Tetrakis(2-ethylhexyl) benzene-1,2,4,5-tetracarboxylate

Endpoint summary

Description of key information

Read-across - Skin Sensitisation in vivo, modified Buehler method similar to OECD Guideline 406: No sensitisation response was reported at challenge following a period of induction exposures to the substance.

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records

Reference

Endpoint:

skin sensitisation: in vivo (non-LLNA)

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Justification for type of information:

REPORTING FORMAT FOR THE ANALOGUE APPROACH

INTRODUCTION
In order to fulfil the information requirements according to Annex VIII to Regulation (EC) No1907/2006 which applies for tonnages in the range between 10 and 100 tonnes/year, data on physico-chemical, toxicity, ecotoxicity and environmental fate properties of a chemical must be submitted. For the registration of tetrakis(2-ethylhexyl) benzene-1,2,4,5-tetracarboxylate (EC No 221-508-0, CAS No 3126-80-5), available experimental data are confined to some physical-chemical and environmental fate information. Further information, notably for toxicicological and ecotoxicological endpoints, can be obtained from studies using the source substance tris(2-ethylhexyl) benzene-1,2,4-tricarboxylate, with the abbreviation TOTM (EC No 222-020-0, CAS No 3319-31-1). Data on structurally related ester compounds with other aliphatic alcohols can strengthen the read-across approach. In this regard, trioctyl benzene-1,2,4-tricarboxylate is considered as supporting compound.

The read-across justification relies on the principles detailed in the Guidance on information requirements and chemical safety assessment, Chapter R.6: QSARs and grouping of chemicals (ECHA, 2008), and the Read-Across Assessment Framework document (ECHA, 2017). The read-across hypothesis implies that different, but structurally similar compounds produce the same type of effects, or both are characterized by the absence of effects (analogue approach - Scenario 2). The properties of the target substance are predicted to be quantitatively equal or lower when compared to those of the source substance (worst-case prediction). Similar but not identical (bio-)transformation products or metabolites with the same type of functional groups may occur but are not exclusively the basis for the read-across hypothesis.

The source and the supporting compounds are characterized by a low-toxicity profile, with minor concerns arising from repeated dose and reproduction toxicity testing of the source substance. Due to the low systemic toxicity, information on the mode of action is limited which otherwise could be used to improve the read-across hypotheses. On the other hand, regarding the environmental fate, the source substance tris(2-ethylhexyl) benzene-1,2,4-tricarboxylate is known to be not readily biodegradable.

It will have to be shown that tris(2-ethylhexyl) benzene-1,2,4-tricarboxylate (TOTM) and tetrakis(2-ethylhexyl) benzene-1,2,4,5-tetracarboxylate do not share the properties, especially the mammalian toxicity, of phthalates such as bis(2-ethylhexyl) phthalate, with the abbreviation DEHP (EC No 204-211-0, CAS No 117-81-7), which proved to be an endocrine disruptor. Toxicokinetic studies in mammals indicate significant differences in gastrointestinal hydrolysis, metabolism and absorption between TOTM and DEHP which can explain the dissimilarity in the toxicity profile.


1. HYPOTHESIS FOR THE ANALOGUE APPROACH
The rationale for the hypothesis is described in the Guidance on information requirements and chemical safety assessment, Chapter R.6: QSARs and grouping of chemicals (ECHA, 2008), and the Read-Across Assessment Framework document (ECHA, 2017). The read-across hypothesis implies that different, but structurally closely related compounds produce the same type of effects, or are characterized by the absence of effects, due to similar, biological active or inactive structural characteristics (analogue approach - Scenario 2).

Here, the properties of the target substance are predicted to be quantitatively equal or lower when compared to those of the source substance which represent the worst-case. This assumption is based on the observation that the toxicity decreases with an increasing number of formic acid residues attached to the phenyl ring (2 in phthalates, 3 in the source, 4 in the target compound). An explanation for this observation would be that the hydrolysis rate decreases with an increasing number of formic acid residues which are in an ester bond with 2-ethylhexan-1-ol. At the same time, resorbable mono-esters are formed to a lower extend. The sub-structure feature, which is shared by phthalates as well as the source and target compound, is phthalic acid, synonym 1,2-benzenedicarboxylic acid. Except for the hydrolysis product 2-ethylhexan-1-ol, which seems to be of low toxicological relevance, the biotransformation products or metabolites are similar as they show the same type but not the same number of functional groups. Details are reported in sections 4.1-3.

