Registration Dossier

Administrative data

Description of key information

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records
Reference
Endpoint:
skin sensitisation: in vivo (LLNA)
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Study period:
19 Oct - 09 Nov 1999
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: GLP guideline study with acceptable restrictions
Qualifier:
according to
Guideline:
OECD Guideline 429 (Skin Sensitisation: Local Lymph Node Assay)
Deviations:
yes
Remarks:
: Lack of details on test substance, no dose selection rationale given, no data on clinical signs or dermal irritation given.
Principles of method if other than guideline:
In the study report OECD guideline 406 was cited as the underlaying protocol.
GLP compliance:
yes
Type of study:
mouse local lymph node assay (LLNA)
Species:
mouse
Strain:
other: CBA/Ca/Ola/Hsd
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Harlan UK, Blackthorne, Bicester, Oxon, UK.
- Age at study initiation: Young adults
- Weight at study initiation:
- Housing: maximally 4 animals per cage
- Diet (e.g. ad libitum): Diet (RMI), Special Diet Services Ltd., Witham, Essex, UK
- Water (e.g. ad libitum): mains water
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/-3
- Humidity (%): 30 - 70
- Air changes (per hr): min. 15
- Photoperiod (hrs dark / hrs light): 12/12
Vehicle:
other: acetone
Concentration:
3, 10 and 30 % w/v
No. of animals per dose:
4
Details on study design:
MAIN STUDY
ANIMAL ASSIGNMENT AND TREATMENT
- Name of test method: Local Lymph Node Assay
- Criteria used to consider a positive response: 3-fold increase: the results were expressed as counts per minute (cpm) value per lymph node for each group. The activity of each test group was then divided by the activity of the vehicle control group to give a test control ratio for each concentration.

TREATMENT PREPARATION AND ADMINISTRATION:
Approx. 25 µL of the test substance was applied, using a variable volume micro-pipette, to the dorsal surface of each ear.
A vehicle control group was similarly treated using acetone alone.
The procedure was repeated daily for 3 consecutive days. 3 days after the third application, all animals were injected with 3H-methyl thymidine via the tail vein.
Approx. 5 h later, the animals were killed and the auricular lymph nodes were removed from each animal.
Single cell suspensions of the lymph nodes were measured using a Liquid Scintillation Counter.


Positive control substance(s):
hexyl cinnamic aldehyde (CAS No 101-86-0)
Positive control results:
Hexylcinnamaldehyde in acetone resulted in a greater than 3-fold increase in isotope incorporation at the 3 % and 10 % w/v concentrations.
Parameter:
SI
Remarks on result:
other: The stimulation index was < 3 (see table below).
Parameter:
other: disintegrations per minute (DPM)
Remarks on result:
other: The application of the test substance at concentrations of 3, 10 and 30 % w/v in acetone resulted in an isotope incorporation which was less than 3-fold at all tested concentrations.

Table 1: Results of LLNA

Concentration of test substance (% w/v)

Number of lymph nodes assayed

Counts per minute (cpm)

cpm per lymph node (x 10-2)

Test: control ratio (Stimulation index)

0 (vehicle only)

8

839

1.05

N/A

3

8

736

0.92

0.88

10

8

1007

1.26

1.20

30

8

1401

1.75

1.67

 

Interpretation of results:
not sensitising
Remarks:
Migrated information
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not sensitising)
Additional information:

Justification for grouping of substances and read-across

There are only limited data available on the skin sensitisation potential of diisodecyl azelate (CAS 28472-97-1). In order to fulfil the standard information requirements set out in Annex VII, 8.3, 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 skin sensitisation

CAS

Chemical name

Molecular weight

Sensitisation

28472-97-1 (a)

Diisodecyl azelate

468.75

WoE:

RA: CAS 27178-16-1
RA: CAS 103-24-2

RA: CAS 897626-46-9

RA: CAS 7491-02-3

27178-16-1 (b)

Diisodecyl adipate

426.67

Experimental result:
not sensitising

103-24-2

Bis(2-ethylhexyl) azelate

412.65

Experimental result:
ambiguous

897626-46-9

Bis(2-octyldodecyl) azelate

749.28

Experimental result:
not sensitising

7491-02-3

Diisopropyl sebacate

286.41

Experimental result:
not sensitising (human data)

(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 diisodecyl azelate (CAS 28472-97-1). A detailed analogue approach justification is provided in the technical dossier (see IUCLID Section 13).

 

Discussion

Skin sensitisation

CAS 27178-16-1

The sensitising potential of diisodecyl adipate (CAS No. 27178-16-1) was tested at concentrations of 3, 10 and 30 % w/v in acetone in a Local Lymph Node Assay according to OECD Guideline 429 (Noakes, 1999). Each dose level was tested in groups of four mice of the CBA/Ca/Ola/Hsd strain. Approx. 25 µL of the test substance was applied to the dorsal surface of each ear. A vehicle control group was treated with acetone alone. The procedure was repeated daily for 3 consecutive days. 3 days after the third application, all animals were injected with 3H-methyl thymidine via the tail vein. Approximately 5 hours later, the animals were killed and single cell suspensions of the auricular lymph nodes were measured using a Liquid Scintillation Counter. The isotope incorporation was less than 3-fold at all tested concentrations. Based on the study results no sensitising potential of diisodeyl adipate was observed.

 

CAS 897626-46-9

In a study according to OECD guideline 406, the skin sensitisation potential of Bis(2-octyldodecyl) azelate (CAS 897626-46-9) was investigated in female guinea pigs according to the non-adjuvant Buehler method (Richeux, 2013).

