Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
388 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
The available information comprises adequate, reliable (Klimisch score 2) and consistent studies from a reference substance with similar structure and intrinsic properties. Read-across is justified based on structural similarity between the source and target substance.
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

There are only limited data available on the toxicity to reproduction of 1,2-Benzenedicarboxylic acid, di-C16-C18-alkyl esters (CAS 90193-76-3). In order to fulfil the standard information requirements set out in Annex VII and VIII, 8.4, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006, read-across from structurally related substances was conducted.

In accordance with Article 13 (1) of Regulation (EC) No 1907/2006, "information on intrinsic properties of substances may be generated by means other than tests, provided that the conditions set out in Annex XI are met.” In particular for human toxicity, information shall be generated whenever possible by means other than vertebrate animal tests, which includes the use of information from structurally related substances (grouping or read-across).

Having regard to the general rules for grouping of substances and read-across approach laid down in Annex XI, Item 1.5, of Regulation (EC) No 1907/2006 whereby substances may be predicted as similar provided that their physicochemical, toxicological and ecotoxicological properties are likely to be similar or follow a regular pattern as a result of structural similarity.

Overview of reproduction toxicity

CAS

Toxicity to reproduction

90193-76-3 (a)

RA: CAS 68515-43-5

68515-43-5 (b)

2 -generation study: NOAEL = 300 mg/kg bw/day

(a) The substance subject to registration is indicated in bold font.

(b) Reference (read-across) substances are indicated in normal font. Lack of data for a given endpoint is indicated by “--“.

The above mentioned substance is considered to be similar on the basis of the structural similar properties and/or activities. The available endpoint information is used to predict the same endpoints for 1,2-Benzenedicarboxylic acid, di-C16-C18-alkyl esters (CAS 90193-76-3). A detailed analogue approach justification is provided in the technical dossier (see IUCLID Section 13).

Discussion

CAS 68515-43-5

The toxicity to reproduction of 1,2-Benzenedicarboxylic acid, di-C9-11-branched and linear alkyl esters (CAS No. 68515-43-5) has been investigated in a two generation toxicity study according to EPA OPPTS 870.3800.

A two generation oral feeding study on reproduction and fertility effects was performed with 1,2-Benzenedicarboxylic acid, di-C9-11-branched and linear alkyl esters (CAS No. 68515-43-5) according to EPA OPPTS 870.3800 (Willoughby, 2000). The major treatment-related effect was a severe reduction in adult male body weight gain, with a lesser effect in females. There was no treatment-related deterioration of fertility or fecundity at any dose level. The only effect upon reproductive parameters attributable to treatment was a reduction in epididymides weight at the highest dose level of 1,2-Benzenedicarboxylic acid, di-C9-11-branched and linear alkyl esters. However, in the absence of functional or histopathologic changes, the significance of these observations is unclear.

Transiently reduced body weight of offspring in both generations may be a secondary response to depression of maternal body weight gain or a direct effect of the test substance in the diet resulting from pups eating it. Reductions in organ weights (except liver) are also attributed to a nonspecific response to reduced body weight. The livers of male rats, and to a lesser extent females, showed the classic biochemical, morphologic, and histologic changes that would be expected of a substance of the peroxisome proliferator class—specifically hypertrophy, hyperplasia, and an increase in the activity of palmitoyl CoA oxidase.

The NOAEL for effects upon reproductive health parameters and general systemic toxicity for 1,2-Benzenedicarboxylic acid, di-C9-11-branched and linear alkyl esters was 0.5% in the diet (approx. 300 mg/kg bw/day) for F0 and F1 animals. This NOAEL was based on transient depression of offspring body weight gain (males and females), reduced parental body weight gain (males), and reduced reproductive organ weights (males and females).

 

Additionally, a 90-d oral feeding study with 1,2-Benzenedicarboxylic acid, mixed cetyl and stearyl esters (CAS No. 68442-70-6) was performed similar to OECD guideline 408 (Rivett, 1972). Upon oral feeding with doses up to 1200 mg/kg bw/day no histopathologic changes were observed in ovaries and testes.

 

Conclusion for toxicity to reproduction

A two generation study is available for 1,2-Benzenedicarboxylic acid, di-C9-11-branched and linear alkyl esters (CAS No. 68515-43-5) with a NOAEL of 300 mg/kg bw/day based on adverse effects on transient depression of offspring body weight gain (males and females), reduced parental body weight gain (males), and reduced reproductive organ weights (males and females). In a 90-d oral feeding study with doses up to 1200 mg/kg bw/day no histopathologic changes were observed in ovaries and testes.


Short description of key information:
A NOAEL for fertility of 300 mg/kg bw/d in parental and F1 rats was determined in a two-generation reproduction toxicity study with the Read Across substance 1,2-Benzenedicarboxylic acid, di-C9-11-branched and linear alkyl esters (MW 418.62 – 474.73). This would refer to an equimolar NAEL of 388 mg/kg bw/d for 1,2-Benzenedicarboxylic acid, di-C16-18-alkyl esters (MW 614.98 – 671.09) using a conversion factor of 1.29 (614.98 / 474.73).

Justification for selection of Effect on fertility via oral route:
Hazard assessment is conducted by means of read-across from structural analogues. The selected study is the most adequate and reliable study based on the identified similarities in structure and intrinsic properties between source and target substances and overall assessment of quality, duration and dose descriptor level (refer to the endpoint discussion for further details).