Moreover, lower toxicity of the target is also expected since the phthalate DEHP is specified as an impurity of the source but not of the target compound. Actually, the low concentrations of DEHP present as an impurity showed no significant influence on the outcome of toxicity studies. Thus, the hazard values established for the source substance constitute a worst-case because the target substance is less potent in terms of biological effects (“inert”).

For the source chemical, a comprehensive database is available which shows that the substance has a low toxicity profile. Irritating/corrosion effects on skin and eye, and skin sensitization were not observed. An OECD 422 screening test did not indicate developmental toxicity effects. Only marginal effects on reproductive organs were considered as not adverse. Observed changes in clinical chemistry parameters and liver weights of lower toxicological relevance could have been caused by an adaptive response. The target chemical is expected to share the low toxicity profile due to similar structural features.

Although the target and source chemicals are proposed by OECD Toolbox (v. 4.1) profiling to be attributed to the OECD HPV Chemical Category of High molecular weight phthalate esters this not constructive for the prediction of (eco-) toxicological effects. Well established differences in toxicokinetics (absorption, metabolism) of the source chemical and supporting compounds in comparison to phthalate esters such as bis(2-ethylhexyl) phthalate (DEHP, EC No 204-211-0, CAS No 117-81-7) can endorse this view and provide an explanation for the divergence in the biological activity found in toxicity and ecotoxicity studies. All these outlined arguments will be elucidated in more detail in the following sections.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
The compound to be registered, tetrakis(2-ethylhexyl) benzene-1,2,4,5-tetracarboxylate (EC No 221-508-0, CAS No 3126-80-5), with the IUPAC name 1,2,4,5-tetrakis(2-ethylhexyl) benzene-1,2,4,5-tetracarboxylate, is a mono constituent substance in the physical form of a liquid (also identified as tetra(2-ethylhexyl) pyromellitate, common name tetraoctyl pyromellitate, abbreviation TOPM). The purity grade is ≥ 99 % (w/w), with water and ethanol as main impurities.

The source, specified as tris(2-ethylhexyl) benzene-1,2,4-tricarboxylate (EC No 222-020-0, CAS No 3319-31-1), is also a mono constituent chemical. The following alternative names are known:1,2,4-tris(2-ethylhexyl) benzene-1,2,4-tricarboxylate, TOTM, tris(2-ethylhexyl) benzene-1,2,4-tricarboxylate, and tris(2-ethylhexyl) trimellitate. The common name is trioctyl trimellitate. According to information on the appearance, physical state, and colour of the registered source substance, the substance is liquid at standard temperature and pressure with pale yellow colour and faint odour. The purity grade is in the range between 98.29% and 100% (w/w). Chemical analysis revealed bis(2-ethylhexyl) phthalate (abbreviation DEHP, EC No 204-211-0, CAS No 117-81-7) as an impurity which is found in the concentration range from 0.0 to 0.07% (w/w), with a typical concentration of 0.05% (w/w). The identity of other impurities is unknown.

Identity of the source and target substance:

Chemical Target substance Source substance
EC number 221-508-0 222-020-0
EC name Tetrakis(2-ethylhexyl) Tris(2-ethylhexyl) benzene-1,2,4-tricarboxylate
benzene-1,2,4,5-tetracarboxylate
CAS number 3126-80-5 3319-31-1
IUPAC name 1,2,4,5-tetrakis(2-ethylhexyl) Tris(2-ethylhexyl) benzene-1,2,4-tricarboxylate
benzene-1,2,4,5-tetracarboxylate
Other names Tetra(2-ethylhexyl) pyromellitate, 1,2,4-tris(2-ethylhexyl) benzene-1,2,4-tricarboxylate, TOTM, tris(2-ethylhexyl)
tetraoctyl pyromellitate, trimellitate, trioctyl trimellitate.
abbreviation TOPM
Molecular formula C33H54O6 C33H54O6
Smiles CCCCC(CC)COC(=O)c1cc(C(=O)OCC CCCCC(CC)COC(=O)c1ccc(C(=O)OCC(CC)CCCC)c(c1)C(=O)OCC(CC)CCCC
(CC)CCCC)c(cc1C(=O)OCC(CC)CCCC)C(=O)OCC(CC)CCCC
Molecular weight 702.507 g/mol 546.7783
Description Discrete chemical, mono constituent, organic Discrete chemical, mono constituent, organic
Physical form Liquid at 25°C Liquid at 25°C
Purity grade ≥ 99 % (w/w) 98.29%-100% (w/w)
Impurities Water and ethanol 0.0-0.07% (w/w) bis(2-ethylhexyl) phthalate (EC No 204-211-0),
and impurities of unknown identity

