Registration Dossier

Administrative data

Description of key information

All available acute oral toxicity studies within this category resulted in acute oral LD50 > 2000 mg/kg bw. 
All available acute inhalation toxicity studies within the category resulted in acute inhalation LC50 > 2.6 mg/L.
All available acute dermal toxicity studies within the category resulted in acute inhalation LD50 > 2000 mg/kg bw.

Key value for chemical safety assessment

Acute toxicity: via oral route

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Acute toxicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Acute toxicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Additional information

Justification for grouping of substances and read-across

The Polyfunctional acid ester (PFAE) aromatic category covers fatty alcohol esters of Benzene-1,2,4-tricarboxylic acid. The category contains both mono constituent and UVCB substances with fatty alcohol carbon chain lengths from C8-C13 (linear and iso-alcohols) building tri-esters with Benzene-1,2,4-tricarboxylic acid in variable proportions. A further surrogate substance of similar structure is included, namely a triester of Benzene-1,2,4-tricarboxylic acid with a C8 alcohol, but the alcohol moiety is branched (2-ethylhexyl).

The available data allows for an accurate hazard and risk assessment of the category and the category concept is applied for the assessment of environmental fate, environmental and human health hazards. Thus, where applicable, environmental and human health effects are predicted from adequate and reliable data for source substance(s) within the group by interpolation to the target substances in the group (read-across approach) applying the group concept in accordance with Annex XI, Item 1.5, of Regulation (EC) No 1907/2006. In particular, for each specific endpoint the source substance(s) structurally closest to the target substance is/are chosen for read-across, with due regard to the requirements of adequacy and reliability of the available data. Structural similarities and similarities in properties and/or activities of the source and target substance are the basis of read-across.

A detailed justification for the grouping of chemicals and read-across is provided in the technical dossier (see IUCLID Sections 7.1 and 13) and within Chapter 5.1 of the CSR.

Endpoint specific data matrix:

Table: Acute toxicity

ID No.

CAS

Acute toxicity: Oral

Acute toxicity: Inhalation

Acute toxicity: Dermal

#1

3319-31-1 (c)

Experimental result:
LD50 > 2000 mg/kg bw

Experimental result:
LD50 > 2.6 mg/L

--

#2

90218-76-1 (b) (former CAS: 67989-23-5)

Experimental result:
LD50 > 3000 mg/kg bw

--

Experimental result:
LD50 > 2000 mg/kg bw

#3

36631-30-8

Experimental result:
LD50 > 4800 mg/kg bw

--

--

#4

94279-36-4 (a)

Experimental result:
LD50 > 2000 mg/kg bw

RA: CAS 3319-31-1

 

RA: CAS 90218-76-1

#5

72361-35-4

RA: CAS 90218-76-1

RA: CAS 36631-30-8

RA: CAS 3319-31-1

RA: CAS 3319-31-1

 

RA: CAS 90218-76-1

(a) Category members subject to the REACh Phase-in registration deadline of 31 May 2013 are indicated in bold font.

(b) Substances that are either already registered under REACh or not subject to the REACh Phase-in registration deadline of 31 May 2013 are indicated in normal font. Lack of data for a given endpoint is indicated by “--“.

(c) Surrogate substances are either chemicals forming part of a related category of structurally similar fatty acid esters or precursors/breakdown products of category members (i.e. alcohol and fatty acid moieties). Available data on these substances are used for assessment of toxicological properties by read-across on the same basis of structural similarity and/or mechanistic reasoning as described below for the present category.

 

Acute oral toxicity

CAS 94279-36-4

One study performed according to OECD 401 under GLP conditions is available to evaluate the acute oral toxicity of 1,2,4-Benzenetricarboxylic acid, tri-C9-11-alkyl esters (CAS 94279-36-4). The acute oral toxicity of 1,2,4-Benzenetricarboxylic acid, tri-C9-11-alkyl esters (no data on purity) was investigated in 5 Sprague-Dawley rats per sex, which received the undiluted test substance at a limit dose of 2000 mg/kg bw via oral gavage (Dreher, 1991). No mortality occurred during the 14-day observation period and no clinical signs were observed. Based on the results, the oral LD50 value was considered to be greater than 2000 mg/kg bw.