Effects on developmental toxicity

Description of key information
The equimolar NAEL of 1290 mg/kg bw/d for developmental toxicity for 1,2-Benzenedicarboxylic acid, di-C16-18-alkyl esters (MW 614.98 – 671.09) was derived from the developmental NOAEL value established at 1000 mg/kg/day for the Read Across substance 1,2-Benzenedicarboxylic acid, di-C9-11-branched and linear alkyl esters (CAS No. 68515-43-5, MW 418.62 – 474.73) using a conversion factor of 1.29 (614.98/474.73).
Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
The available information comprises adequate, reliable (Klimisch score 2) and consistent studies from a reference substance with similar structure and intrinsic properties. Read-across is justified based on structural similarity between the source and target substance.
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

Developmental toxicity/teratogenicity

Justification for grouping of substances and read-across

There are only limited data available on the developmental toxicity of 1,2-Benzenedicarboxylic acid, di-C16-C18-alkyl esters (CAS 90193-76-3). In order to fulfil the standard information requirements set out in Annex VII and VIII, 8.4, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006, read-across from structurally related substances was conducted.

In accordance with Article 13 (1) of Regulation (EC) No 1907/2006, "information on intrinsic properties of substances may be generated by means other than tests, provided that the conditions set out in Annex XI are met.” In particular for human toxicity, information shall be generated whenever possible by means other than vertebrate animal tests, which includes the use of information from structurally related substances (grouping or read-across).

Having regard to the general rules for grouping of substances and read-across approach laid down in Annex XI, Item 1.5, of Regulation (EC) No 1907/2006 whereby substances may be predicted as similar provided that their physicochemical, toxicological and ecotoxicological properties are likely to be similar or follow a regular pattern as a result of structural similarity.

Overview of reproduction toxicity

CAS

Developmental toxicity

90193-76-3 (a)

RA: CAS 68515-43-5

RA: CAS 68442-70-6

68515-43-5 (b)

NOAEL = 1000 mg/kg bw/day

68442-70-6

NOAEL ≥ 90 mg/kg bw/day

(a) The substance subject to registration is indicated in bold font.

(b) Reference (read-across) substances are indicated in normal font. Lack of data for a given endpoint is indicated by “--“.

The above mentioned substance is considered to be similar on the basis of the structural similar properties and/or activities. The available endpoint information is used to predict the same endpoints for 1,2-Benzenedicarboxylic acid, di-C16-C18-alkyl esters (CAS 90193-76-3). A detailed analogue approach justification is provided in the technical dossier (see IUCLID Section 13).

CAS 68515-43-5

A prenatal developmental toxicity study was performed with the read across substance 1,2-Benzenedicarboxylic acid, di-C9-11-branched and linear alkyl esters (D911P, CAS No. 68515-43-5) according to EPA OPPTS 870.3700 (Fulcher, 2001). Groups of 22 timed-mated Sprague-Dawley rats were administered 250, 500, or 1000 mg/kg D911P daily by oral gavage (5 mL/kg) between gestation days (GD) 1 and 19. Control animals received the vehicle (olive oil) alone. On GD20, the animals were sacrificed and the fetuses examined. In this study the only findings in fetuses were increased incidence of rudimentary supernumerary ribs at 500 mg/kg bw/d and increased incidence of dilated renal pelves at 1000 mg/kg bw/d. Rudimentary supernumerary ribs, defined as being less than 50% the length of the 13th rib, are a common skeletal variation that occurs spontaneously at a high frequency in rats. This variation is spontaneously reversible in rats and its incidence diminishes as the animals mature. In conclusion, D911P has a low potential to adversely affect development in the rat. Administration of doses up to 1000 mg/kg/day throughout gestation induced no detectable toxicity in the dams, and resulted only in minor skeletal and visceral variations (non-adverse). There was no evidence of malformations following treatment. The NOAEL for maternal and developmental toxicity is therefore established at 1000 mg/kg/day.

 

CAS 68442-70-6

1,2-Benzenedicarboxylic acid, mixed cetyl and stearyl esters (CAS No. 68442-70-6) was tested for its teratogenicity in a Prenatal Developmental Toxicity Study performed equivalent to OECD Guideline 414 (Derache, 1983). The highest tested dose of only 90 mg/kg bw/day did not induce abnormalities in the implantation rates, number of abortions, number of resorptions or number of living fetuses. No malformations or nanisms occurred in the control and treated groups. Litter sizes and average body weight of fetuses were comparable between control and treated animals.

 

Conclusion for developmental toxicity/teratogenicity

Two studies investigating the developmental toxicity via the oral route are available for the structural analogues 1,2-Benzenedicarboxylic acid, di-C9-11-branched and linear alkyl esters (D911P, CAS No. 68515-43-5) and 1,2-Benzenedicarboxylic acid, mixed cetyl and stearyl esters (CAS No. 68442-70-6). Due to no observed adverse effetcs the NOAEL for maternal and developmental toxicity was set at 1000 mg/kg bw/day.

Effects on developmental toxicity:

A waiver for the requirement to perform a prenatal developmental toxicity study in a 2nd species was included, as this requirement is considered not to add new information for hazard assessment and therefore is scientifically and, considering concerns regarding the use of vertebrate animals for experimental purposes, unjustified.


Justification for selection of Effect on developmental toxicity: via oral route:
Hazard assessment is conducted by means of read-across from structural analogues. The selected study is the most adequate and reliable study based on the identified similarities in structure and intrinsic properties between source and target substances and overall assessment of quality, duration and dose descriptor level (refer to the endpoint discussion for further details).

Justification for classification or non-classification

Based on read-across from the structurally similar substances, the available data on the toxicity to reproduction 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.