3. ANALOGUE APPROACH JUSTIFICATION
[Summarise here based on available experimental data how these results verify that the read-across is justified]

Functional groups and substituents
The chemical structures of the target and the source substances can be described as esters of 2-ethylhexanol with pyromellitic acid and trimellitic acid, respectively. Four or three formic acid residues which show an ester bond with branched alkane substituents are attached to an aromatic ring (benzol), respectively. The organic functional groups are specified in Table 3 (see attached 'Read-across justification' in IUCLID section 13.2) which shows that the target and the source chemical are characterized by the same type of organic functional groups. Only the number of ‘carboxylic acid esters’ with ‘alkanes, branched with tertiary carbon’ is varying (4 vs 3, respectively). The sub-structure feature, which is shared by phthalates as well as the source and target compound, is phthalic acid, synonym 1,2-benzenedicarboxylic acid. The conformation, i.e. spatial arrangement of atoms in the molecules of the target and the source substance, is flexible.

PubChem substructure similarity features
The structural similarity of the target and source read-across substances has in addition been verified by application of PubChem substructure similarity features which are implemented in OECD Toolbox (v. 4.1).

Method: The PubChem generates a substructure fingerprint for each chemical structure. These fingerprints are used for similarity neighboring. In this context, a substructure is a fragment of chemical structure. A fingerprint is an ordered list of binary (1/0) bits. Each bit represents a Boolean determination of specific atom or test features. 7 groups of PubChem features have been defined:
• Hierarchical element counts;
• Rings;
• Simple atom pairs;
• Simple atom nearest neighbors;
• Detailed atom neighbors;
• Simple SMARTS patterns (SMART is a language that allows specifying substructures by using rules that are straightforward extensions of SMILES);
• Complex SMARTS patterns.

Results: The target compound shares 111 out of 112 substructure features with the source whereas the source compound shares 111 out of 113 substructure

The assessment of similarities in compounds the organism is exposed to relies on experimental data regarding the toxicokinetics of tris(2-ethylhexyl) benzene-1,2,4-tricarboxylate as well as the prediction of hydrolysis products and metabolites by OECD Toolbox (v. 4.1) both for the source and target read-across substance. Hydrolysis of ester bonds by intestinal and liver esterases is also well established (Younggil, 2001). Moreover, substantial information on in vivo metabolism of phthalates such as mono(2-ethylhexyl) phthalate (MEHP, CAS No 4376-20-9, EC No 224-477-1) is considered since differences in metabolism can endorse the view that tris(2-ethylhexyl) benzene-1,2,4-tricarboxylate and tetrakis(2-ethylhexyl) benzene-1,2,4,5-tetracarboxylate are less toxic than low molecular weight phthalates.

Please refer to IUCLID section 7.1.1 'Basic toxicokinetis' and IUCLID section 13.2 'read-across justification' for detiailed information about absorption, distribution, metabolism and excretion of the source and target substance.

Prediction of metabolites by the hydrolysis simulator (acidic) and hydrolysis simulator (basic) resulted in an identical set of 7 metabolites in each case for tetrakis(2-ethylhexyl) benzene-1,2,4,5-tetracarboxylate, and a set of 8 metabolites for tris(2-ethylhexyl) benzene-1,2,4-tricarboxylate. Obviously, the prediction is based on the assumption that the ester bonds of trimellitic acid and pyromellitic acid, respectively, are successively hydrolysed, with the result that all of the possible isomers are released. An overview of predicted hydrolysis products and compounds yielded by the metabolism simulators is presented below, along with experimental data.

