Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
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: Reproduction toxicity

ID No.

CAS

Toxicity to reproduction – Fertility

#1

3319-31-1 (c)

Disregarded study:
NOAEL P (reproduction, female) = 1000 mg/kg bw/day
NOAEL P (reproduction, males) =

100 mg/kg bw

#2

90218-76-1 (b) 

(former CAS: 67989-23-5)

Data waiving

#4

94279-36-4 (a)

Data waiving

#5

72361-35-4

Data waiving

(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.

 

Toxicity to reproduction

CAS 90218-76-1

In the histological examination of the 28-d study (Longobardi, 2010) the evaluation of the reproductive system of male (testis, epididymis, prostate, coagulating gland and seminal vesicles) and female (ovary, uterus and vagina) animals did not show any pathological alteration in the spermatogenesis as well no irregularity in the oestrus cycle. And no changes in organ weights (ovaries, uterus, prostate gland, seminal vesicles, epididymides, and testes) were observed.

In addition, a mechanistic study was conducted to assess the potential to induce testicular mal-development (TMD) in the rat by studying effects on the expression of genes in pathways known to be involved in steroidogenesis and testes development (Plummer, 2010). 1,2,4-benzenetricarboxylic acid, mixed decyl and octyl triesters did not repress TMD target genes. It is concluded that it is highly unlikely that 1,2,4-benzenetricarboxylic acid, mixed decyl and octyl triesters would cause testicular dysgenesis in rats under these treatment conditions.

A 90-d oral toxicity study in the rat has been proposed for 1,2,4-benzenetricarboxylic acid, mixed decyl and octyl triesters (CAS 90218-76-1), a member of the PFAE aromatic Category, according to guideline OECD 408. The duration of treatment in this study is long enough to cover the full spermatogenic cycle and the reproductive male and female organs (testes/epididymides, seminal vesicles, prostate gland, ovaries, uterus, cervix, vagina, mammary gland) will be harvested at necropsy examination, selected tissues will be weighed and all tissues will be examined histologically. A further review of the need for a two-generation reproductive toxicity study may be made based on the findings in the reproductive organs from the 90-d oral toxicity study in rats.

Based on the available data it is therefore concluded that currently there is no evidence of a reproductive toxic effect for 1,2,4-benzenetricarboxylic acid, mixed decyl and octyl triesters and a two-generation reproductive toxicity study is not proposed. A further review of the need for a two-generation reproductive toxicity study may be made based on the findings in the reproductive organs from the 90-d oral toxicity study in rats.

CAS 3319-31-1

An oral gavage reproduction/developmental screening study with the surrogate substance Tris(2-ethylhexyl) benzene-1,2,4-tricarboxylate was performed in Crj:CD(SD) rats according to OECD guideline 421 under GLP conditions (Yoshimura, 1998). This study is unsuitable for an assessment of the endpoint toxicity to reproduction within the PFAE aromatic category for the following reasons: The alcohol moiety of Tris(2-ethylhexyl) benzene-1,2,4-tricarboxylate is a C8 branched molecule (2-ethylhexanol). In contrast to that, all the members of the PFAE aromatic category consist of linear (or iso) alcohol chains >/= C8. The triester Tris(2-ethylhexyl) benzene-1,2,4-tricarboxylate is structurally similar to the diester Bis(2-ethylhexyl) benzene-1,2-dicarboxylate (CAS 117-81-7). The only structural difference is that the third ester bond in para position of the aromatic ring is missing. The toxicity of Bis(2-ethylhexyl) benzene-1,2-dicarboxylate has been extensively investigated in the past and the substance has been classified as toxic to reproduction (Category 1B) according to the CLP regulation. Long chain linear Benzene-1,2-dicarboxylates (>/= C8) have not provided any evidence for reprotoxic effects. Therefore it is concluded that a read across to Tris(2-ethylhexyl) benzene-1,2,4-tricarboxylate at the endpoint toxicity to reproduction is unsuitable within the PFAE aromatic category.

Conclusion for toxicity to reproduction

In a subacute repeated dose toxicity study performed according to OECD 407 with 1,2,4-benzenetricarboxylic acid, mixed decyl and octyl triesters (CAS 90218-76-1) (dose levels: 100, 300 and 1000 mg/kg bw/day, respectively) no substance-related effects were observed on sperm parameters and histopathology of reproductive organs in males. Female fertility was also not affected. A testing proposal for a subchronic (OECD 408) study for 1,2,4-benzenetricarboxylic acid, mixed decyl and octyl triesters (CAS 90218-76-1) was made in 2010. The performance of a two generation study is only necessary if the results of this subchronic study would indicate effects on reproduction.


Short description of key information:
In a subacute repeated dose toxicity study performed according to OECD 407 with 1,2,4-benzenetricarboxylic acid, mixed decyl and octyl triesters (CAS 90218-76-1) (dose levels: 100, 300 and 1000 mg/kg bw/day, respectively) no substance-related effects were observed on sperm parameters and histopathology of reproductive organs in males. Female fertility was also not affected. A testing proposal for a subchronic (OECD 408) study for 1,2,4-benzenetricarboxylic acid, mixed decyl and octyl triesters (CAS 90218-76-1) was made in 2010. The performance of a two generation study is only necessary if the results of this subchronic study would indicate effects on reproduction.

