Registration Dossier

Administrative data

Description of key information

Skin irritation (OECD 404): not irritating (based on read-across from CAS 59219-71-5)
Eye irritation: not irritating (based on read-across from CAS 59219-71-5 and in vitro studies of the target substance in a weight of evidence approach)

Key value for chemical safety assessment

Skin irritation / corrosion

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Eye irritation

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Justification for grouping of substances and read-across

There are no data available on the in vivo skin and eye irritation potential of isononyl isononanoate. In order to fulfil the standard information requirements set out in Annex VIII, 8.1 and 8.2, 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 irritation / corrosion

CAS

Chemical name

Molecular weight

Skin irritation

Eye irritation

(previously 42131 -25 -9) (a)

Isononyl isononanoate

ca. 285

WoE:
Experimental result: not irritating
RA: CAS 59219-71-5

WoE:
Experimental result: not corrosive (in vitro)
RA: CAS 59219-71-5

59219-71-5 (b)

3,5,5-trimethylhexyl 3,5,5 -trimethylhexanoate

284.48

Experimental result:
not irritating

Experimental result:
not irritating

(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 substances are 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 isononyl isononanoate.

A detailed analogue approach justification is provided in the technical dossier (see IUCLID Section 13).

 

Discussion

Skin irritation

(previously CAS 42131-25-9)

A human patch test was conducted to assess the irritation potential of isononyl isononanoate to the skin of human volunteers from the general population (Guidaud, 2004). A single epicutaneous occlusive application of 20 µL on the upper back of 12 human volunteers for 24 hours was assessed for skin irritation potential 30 minutes and 24 hours after patch removal. Skin reactions were scored according to a system of no reactions to intense reactions (score of 1 – 4) for erythema, edema, vesicles, cutaneous dryness, wrinkling and glazing. The skin irritation index was calculated in comparison to reactions induced by the positive control (1% sodium lauryl sulfate). One volunteer had to be excluded from the study since no skin reactions were seen at the site exposed to the positive control. Very slight erythema was recorded for 2 subjects, whereas the remaining subjects did not show any skin reactions. Overall, a skin irritation index of 0.02 was calculated for the 11 volunteers. Since irritation indices below 0.1 signify no irritation, isononyl isononanoate was found not to be irritating to the human skin in a patch test.

CAS 59219-71-5

A primary dermal irritation study was performed with 3,5,5-trimethylhexyl 3,5,5-trimethylhexanoate (CAS 59219-71-5) similar to OECD Guideline 404 (Dufour, 1991). The shaved skin of 6 rabbits was exposed to 0.5 mL undiluted test material for 24 hours under occlusive conditions. The skin irritation effects were evaluated 24 and 72 hours after patch removal. At the 24-hour reading time point, very slight erythema (score 1) was noted in 5/6 rabbits and well-defined erythema (score 2) in 1/6 rabbits, respectively. The skin irritation effects were completely reversible within 72 h. No edema was observed in any animal.

Eye irritation

(previously CAS 42131-25-9)

Two in vitro eye irritation studies were performed using isononyl isononanoate (Boue-Grabot, 2004). In a Hen’s Egg Test Chorioallantoic Membrane (HET-CAM) assay the test substance was assessed for its acute eye irritation potential in vitro on the chorioallantoic membranes of chicken eggs (Boue-Grabot, 2004). The membranes of 4 eggs were exposed to 0.3 mL of the test substance for 20 seconds. After washing of the membranes with 5 mL saline the membranes were assessed for hyperaemia, haemorrhage and coagulation 30 seconds, and 2 and 5 minutes after removal of the test substance. The observations are scored depending on the time point for each reaction to occur (each parameter is scored at the time the effect occurs the first time). The scores obtained for the 3 parameters are summed up to give the irritation index for each egg. The mean score is calculated to obtain the primary irritancy index (IP-CAM). A positive control (3% sodium lauryl sulfate) was likewise done to ensure functionality of the assay. No reactions on the membrane could be observed following exposure to isononyl isononanoate.The irritation score was reported to be 0. The positive control, induced clear irritating phenomena on every membrane, hyperaemia and haemorrhage were observed after 30 s and 2 min, respectively, in all 4 eggs. A primary irritation index, IP-CAM, of 10.0 was obtained. In conclusion,isononyl isononanoate is not considered corrosive to the eyes in this test.

In the second in vitro study, isononyl isononanoate was tested for its cytotoxicity in fibroblasts from rabbit cornea (SIRC cell line)(Boue-Grabot, 2004). The cells were exposed in triplicates to the test substance for 30 minutes, 1 hour and 4 hours. Cytotoxicity was then determined by means of the MTT test and absorption was measured at 570 nm. The Ocular Irritation Index (IOeq) was calculated over all three incubation times. It is based on the Mean Cytotoxicity Index and calculated according to the equations established from results obtained from in vivo/in vitro correlation studies. For isononyl isononanoate the ocular irritation index was found to be 7.3. According to an interpretation scheme isononyl isononanoate is considered to be slightly irritating. However, since this is a non-validated in vitro method, the results are insufficient and inadequate for classification purposes.

CAS 59219-71-5

An acute eye irritation study was performed with 3,5,5-trimethylhexyl 3,5,5-trimethylhexanoate (CAS 59219-71-5) according to a protocol similar to OECD 405, on 3 New Zealand White rabbits (Dufour, 1990). One eye of the rabbits was exposed to 0.1 mL of the undiluted test substance and scored for eye reactions. The animals were observed for 7 days and scoring was performed 24, 48 and 72 h and 4 and 7 days after application. 3/3 rabbits had slight to moderate chemosis and severe redness (conjunctivae, score 3 of 3) at the 1-hour reading time point. The mean chemosis scores were 0, 0, 0.33, respectively and the effect was completely reversible within 48 hours. The severity of the conjunctivae decreased gradually and cleared completely within 72 hours, with individual mean scores of 1.67, 0.67, 1.00, respectively. No effects on the cornea or iris were noted at any time point.

Conclusions for irritation / corrosion

A human patch test with isononyl isononanoate is available, indicating no skin irritation potential in human volunteers (Gibaud, 2004). Furthermore, read-across from the structurally related substance 3,5,5-trimethylhexyl 3,5,5-trimethylhexanoate (CAS 59219-71-5) indicates no skin irritating potential in rabbits (Masson, 1986). Based on the weight of evidence of all available data, isononyl isononanoate is not considered to be irritating to the skin.

The results of the in vitro eye irritation and corrosion studies of isononyl isononanoate (Boue-Grabot, 2004) as well as an in vivo eye irritation studies with the analogue substance 3,5,5-trimethylhexyl 3,5,5-trimethylhexanoate (CAS 59219-71-5) (Dufour, 1990) demonstrate that isononyl isononanoate does not show the potential to cause eye irritation.


Justification for selection of skin irritation / corrosion endpoint:
Hazard assessment is conducted by means of read-across from a structural analogue and a substance-specific study in humans and based on the weight of evidence from all available studies.

Justification for selection of eye irritation endpoint:
Hazard assessment is conducted by means of read-across from a structural analogue and in vitro studies of the target substance and based on the weight of evidence from all available studies.

Justification for classification or non-classification

Based on substance-specific data and read-across from the structurally similar substances, the available data on skin and eye irritation 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.