Summary of toxicokinetics with conclusions on similarities:

Hydrolysis by esterases is considered to be an important first step in the oral absorption of ortho-phthalates. The potential for such hydrolysis to occur with the source substance tris(2-ethylhexyl) benzene-1,2,4-tricarboxylate has been examined in an in-vitro study using rat gut homogenate. There was no evidence of hydrolysis occurring wheras the corresponding phthalate, bis(2-ethylhexyl) phthalate (abbreviation DEHP, EC No 204-211-0, CAS No 117-81-7), was significantly hydrolysed.
The absorption, distribution, metabolism and elimination of the radiolabeled source substance have been investigated in the rat following oral administration of a single dose. Recovery of the administered dose was 94%, with approximately 75% eliminated unchanged in the faeces, 16.3% found in the urine and 1.9% in expired air. Residual radioactivity in the carcass after 6 days was <0.6% of the administered dose. Findings indicate that the compound may be partially hydrolysed in the gastro-intestinal tract to 2-ethylhexan-1-ol and the corresponding di-ester and, following further hydrolysis, the mono-ester. Only 2-ethylhexanol and a single isomer of the monoester (i.e. mono-(2-ethylhexyl) trimellitate) appear to be absorbed. Following absorption, 2-ethylhexanol was extensively metabolised with metabolites eliminated in the urine and as expired 14CO2. There was no evident metabolism of mono-(2-ethylhexyl) trimellitate, this being eliminated unchanged. Urinary excretion of radioactivity was bi-phasic with half-lives of 3.1 and 42 hours.
When barriers to absorption are by-passed by intravenous administration, the source chemical has been found to distribute mainly in the liver, lungs and spleen. Excretion of the substance or its metabolites over 14 days was slow with 21.3% and 2.8% of the administered dose found in the faeces and urine, respectively, suggesting a half-life of approximately 40 days. While data from the intravenous route may suggest a possible concern for potential bioaccumulation, the substance is poorly absorbed by the oral route, and the kinetics of urinary elimination suggest a far shorter half-life, indicating a lower potential for bioaccumulation.
An in vitro dermal absorption study using full-thickness skin samples in a Franz diffusion cell system showed that the compound is not systemically bioavailable after dermal exposure. This finding is supported by the results of the IH SkinPerm model. Due to the low vapor pressure, a significant respiratory uptake from airborne vapors can be excluded.

Regarding similarities in chemical structures, physico-chemical properties (see below), and in addition results of OECD Toolbox profiling, similar toxicokinetic characteristics are expected for the target substance. This means that the ester bonds of tetrakis(2-ethylhexyl) benzene-1,2,4,5-tetracarboxylate will probably be successively hydrolysed at a low rate in the gastrointestinal tract. The hydrolysis products 2-ethylhexan-1-ol and mono-(2-ethylhexyl) pyromellitate will likely be absorbed to a low extend. 2-Ethylhexan-1-ol but not the mono-ester will undergo further phase-I metabolism. There is no evidence that carboxyl groups of the source and target compounds are modified during phase I-metabolism, or metabolites are produced which play a role for the toxicological behavior of phthalates.
In conclusion, except for the hydrolysis product 2-ethylhexan-1-ol, the biotransformation products or metabolites of the source and target compound are similar as they show the same type but not the same number of functional groups. Available toxicokinetic data may imply that the extend of monoester formation in the gastrointestinal tract, as well as the absorption and systemic bioavailability decreases with an increasing number of ester bonds (2 ester bonds occur in phthalates, 3 in the source substance, 4 in the target substance). Therefore, it seems to be plausible that the gastrointestinal absorption of hydrolysis products of the target substance, i.e. the potential metabolites 2-ethylhexan-1-ol and mono-(2-ethylhexyl) pyromellitate, is very low. The latter metabolite will possibly not undergo a phase-I metabolism but rather be excreted unchanged in the urine, similarly to mono-(2-ethylhexyl) trimellitate. Especially due to low water solubility < 1 mg/L, the target substance is predicted by the IH SkinPerm model to be not absorbed through the skin. The low volatility of the target substance as well as the octanol-water partition coefficient (log Po/w of 6.01) will obviate a significant respiratory uptake


