study was performed to assess the acute oral toxicity of 1,2,4-Benzenetricarboxylic acid, mixed decyl and octyl triesters to the rat. A group of 10 rats (5 male and 5 female) was given a single oral application of the test substance at a dose level of 3000 mg/kg bodyweight. The undiluted liquid test substance was administered by gavage using a stomach tube with an application volume at 3.06 cm³/kg bodyweight.

There were no deaths and no signs of systemic reaction to treatment. All animals achieved satisfactory bodyweight gains throughout the study.

The rats were killed and examind macroscopically on day 14, the end of the observation period. The macroscopical examination revealed no abnormalities.

The dosis letalis media (LD50 oral) to male and female rats of 1,2,4-Benzenetricarboxylic acid, mixed decyl and octyl triesters was found to be > 3000 mg/kg.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
> 3 000 mg/kg bw

Acute toxicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Acute toxicity: via dermal route

Link to relevant study records

Referenceopen allclose all

Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
12 March 2014 to 26 March 2014
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP study conducted in accordance with OECD and US Guidelines.
Qualifier:
according to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
yes
Remarks:
On Day 1, the 4 hour postdose detailed clinical observations were conducted between 11 and 12 minutes late for animal numbers 9001 and 9002. In the opinion of the Study Director, this deviation did not affect the quality or integrity of the study.
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.1200 (Acute Dermal Toxicity)
Deviations:
yes
Remarks:
On Day 1, the 4 hour postdose detailed clinical observations were conducted between 11 and 12 minutes late for animal numbers 9001 and 9002. In the opinion of the Study Director, this deviation did not affect the quality or integrity of the study.
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
other: CD® [Crl:CD®(SD)]
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Portage, Michigan
- Age at study initiation: Approximately 7 weeks
- Weight at study initiation: Males: 187 to 196 g Females: 159 to 165 g
- Fasting period before study: Not specified.
- Housing: The animals were individually housed in solid bottom cages with non-aromatic bedding.
- Diet: Lab Diet® (Certified Rodent Diet #5002, PMI Nutrition International, Inc.) was available ad libitum.
- Water: Tap water was available ad libitum via an automatic watering system.
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): Temperature was continuously monitored, recorded, and maintained to the maximum extent possible within the range of 68 to 79°F
- Humidity (%): Humidity was continuously monitored, recorded, and maintained to the maximum extent possible within the range of 30 to 70%, respectively.
- Air changes (per hr): NOt specified.
- Photoperiod (hrs dark / hrs light): Fluorescent lighting was provided for approximately 12 hours per day. On occasion, the dark cycle may have been interrupted intermittently due to study-related activities.

IN-LIFE DATES: From: 5 March 2014 To: 26 March 2014

Type of coverage:
semiocclusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- Area of exposure: 10% of the body surface area.
- Type of wrap if used: gauze dressing (<8 ply) and secured with non-irritating tape.

REMOVAL OF TEST SUBSTANCE
- Washing: washed with tepid tap water and a Wypall®
- Time after start of exposure: 24 hours

TEST MATERIAL
- Amount(s) applied: 2000 mg/kg

Approximately 24 hours prior to administration on Day 1, the hair was clipped with an electric clipper and fine clipper blade from the dorsal surface of the animal (at least 15% of the body surface area [BSA] or most of the dorsal surface area).

BSA (10%) was determined by identifying the individual animal body weight (g), approximating the total BSA (cm2), and then determining the dosing surface area (cm x cm). This dosing surface area was measured and used per individual to evenly distribute the test article with the side of the plastic syringe used for withdrawing the test article.

Appropriately sized Elizabethan collars (e-collars) were applied following administration.


Duration of exposure:
24 hours
Doses:
2000 mg/kg
No. of animals per sex per dose:
5 per sex per dose
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Observations for morbidity, mortality, injury, and the availability of food and water were
conducted twice daily for all animals. Observations for clinical signs were conducted approximately 30 postdose and at 2 and 4 hours postdose on the day of administration and daily until Day 14. Body weights were measured and recorded prior to administration on Day 1 and weekly thereafter (Days 8 and 15).
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weights.
Statistics:
No statistical analyses were required or performed for this study.
Preliminary study:
Not applicable.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
All animals survived to study termination.
Clinical signs:
other: Red and black material was noted around the nose and eyes of several animals beginning at approximately 30 minutes postdose. The findings were no longer present by Day 2. These findings are most likely attributed to the wearing of the Elizabethan collars
Gross pathology:
No test article-related macroscopic observations were made in male or female rats. All tissues of all animals examined at necropsy were within normal limits.
Other findings:
None
Interpretation of results:
GHS criteria not met
Conclusions:
Under the conditions of this study, where the substance was applied as a single dermal dose to rats, the LD50 was greater than 2,000 mg/kg.
Executive summary:

The acute dermal toxicity of the test substance was determined in accordance with OECD Guideline 402.

