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EC number: 615-086-0 | CAS number: 70225-05-7
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data

Repeated dose toxicity: oral
Administrative data
- Endpoint:
- short-term repeated dose toxicity: oral
- Type of information:
- migrated information: read-across based on grouping of substances (category approach)
- Adequacy of study:
- key study
- Study period:
- 1984
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: Conducted according to sound scientific principles. GLP.
Data source
Referenceopen allclose all
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 984
- Reference Type:
- publication
- Title:
- Tris(2-ethylhexyl)benzene-1,2,4-tricarboxylate
- Author:
- ACC Phthalate Esters Panel HPV Testing Group
- Year:
- 2 006
- Bibliographic source:
- IUCLID 4 Data Set, HPV chemical
Materials and methods
Test guideline
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- Tris(2-ethylhexyl)benzene-1,2,4-tricarboxylate
- IUPAC Name:
- Tris(2-ethylhexyl)benzene-1,2,4-tricarboxylate
- Reference substance name:
- Tris(2-ethylhexyl) benzene-1,2,4-tricarboxylate
- EC Number:
- 222-020-0
- EC Name:
- Tris(2-ethylhexyl) benzene-1,2,4-tricarboxylate
- Cas Number:
- 3319-31-1
- Molecular formula:
- C33H54O6
- IUPAC Name:
- tris(2-ethylhexyl) benzene-1,2,4-tricarboxylate
- Reference substance name:
- Nuoplaz 6959
- IUPAC Name:
- Nuoplaz 6959
- Details on test material:
- Tris(2-ethylhexyl)benzene-1,2,4-tricarboxylate Source: Nuoplaz 6959 Purity: 98.2% (GC/FID) 97.9% (HPLC) Impurities were detected at level than 0.1-0.5%, one being di(2-ethylhexyl) phthalate (DEHP).
Constituent 1
Constituent 2
Constituent 3
Test animals
- Species:
- rat
- Strain:
- Fischer 344
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- Age at study initiation: 48-51 days old for males and females.
Weight at study initiation: 137-154g for male; 111-132g for female.
No. of animals per sex per dose: 5 Rats per sex per dose group.
Administration / exposure
- Route of administration:
- oral: feed
- Vehicle:
- other: diet
- Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Food intakes were measured over the period day -3 to 0 and continuos intakes were measured at twice-weekly intervals until the day preceding autopsy. The intakes of test article or reference compound for each animal were calculated twice weekly using the analysed dietary concentrations of TOTM or DEHP, and the individual valued for bodyweight and food intake.
- Duration of treatment / exposure:
- 28 days
- Frequency of treatment:
- once daily, 7 days/week
Doses / concentrationsopen allclose all
- Remarks:
- Doses / Concentrations:
0, 0.2, 0.67, 2.0 %
Basis:
actual ingested
- Remarks:
- Doses / Concentrations:
0, 184, 650, 1826 mg/kg bw/day
Basis:
actual ingested
- No. of animals per sex per dose:
- 5 Rats per sex per dose group.
- Control animals:
- yes, plain diet
- Details on study design:
- Vehicle: Diet
Clinical observations performed and frequency: Body wt. was recorded immediately prior to the first exposure and again for each animal 1, 3, 7, 10, 14, 17, 21, 24, 27th days. Twice each day the animals were observed in their cages for variations in behaviour or condition, and once weekly a more detailed examination was made at the time of a weighing. Food intakes were measured over the period day -3 to 0 and continuos intakes were measured at twice-weekly intervals until the day preceding autopsy. The intakes of test article or reference compound for each animal were calculated twice weekly using the analysed dietary concentrations of TOTM or DEHP, and the individual valued for bodyweight and food intake.
Haematologic parameters were evaluated for each animal. On the day preceding the start of the autopsies a sample of blood was collected from a caudal vein of each animal. Autopsy: At the end of the 28th day treatment period the rats were deprived of food overnight, with water available. On the day of autopsy each animal was weighted and then killed. The blood was used to provide serum for clinical chemistry. During the autopsy any abnormalities of the external condition and of the thoracic or abdominal viscera were noted.