Based on a primary irritation test, the induction treatment of the main assay was performed with the neat test substance (100%). In the induction phase, the test material was applied to the shorn skin of the scapular zone of 20 animals using an occlusive dressing. During induction, three consecutive topical applications for a period of 6 h were performed at intervals of 7 days. A group of 10 animals served as controls and received paraffin oil. After a 14-day rest period, the challenge exposure was performed in control and treated animals. The test substance was applied to the shorn skin of the left flank of the animals for 6 h and skin reactions were evaluated 24 and 48 h after application. Accordingly, a patch without test material was applied to the animals’ right flanks. No positive skin reactions were observed in any of the animals of the test group and the control group. During the study no mortality occurred and no effects on body weight gain were observed. The sensitivity of the test species was confirmed with the positive control substance α-Hexylcinnamaldehyde (CAS 101-86-0) routinously tested in this laboratory (data of the three latest positive control tests are provided in the study report).

Based on these results, Bis(2-octyldodecyl) azelate was found to be a not sensitising in guinea pigs under the conditions of the non-adjuvant Buehler test.

 

CAS 7491-02-3

A human volunteer study was performed under GCP conditions to assess the sensitising potential of diisopropyl sebacate (CAS No. 7491-02-3) using the Marzulli and Maibach method (Cathalot, 2002). As induction treatment the back skin of 51 volunteers was exposed to the undiluted test substance for 48 hours under occlusive conditions three times a week for three weeks. After a two week recovery period, a challenge exposure was performed under an occlusive dressing for 48 h either on the same site as the induction or another site that had never had contact with the test substance. None of the 51 persons showed any sensitisation to the test material and only one showed slight skin irritation (+) at Day 9 of induction. Thus, the test material at 100% when applied to the human skin was not irritating and not sensitising.

 

CAS 103-24-2

The skin sensitising potential of bis(2-ethylhexyl) azelate (CAS 103-24-2) was investigated in a Local Lymph Node Assay (LLNA) in mice according to OECD guideline 429 and in compliance with GLP (Bradshaw, 2012).

Based on a range-finding test in one female CBA/CaOlaHsd mouse, the undiluted test substance (100%) and concentrations of 25% and 50% (v/v) in acetone/olive oil (4:1 v/v) were selected for the treatment of mice in the main study. In this experiment, 4 female CBA/CaOlaHsd mice per test group were treated with the test substance or vehicle alone, respectively. The test substance or the vehicle was applied on the external surface of each ear (25 µL/ear) for three consecutive days. Five days after the first topical application, the cell proliferation of pooled lymph nodes per group was measured by incorporation of ³H-methyl thymidine and expressed as the amount of radioactive disintegration per minute (DPM). The DPM/lymph node for each test group was 5244.83, 5178.42 and 8048.58 at concentrations of 25%, 50% and 100% of the test substance, respectively. For the control group, a DPM/lymph node of 1553.82 was determined. Based on these results, stimulation indices of 3.38, 3.33 and 5.18 were calculated for treatment concentrations of 25%, 50% and 100%, respectively. No local or systemic toxicity and no effects on body weights were observed. The historical positive control substance α-Hexylcinnamaldehyde (25% in acetone:olive oil (4:1 v/v)) produced a stimulation index (SI) of 5.76, thus meeting the reliability criteria for the LLNA (SI > 3).

As no structural analogue showed sensitising potential and the test substance is unlikely to penetrate the skin (0.00001 mg/cm²/event, QSAR, Danish EPA, 2010) the result of the above mentioned LLNA is regarded as inconclusive.

Conclusions for skin sensitisation

No studies assessing the skin sensitising properties of Diisodecyl azelate (CAS 28472-97-1) are available.

However, two local lymph node assays (LLNA) were performed with the structurally related substances diisodecyl adipate (CAS 27178-16-1) andbis(2-ethylhexyl) azelate (CAS 103-24-2), in which no skin sensitisation was observed (Noakes, 1999; Bradshaw, 2012). A Buehler test was performed with the analogue substance Nonanedioic acid, 1,9-bis(2-octyldodecyl) ester (CAS 897626-46-9), in which no skin sensitisation was induced (Richeux, 2013). The results of a human patch test (epicutaneous test) performed in 51 human volunteers with the analogue substance Diisopropyl sebacate (CAS 7491-02-3) showed that the substance had no skin sensitising effects (Cathalot, 2002).

Taking all the available data into consideration, Diisodecyl azelate (CAS 28472-97-1) is considered not to be a skin sensitiser.

 

 


Migrated from Short description of key information:
WoE:
No experimental data on skin sensitisation were available for diisodecyl azelate (CAS No. 28472-97-1).
Human and animal data on skin sensitisation of similar Read Across substances (Diisodecyl adipate, CAS No. 27178-16-1; Bis(2-ethylhexyl) azelate, CAS No. 103-24-2; Bis(2-octyldodecyl) azelate, CAS No. 897626-46-9) were all negative for a skin sensitising potential.
Thus, diisodecyl azelate is expected to have no skin sensitising potential.

Justification for selection of skin sensitisation endpoint:
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).

Respiratory sensitisation

Endpoint conclusion
Endpoint conclusion:
no study available

Justification for classification or non-classification

Based on read-across substances following an analogue approach and based on a weight of evidence approach, the available data on the skin sensitisation potential 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.

There are no data available on respiratory sensitisation.