The acute dermal LD50 was greater than 2,000 mg/kg.

Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
from 2009-05-18 to 2009-06-18
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Harlan Italy S.r.l., San Pietro al Natisone (UD), Italy
- Age at study initiation: 6 to 8 weeks
- Weight at study initiation: 275.0 ± 3.7 g (mean weight males), 215.6 ± 10.9 g (mean weight females)
- Housing: Polycarbonate cages measuring 42.5x26.6x18 cam with stainless steel mesh lid and floor
- Diet (e.g. ad libitum): 4 RF 18 ad libitum, supplied by Mucedola S.r.l., Settimo Milanese (MI), Italy
- Water (e.g. ad libitum): drinking water ad libitum
- Acclimation period: at least 5 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 2
- Humidity (%): 55 ± 15
- Air changes (per hr): 15 - 25
- Photoperiod (hrs dark / hrs light): 12/12


IN-LIFE DATES: From: 2009-06-3 To: 2009-06-18
Type of coverage:
semiocclusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- Area of exposure: dorsal surfaces of the trunk
- % coverage: 10 %
- Type of wrap if used: A patch of surgical gauze covered by a strip of synthetic film was placed over the treated site and the whole assembly held in place by encyrcling the trunk of the animal with a lenght of elastic adhesive bandage.


REMOVAL OF TEST SUBSTANCE
- Washing (if done): yes, by gentle swabbing of the skin with cotton wool soaked with lukewarm water
- Time after start of exposure: 24 hours


TEST MATERIAL
- Amount(s) applied (volume or weight with unit): Aliquots were weighed accordingly to the body weight of each animal measured prior to dosing, no further details mentioned
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: Mortality and morbidity twice daily, clinical signs were recorded on dosing, approx. 1, 2 and 4 hours after dosing and daily thereafter, body weights were recorded on the day of allocation (day -1), days 1, 8 and 15 (day of necropsy)
- Necropsy of survivors performed: yes
- Other examinations performed: no
Statistics:
not performed
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Mortality:
no mortality occurred
Clinical signs:
other: no clinical signs were observed
Gross pathology:
At necropsy examination performed on all animals at termination of the study red areas (multiple, pinpoint) in the right lobe of the thymus were noted in a single female animal. No abnormalities were found in the ranimnif animals.
Interpretation of results:
GHS criteria not met
Conclusions:
The acute toxicity of 1,2,4-Benzenetricarboxylic acid, mixed decyl and octyl triesters was investigated following dermal administration of a single dose to the rat at 2000 mg/kg.
No mortality occurred following dosing and no signs of toxicity were observed.
These results indicated that the test item has no toxic effect on the rat following dermal exposure over a 24 hour period at a level of 2000 mg/kg. The lack of mortality demonstrated the LD50 to be greater than 2000 mg/kg.
Executive summary:

The acute toxicity of 1,2,4-Benzenetricarboxylic acid, mixed decyl and octyl triesters was investigated following dermal administration of a single dose to the rat at 2000 mg/kg according to OECD guideline 402, adopted on 24 February 1987 and Test method B.3 "Acute Toxicity (dermal)" described in Council Regulation (EC) No. 440/2008.

A single dose of 2000 mg/kg was administered to a group o 5 male and 5 female animals for 24 hours. After 14 days all animals were killed and subjected to necropsy examination. No mortality occurred following dosing and no signs of toxicity were observed. The body weight changes observed during the study were within the expected range for this species and age of animals. No significant abnormalities were found at necropsy in the animals at termination of the study. No abnormalities were observed at the treated site.

These results indicated that the test item has no toxic effect on the rat following dermal exposure over a 24 hour period at a level of 2000 mg/kg.

The lack of mortality demonstrated the LD50 to be greater than 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 decyl and octyl triesters has been determined in two acute oral studies (OECD 401 or similar to) and two OECD 402 acute dermal studies in rats.


Experimental studies in rats show a very low acute oral toxicity for 1,2,4-Benzenetricarboxylic acid, mixed decyl and octyl triesters. No clinical effects were observed at doses of 3000 mg/kg. Mortalities occurred at doses of 17319 mg/kg and above.


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


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

Justification for classification or non-classification

The oral and acute LD50 -values exceed clearly the cut-off value for classification according to Regulation (EC) No 1272/2008.


Overall, the acute oral and dermal toxicity of 1,2,4-Benzenetricarboxylic acid, mixed decyl and octyl triesters is low and does not warrant classification.