Organs: The weight of the following organs was recorded: adrenal glands, lungs, brain, ovaries, heart, spleen, kidneys, testes, liver and thyroids.
Serum chemistry was performed for each animal. Serum separated from the blood taken prior to autopsy was analyzed. Liver biochemistry was performed for each animal. Homogenized liver tissues were measured for protein, cyanide-insensitive palmitoyl-CoA, carnitine acetyltranferase and catalase.
Histopathology was made for haematoxylin and eosin stained sections from paraffin embedded samples, of all the preserved tissues. Transmission electron microscopy: Two thin slices of liver, one from the left lobe, the other from the median lobe, were fixed for analysis. (The remainder of the liver was used for biochemical analysis.)
Examinations
- Observations and examinations performed and frequency:
- Body wt. was recorded immediately prior to the first exposure and again for each animal 1, 3, 7, 10, 14, 17, 21, 24, 27th days. Twice each day the animals were observed in their cages for variations in behaviour or condition, and once weekly a more detailed examination was made at the time of a weighing. Food intakes were measured over the period day -3 to 0 and continuos intakes were measured at twice-weekly intervals until the day preceding autopsy. The intakes of test article or reference compound for each animal were calculated twice weekly using the analysed dietary concentrations of TOTM or DEHP, and the individual valued for bodyweight and food intake.
- Sacrifice and pathology:
- At the end of the 28th day treatment period the rats were deprived of food overnight, with water available. On the day of autopsy each animal was weighted and then killed. The blood was used to provide serum for clinical chemistry. During the autopsy any abnormalities of the external condition and of the thoracic or abdominal viscera were noted.
- Statistics:
- The control and TOTM treated groups were subject to analysis of variance, and if this was significant the treated groups were compared with the controls using the Least Significant Difference test. The controls and DEHP groups were compared using a two-tailed pooled student t test with Welch's correction. In all cased a probability level of P<0.05 was taken to indicate statistical significance.
Results and discussion
Results of examinations
- Clinical signs:
- no effects observed
- Mortality:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- no effects observed
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- no effects observed
- Ophthalmological findings:
- not examined
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- effects observed, treatment-related
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Gross pathological findings:
- no effects observed
- Histopathological findings: non-neoplastic:
- no effects observed
- Histopathological findings: neoplastic:
- no effects observed
- Details on results:
- Body weight: No statistically significant differences of bodyweight between the control and TOTM treated groups of either sex. There was a trend for the male rats from all the TOTM treated groups to be lighter than the controls (92 to 97% of control). In the females, this trend was only evident in the 2.0% TOTM group (94% of control).
Food/water consumption: Female rats fed 2.0% TOTM consumed significantly less diet than the controls during first seven days of treatment after which their intakes increased but remained lower than those of the controls. In the males there were no statistically significant differences between the control and TOTM fed groups during the treatment period.
Haematology: In both sexes haemoglobin concentration of the rats given diet containing 0.67 or 2.0% TOTM were statistically significantly lower than the control (94 to 97% of control). In the males there was a small lowering of erythrocyte count in all groups given TOTM (96 to 97% of control) but this was not reproduced in the females. Both sexes given the two higher dietary concentrations of TOTM had higher leucocyte counts than the control (118 to 123% of control), but the differences were statistically significant only in the males. These male groups also had lower proportions of the leucocytes as eosinophils and monocytes (42 to 67 and 26 to 37%, respectively). Significantly lower values for haemotocrit and mean cell volume were limited to females given the two lower dose levels of TOTM (91 to 95 and 96 to 97% , respectively).
Organ weights: In both sexes the liver weights, and liver weights relative to bodyweight, were increased in the TOTM (114 to 135% of control) treated animals compared to the controls. These differences were small and not statistically significant in the 0.2% TOTM group. In the males fed TOTM the higher values for brain weights relative to body weight, in the absence of any significant differences in the recorded weight probably reflect the lower bodyweights in the groups concerned. In the females there were statistically significant higher lung weights in the rats fed 0.2 or 0.67% TOTM when compared to the controls. In the case of the TOTM treated animals this difference was not dose related and not statistically significant when expressed relative to bodyweight.