Effects on developmental toxicity

Description of key information
One study investigating the developmental toxicity via the oral route is available for 1,2,4 -Benzenetricarboxylic acid, decyl octyl ester (CAS 90218-76-1). Due to the absence of any adverse effect, the NOAEL for developmental toxicity was set at 1000 mg/kg bw/day. 
Therefore, no hazard for developmental toxicity was identified for the members of the PFAE aromatic category.
Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
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 1: Developmental toxicity

ID No.

CAS

Toxicity to reproduction – Developmental Toxicity oral

#1

3319-31-1 (c)

 

Disregarded study:

NOAEL, fetotoxicity

 >/= 1000 mg/kg bw/day NOAEL, maternal

>/= 1000 mg/kg bw/day

#2

90218-76-1 (b)  

(former CAS: 67989-23-5)

 

Experimental result:

NOAEL, fetotoxicity

 >/= 1000 mg/kg bw/day NOAEL, maternal

= 300 mg/kg bw/day

#4

94279-36-4 (a)

RA: CAS 90218-76-1

#5

72361-35-4

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.

 

Developmental toxicity/teratogenicity

CAS 90218-76-1

The category member 1,2,4 -Benzenetricarboxylic acid, decyl octyl ester was tested in a prenatal developmental toxicity study in rats to detect the effects on pregnant animals, when the material was administered during the period of organogenesis. The study was performed according to OECD guideline 414 under GLP conditions. The test substance (≥ 97.5% pure) was administered to 24 mated female Sprague Dawley rats per group via gavage on days 6 to 19 of gestation. The animals were dosed with 100, 300, and 1000 mg/kg bw/day of the test substance in corn oil or with the vehicle alone. Animals were regularly monitored during gestation for clinical signs of toxicity and for effects on body weight and food consumption. They were killed on Day 20 of gestation. The status of each implantation was recorded and the foetuses were weighed and examined for visceral and skeletal abnormalities, including the state of skeletal ossification. No mortality occurred during the study. A total of 4 females were found not pregnant at necropsy (one in the control and mid- dose groups and two in the low dose group). Total resorption was detected in two low dose females. Both incidences were considered to be within a normal variability. The number of females with live foetuses on gestation day 20 was 23 in the control and mid-dose groups, 20 in the low dose group and 24 in the high dose group. Soft faeces and a statistically significant decrease in body weight (approximately from 4% on gestation Day 12 to 17% on gestation Day 20) and body weight gain (approximately from 34% on gestation Day 9 to 54% on gestation Day 20), corresponding to a decrease in food consumption, was found in the high dose group. Furthermore, significant reductions in terminal body weight and gravid uterus weight (approx. 16%) and absolute weight gain (approx. 67%) were evident. At post mortem examination staining of different regions of the head in 8/24 females and hair loss of different regions of the body surface in 4/24 females of the high dose group was observed. Foetal weight and consequently litter weight at 1000 mg/kg/day were statistically significantly lower than control (-12 %). A marked increase in small foetuses was noted at 1000 mg/kg/day compared with all other groups, this finding could be considered as a consequence of the maternal toxicity noted in this group. The incidence of major abnormalities (astomia, agnatia, anomaly of forepaw in only one foetus, respectively) were considered within a normal variability. Malformations such as absence of skull bones, pubis no ossification and malpositioned bones were detected in two mid-dose foetuses and two high dose foetuses, an increased incidence in incomplete or no ossification of most parts of the skeleton was noted in high dose foetuses compared to control foetuses, most of these changes were considered correlated to the lower foetal weight associated with maternal toxicity noted in this group malformations such as extremely enlarged ureter associated with extreme pelvic dilatation of kidneys were noted in one mid- and one high dose foetus, extremely enlarged ureter was also detected in two control foetuses, because the incidence of these malformations was low and not dose-related, they were considered to be incidental. On the basis of the results obtained in this study, the dosage of 300 mg/kg/day could be considered the NOAEL for maternal toxicity and the dosage of 1000 mg/kg/day the NOAEL for embryo-foetal effects. No exposure related developmental toxic effects were observed in the study.

CAS 3319-31-1

An oral gavage reproduction/developmental screening study with the surrogate substance Tris(2-ethylhexyl) benzene-1,2,4-tricarboxylate was performed in Crj:CD(SD) rats according to OECD guideline 421 under GLP conditions (Yoshimura, 1998). This study is unsuitable for an assessment of the endpoint toxicity to reproduction within the PFAE aromatic category. A detailed justification can be found in section toxicity to reproduction.

Conclusion for developmental toxicity/teratogenicity

One study investigating the developmental toxicity via the oral route is available for 1,2,4 -Benzenetricarboxylic acid, decyl octyl ester (CAS 90218-76-1). Due to the absence of any adverse effect, the NOAEL for developmental toxicity was set at 1000 mg/kg bw/day.

Therefore, no hazard for developmental toxicity was identified for the members of the PFAE aromatic category.

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 reproductive 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.