CAS 90218-76-1

The acute toxicity via the oral route of 1,2,4-Benzenetricarboxylic acid, mixed decyl and octyl triesters has been investigated in rats in two studies (CAS 90218-76-1).

In an acute oral study performed according to OECD 401(no GLP), 5 Wistar rats per sex were treated via oral gavage with undiluted 1,2,4-Benzenetricarboxylic acid, mixed decyl and octyl triesters (99% pure) at a limit dose of 3000 mg/kg bw (Mürmann, 1989). No mortality or clinical effects were seen within the observation period of 14 days. Thus, the oral LD50 value for rats was considered to be greater than 3000 mg/kg bw.

In a further study performed according to a protocol similar to OECD 401 (no GLP), Wistar rats were orally administered different doses of 1,2,4-Benzenetricarboxylic acid, mixed decyl and octyl triesters (no data on purity) per gavage and observed for 14 days (Billmeyer, 1978). Applied doses included 10.0, 13.3, 17.8, 23.7, and 31.6 mL/kg body weight, corresponding to 9730, 12940, 17320, 23060, and 30750 mg/kg bw, respectively (based on a density of 0.973 g/mL). The dose groups consisted of 5 rats in the low dose group and 10 rats in the remaining groups. Mortality occurred in the three higher dose groups; 3/10 both at 17320 and 23060 mg/kg bw and 8/10 at 30750 mg/kg bw. No animal died at a dose of 9730 or 12940 mg/kg bw. Based on this result, the LD50 was calculated to be 24230 mg/kg bw. Animals of all dose groups showed reduced spontaneous activity, narrow palpebral fissures, soft faeces, and reduced quantity of faeces.

In summary, the oral LD50 of 1,2,4-Benzenetricarboxylic acid, mixed decyl and octyl triesters was greater than 3000 mg/kg bw.

CAS 3319-31-1

The acute toxicity via the oral route of Tris(2-ethylhexyl) benzene-1,2,4-tricarboxylate has been investigated in rats in two studies (CAS 3319-31-1).

The acute oral toxicity of Tris(2-ethylhexyl) benzene-1,2,4-tricarboxylate (> 99% pure) was investigated in a study performed according to OECD guideline 401 under GLP conditions (Ohba, 1996). 5 Crj: CD(SD) rats per sex were treated with Tris(2-ethylhexyl) benzene-1,2,4-tricarboxylate (40% in corn oil) via oral gavage at a limit dose of 2000 mg/kg bw followed by a 14-day observation period. No mortality occurred and no clinical signs were observed except loose stool until 5 hours after administration. Based on this results the LD50 was greater than 2000 mg/kg bw.

In the second study that was performed equivalent to OECD 401 (no data on GLP), 5 Alderley Park SPF albino rats per sex were treated with Tris(2-ethylhexyl) benzene-1,2,4-tricarboxylate (no data on purity) in corn oil at a limit dose of 5200 mg/kg bw via oral gavage (Southwood, 1987). No mortality occurred and no significant clinical signs were observed during the observation period of 14 days. Thus, the LD50 was greater than 5200 mg/kg bw based on the result of this study.

In summary, the oral LD50 with Tris(2-ethylhexyl) benzene-1,2,4-tricarboxylate was greater than 2000 mg/kg bw.

CAS 36631-30-8

The acute toxicity via the oral route of Triisodecyl benzene-1,2,4-tricarboxylate has been investigated in rats in one study (CAS 36631-30-8).