Synopsis of physico-chemical properties
Pyromelliate (Target) TOTM (Source)
Physical state Liquid at 20 °C and 101.3 kPa Liquid at 20 °C and 101.3 kPa
Melting / freezing point -34°C at 101,3kPa (exp.) -43 °C at 101.3 kPa (exp.)
Boiling point 573.5 °C (QSAR, SPARC by ARChem) 355 °C (exp.)
Relative density 0.9908 g/cm3 at 25 °C 0.9885 g/cm3
Granulometry Not applicable (liquid state) Not applicable (liquid state)
Vapour pressure 2.09E-9 hPa (QSAR, MPBPWIN™ 6.8E-10 hPa at 25 °C (exp.)
by EPI Suite v4.1)
Partition coefficient
n-octanol/water (log value) 6.01 (exp.) 8.00 at 25 °C and pH 4.8 (exp.)
Water solubility < 1 mg/L at 30 °C (exp.) 3.06 µg/L at 25 °C (exp.)
(identical to the cut-off value for insolubility
in water according to ECHA guidance)
Surface tension Study scientifically not necessary in accordance with ECHA guidance
Flash point 262 °C (exp.) 224 °C (exp.)
Autoflammability / self-ignition temperature Study scientifically not necessary, flash point >200 °C at 101.3 kPa
Flammability Study scientifically not necessary, flash point >200 °C at 101.3 kPa
Explosive properties Study scientifically not necessary - the substance contains no chemical groups associated with explosive properties.
Oxidising properties Based on a consideration of the chemical structure of the substance, oxidising properties do not
need to be assessed.
Stability in organic solvents and
identity of relevant degradation products The stability of the substance in organic solvents is not considered to be critical.
Dissociation constant Study scientifically not necessary - the substance does not contain any functional groups that dissociate.
Viscosity 1.7 cm2/s at 40°C 0.87 cm2/s at 40 °C (kinematic viscosity, exp.)
(kinematic viscosity, exp.)
*Published data, cf. UNEP (2002) and ECHA (2013-2017)

Based on experimental data and QSARs, the relevant physico-chemical properties of the source and target substance are similar. This supports the view that their pattern of biological effects and the underlying mechanisms may also show analogies.

The assessment of similarities in compounds the organism is exposed to (section 4.2), with reference to the corresponding Assessment Element 2.1 of the RAAF document (ECHA, 2017), relies on experimental data for the source compound and predictions (OECD Toolbox, IH SkinPerm model) combined with theoretical considerations for the target compound. Due to a very low oral and dermal absorption rate with very low systemic bioavailability, non-common compounds (with the same type but not the same number of functional groups) are considered as not relevant in vivo. On this basis, the assessment option “acceptable with medium confidence” is chosen.

Both the source and supporting compound have shown a low toxicity profile, without local and systemic toxicity effects except for minor findings, which were regarded as non-adverse, after repeated exposure to the supporting chemical. More in detail, in a Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test according to OECD TG 422 using 1,2,4-benzenetricarboxylic acid, trioctyl ester some irregularities in clinical-chemistry parameters were noted in male and female rats at the mid and/or high dose level (125 and 500 mg/kg bw/day orally, respectively). At 500 mg/kg bw/day significant changes in liver weights of females were recorded. These findings may be attributed to treatment but could represent an adaptive response.

The information presented in paragraph 4.3 suggests that the hypothesis of common underlying biological mechanisms, both in qualitative and quantitative aspects (Assessment Elements 2.2 and 2.3 according to the RAAF-document, see ECHA, 2017) is acceptable. With respect to the fact that no toxicity studies for the target compound are available, the assessment option “acceptable with just sufficient confidence” may be appropriate. For the specific case, the Assessment Elements 2.4 (Exposure to other compounds than to those linked to the prediction) and 2.5 (Occurrence of other effects than covered by the hypothesis and justification) are considered as not relevant.

Skin sensitisation properties
Results of the Buehler test show that the source substance does not evoke skin sensitisation. Based on structural similarity, the absence of skin sensitization properties is also expected for the target substance.

4. DATA MATRIX
see Section 13.2 'Read across justification' and 'Data Matrix'

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across: supporting information

Remarks:

read-across justification

Reason / purpose for cross-reference:

read-across: supporting information

Remarks:

Toxicokinetic

Species:

guinea pig

Strain:

other: albino

Sex:

male

Route:

epicutaneous, occlusive

Vehicle:

unchanged (no vehicle)

Concentration / amount:

0.5 mL pure substance

Day(s)/duration:

24 h / 10 times

Adequacy of induction:

not specified

Route:

epicutaneous, occlusive

Vehicle:

unchanged (no vehicle)

Concentration / amount:

0.5 mL pure substance

Day(s)/duration:

24 h

Adequacy of challenge:

not specified

No. of animals per dose:

10

Positive control substance(s):

no

Positive control results:

No positive control group

Key result

Reading:

1st reading

Hours after challenge:

24

Group:

test chemical

Dose level:

pure substance

No. with + reactions:

0

Total no. in group:

10

Clinical observations:

No data

Remarks on result:

other: Reading: 1st reading. . Hours after challenge: 24.0. Group: test group. Dose level: 100% tris(2-ethylhexyl) benzene-1,2,4-tricarboxylate. No with. + reactions: 0.0. Total no. in groups: 10.0. Clinical observations: No data.