Serum analyses: Analysis of serum from the males and females showed statistically significantly increased levels of albumin in the groups given 0.67 or 2.0% TOTM (104 to 108% of control). In the males there were statistically significantly higher cholesterol levels in the 0.67 and 2.0% TOTM groups (115 to 125% of control). Concentration of serum urea was statistically significantly increased in the male 2.0% TOTM group to the control value (115%). In the females there was also an isolated statistically significantly lower value for lipid concentration in the 0.2% TOTM group (83% of control).
Liver Biochemistry: TOTM treatment did not influence to a statistically significant degree the concentration of hepatic protein. After TOTM treatment PCoA activity was statistically significantly higher than controls in both sexes at the highest dose and in the males at the lower two doses (133 to 237% of control). In the groups given TOTM only the highest dose level males had statistically significant increases of catalase level (165% of control). Both sexes given 0.67 or 2.0% TOTM had statistically significantly increased carnitine acetyltransferase activity with little difference between the two sexes (262 to 1002% of control).
Histopathology: No abnormalities were detected in the majority of the animals. The only lesions occurring with any frequency were focal interstitial pneumonitis and nephrocalcinosis in the females. The observations were not firmly dose related. The pneumonitis was of limited extent, often only a single focus. Two female rats fed 2.0% TOTM showed reductions in cytoplasmic basophilia in the liver although it was only marginal.
Transmission Electron Microscopy: In the hepatocytes from the control rats the peroxisomes varied in size from small to moderately large. They had uniformly electron dense contents and some possessed a lattice core. They were ubiquitously distributed throughout the cytoplasm. Feeding diet containing 2.0% TOTM produced a slight increase in the numbers of peroxisomes which varied between cells. No difference was seen between the centrilobular and periportal areas.
Effect levels
open allclose all
- Dose descriptor:
- NOAEL
- Effect level:
- 184 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- clinical biochemistry
- haematology
- immunology
- organ weights and organ / body weight ratios
- Dose descriptor:
- LOAEL
- Effect level:
- 650 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- clinical biochemistry
- haematology
- immunology
- organ weights and organ / body weight ratios
Target system / organ toxicity
- Critical effects observed:
- not specified
Applicant's summary and conclusion
- Conclusions:
- The NOAEL for the test material was determined to be 184 mg/kg bw/day.
Classification as a repeat oral toxicant is not warranted under the new Regulation (EC) 1272/2008 on classification, labeling and packaging of substances and mixtures (CLP) or under Directive 67/548/EEC for dangerous substances and Directive 1999/45/EC for preparations. - Executive summary:
Male and female Fischer 344 rats were exposed to 0(0), 0.2(184), 0.67(650) and 2(1826) % (mg/kg bw/day) of the test material, tris(2-ethylhexyl)benzene-1,2,4-tricarboxylate. The test material was incorporated into the feed and was given once daily for 28 days. Actual consumption was measured. At the end of the 28 day period, the test animals were sacrificed and body weight, food/water consumption, haematology, organ weights, serum analysis, liver biochemistry, and histopathology were performed on all animal. A decrease in hemoglobin and an increase of leucocyte counts and serum cholesterol as well as an incrased liver weight in the mid and high dose groups (0.67 and 2.0%) were noted. Liver biochemistry revealed an increase in palmitoyl CoA oxidation (increased in both sexes at 2.0% and males at all dose levels) and catalase activity (increased in males at 2.0%), suggesting the induction of peroxisome proliferation. Futher analysis by electron microscope indicated a slight increased number of peroxisomes in hepatocytes at the high dose. It is generally accepted that the induction of peroxisome proliferation occurs specifically in rodents but much less in other species including humans. There were no dose-related histopathological changes in any treated groups. The NOAEL for the test material was determined to be 184 mg/kg bw/day.
Classification as a repeat oral toxicant is not warranted under the new Regulation (EC) 1272/2008 on classification, labeling and packaging of substances and mixtures (CLP) or under Directive 67/548/EEC for dangerous substances and Directive 1999/45/EC for preparations.
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