The acute oral toxicity of Triisodecyl benzene-1,2,4-tricarboxylate (no data on purity) was investigated in a study performed according to a protocol equivalent to OECD 401 (no data on GLP). 5 Wistar rats per sex were treated with undiluted Triisodecyl benzene-1,2,4-tricarboxylate via oral gavage (Bouffechoux, 1996) at a limit dose of 5 mL/kg bw (corresponding to 4800 mg/kg bw based on a density of 0.96 g/mL). No mortality occurred and no clinical signs of toxicity were observed. Based on this result the LD50 was greater than 4800 mg/kg bw.

Acute inhalation toxicity

CAS 3319-31-1

The acute inhalation toxicity of Tris(2-ethylhexyl) benzene-1,2,4-tricarboxylate was investigated in an inhalation standard acute test performed equivalent to OECD 403 under GLP conditions (Hagensen and Cholakis, 1982) in male rats (Birch, 1972). 5 Sprague-Dawley rats per sex were whole body exposed to aerosols of Tris(2-ethylhexyl) benzene-1,2,4-tricarboxylate (98.95% pure) at a limit concentration of 2588.6 mg/m³ (approx. 2.6 mg/L) for 4 hours following an observation period of 14 days. The concentration was determined gravimetrically but no data on particle size was given. No mortality occurred and no clinical signs were noted except matted and drenched coats for the first 2 days. At necropsy, reddening patches on the lungs were detected in all males and in 3/5 females. Based on this result, the LC50 (4 h) was greater than 2.6 mg/L.

Acute dermal toxicity

CAS 90218-76-1

In an acute dermal toxicity study performed according to OECD 402 under GLP conditions undiluted 1,2,4-Benzenetricarboxylic acid, mixed decyl and octyl triesters (> 97.5% pure) was dermally applied to 5 Sprague-Dawley rats per sex at a limit dose of 2000 mg/kg bw under semiocclusive conditions (Salvador, 2009). The site of application was the dorsal surface of the trunk with coverage of at least 10%. After treatment duration of 24 hours, test substance residues were gently washed off. No mortality occurred during the observation period of 14 days and no clinical signs of toxicity were observed. At necropsy, red areas (multiple, pinpoint) in the right lobe of the thymus were noted in a single female animal. However, this effect was not considered treatment-related. Based on the result of this study, the dermal LD50 was greater than 2000 mg/kg bw.

Conclusion for acute toxicity

In summary, 6 studies are available studying the acute oral toxicity of PFAE aromatic category members resulting in oral LD50 values greater than 2000 mg/kg bw. For acute inhalation toxicity,one study is available within the PFAE aromatic category. From this study a LC50 value of >2.6 mg/L air were determined for male and female rats at the highest achievable doses. An acute dermal toxicity study from one category member showed no effects at the limit dose of 2000 mg/kg bw.

Thus, the available data indicate a very low level of acute toxicity for the category members and thus no hazard for acute oral, inhalation and dermal toxicity was identified.

Justification for classification or non-classification

According to Article 13 of Regulation (EC) No. 1907/2006 "General Requirements for Generation of Information on Intrinsic Properties of substances", information on intrinsic properties of substances may be generated by means other than tests e.g. from information from structurally related substances (grouping or read-across), provided that conditions set out in Annex XI are met. Annex XI, "General rules for adaptation of this standard testing regime set out in Annexes VII to X” states that “substances whose physicochemical, toxicological and ecotoxicological properties are likely to be similar or follow a regular pattern as a result of structural similarity may be considered as a group, or ‘category’ of substances. This avoids the need to test every substance for every endpoint". Since the group concept is applied to the members of the PFAE aromatic Category, data will be generated from representative reference substance(s) within the category to avoid unnecessary animal testing. Additionally, once the group concept is applied, substances will be classified and labelled on this basis.

Based on the group concept, all available data on acute toxicity do not meet the classification criteria according to Regulation (EC) 1272/2008 or Directive 67/548/EEC, and are therefore conclusive but not sufficient for classification.