Key result

Reading:

2nd reading

Hours after challenge:

48

Group:

test chemical

Dose level:

pure substance

No. with + reactions:

0

Total no. in group:

10

Clinical observations:

No data

Remarks on result:

other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: test group. Dose level: 100% tris(2-ethylhexyl) benzene-1,2,4-tricarboxylate. No with. + reactions: 0.0. Total no. in groups: 10.0. Clinical observations: No data.

Reading:

other:

Group:

negative control

Remarks on result:

not measured/tested

Reading:

other:

Group:

positive control

Remarks on result:

not measured/tested

Table with results is shown in attached file (Skin sesitisation - guinea pig_tables.pdf) on page 2.

Interpretation of results:

other: EU GHS (CLP) criteria not met

Conclusions:

Under the conditions of this test is not a primary irritant, fatiguing agent or skin sensitiser in the albino guinea pig. No skin reactions were seen during the induction (sensitising) phase or subsequent challenge phase. This result can be considered the same for the target substance.

Executive summary:

Delayed dermal sensitisation of the read-across source substance tris(2-ethylhexyl) benzene-1,2,4-tricarboxylate has been assessed using an in vivo modified Buehler method similar to OECD Guideline 406 and in compliance with GLP criteria.

24 hour covered contact with 0.5 ml neat tris(2-ethylhexyl) benzene-1,2,4-tricarboxylate on the intact skin of guinea pigs was repeated on alternate days for 10 applications. After the tenth application the animals were rested for a two week period. A similar challenge application was made after a 2 week rest period. The sites were examined for irritation, if any, using the Draize method of scoring to grade reactions.

No sensitization was seen in any of the 10 animals tested. Tris(2-ethylhexyl) benzene-1,2,4-tricarboxylate did not induce sensitization.

This can be similarly transferred to the target substance tetrakis(2-ethylhexyl) benzene-1,2,4,5-tetracarboxylate, due to strong structural analogies.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not sensitising)

Additional information:

Read-across - Skin sensitization

Delayed dermal sensitisation of the source substance tris(2-ethylhexyl) benzene-1,2,4-tricarboxylate has been assessed using an in vivo modified Buehler method similar to OECD Guideline 406 and in compliance with GLP criteria.

24 hour covered contact with 0.5 ml neat tris(2-ethylhexyl) benzene-1,2,4-tricarboxylate on the intact skin of guinea pigs was repeated on alternate days for 10 applications. After the tenth application the animals were rested for a two week period. A similar challenge application was made after a 2 week rest period. The sites were examined for irritation, if any, using the Draize method of scoring to grade reactions.

No sensitization was seen in any of the 10 animals tested. Tris(2-ethylhexyl) benzene-1,2,4-tricarboxylate did not induce sensitization.

This can be similarly transferred to the target substance tetrakis(2-ethylhexyl) benzene-1,2,4,5-tetracarboxylate, due to strong structural analogies.

This outcome is supported by a QSAR prediction of tetrakis(2-ethylhexyl) benzene-1,2,4,5-tetracarboxylate as NON-Sensitizer using CAESAR computer model, although this may not be reliable.

Respiratory sensitisation

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

The source substance tris(2-ethylhexyl) benzene-1,2,4-tricarboxylate has been assessed for skin sensitization via an in vivo Buehler assay, supported with QSAR information on the target substance tetrakis(2-ethylhexyl) benzene-1,2,4,5-tetracarboxylate. The observed response data in the skin sensitization study revealed no sensitization potential at challenge following a period of induction exposures to the substance. No classification as skin sensitizer according to Regulation (EC) No 1272/2008 (CLP Regulation) is warranted.

This can be similarly transferred to the target substance tetrakis(2-ethylhexyl) benzene-1,2,4,5-tetracarboxylate, due to strong structural analogies.