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Diss Factsheets

Administrative data

Description of key information

Skin sensitisation (OECD Toolbox v4.1): no alert for skin sensitisation

Skin sensitisation (OECD 406): sensitising

RA from source substance Ditridecyl adipate (CAS 16958-92-2)

Skin sensitisation (OECD 429): not sensitising

RA from source substance Hexanedioic acid, di-C16-18 (even numbered)-alkyl esters (CAS 92969-90-9)

Skin sensitisation (HRIPT): not sensitising

RA from source substance Ditridecyl adipate (CAS 16958-92-2)

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records

Referenceopen allclose all

Endpoint:
skin sensitisation, other
Type of information:
(Q)SAR
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
results derived from a valid (Q)SAR model and falling into its applicability domain, with adequate and reliable documentation / justification
Justification for type of information:
1. SOFTWARE
OECD QSAR Toolbox v4.1

2. MODEL (incl. version number)
OECD QSAR Toolbox v4.1

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
See “Test material information”

Qualifier:
according to guideline
Guideline:
other: REACH Guidance on QSARs R.6
Principles of method if other than guideline:
Calculation based on OECD QSAR Toolbox v4.1 QSAR prediction of the skin sensitisation potential of the test substance (2 representative substances of the UVCB substance 1,6-hexandiyl dioleate). The presence of protein binding alerts that may indicate a skin sensitising potential is assessed.

- Software tool(s) used including version: OECD QSAR Toolbox v4.1
- Model(s) used:
Endpoint Specific profilers
- Keratinocyte gene expression
- Protein binding alerts for skin sensitization according to GHS
- Protein binding alerts for skin sensitization by OASIS
- Protein Binding Potency h-CLAT
- Respiratory sensitisation
General Mechanistic profilers
- Protein binding by OASIS
- Protein binding by OECD
- Protein binding potency
- Protein binding potency Cys (DPRA 13%)
- Protein binding potency Lys (DPRA 13%)

- Model description: see field 'Any other information on material and methods incl. tables'
GLP compliance:
no
Key result
Run / experiment:
other: QSAR
Parameter:
other: protein binding potential
Negative controls validity:
not applicable
Positive controls validity:
not applicable
Remarks on result:
other: see "Remarks"
Remarks:
No structural alerts related to protein binding potency or respiratory sensitization have been found in the test substance (2 representative substances of the UVCB substance 1,6-hexandiyl dioleate). It was not possible to classify the molecules according to the endpoint specific profiler “Keratinocyte gene expression” or to the mechanistic profiler “Protein binding potency”. Both Cysteine and Lysine binding profilers classified the two molecules as “non reactive”.

For detailed information on the results please refer to the attached report.

Interpretation of results:
other: not predicted to have skin sensitising potential
Endpoint:
skin sensitisation: in vivo (non-LLNA)
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Remarks:
Well documented study report, but no data on analytical purity of the substance, non-GLP, another positive control substance (DNCB) than recommended by TG OECD 406; 10 animals/group instead of recommended 20/group
Qualifier:
according to guideline
Guideline:
OECD Guideline 406 (Skin Sensitisation)
Version / remarks:
17 July 1992
Deviations:
yes
Remarks:
/ another positive control substance (DNCB) than recommended by the guideline; 10 animals/group instead of 20/group as recommended
Principles of method if other than guideline:
The test procedure was based on the method described by Ritz & Buehler (1980).

Ritz H.L. & Buehler E.V. (1980). Current Concepts in Cutaneous Toxicity. Drill V.A. & Lazar T (Ed.), Academic Press, p. 25
GLP compliance:
no
Type of study:
Buehler test
Justification for non-LLNA method:
Test was done before LLNA as first-choice method for in-vivo testing was set into force.
Species:
guinea pig
Strain:
Hartley
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Strain: outbred Hartley white
- Source: Charles River Kingston, Route 209, Kingston, NY 12484, USA
- Age at study initiation: approx. 4 weeks old
- Weight at study initiation: 360 - 470 g
- Housing: individually in suspended stainless steel cages
- Diet: standard pellet diet (Purina Laboratory Guinea Pig Chow #5025), ad libitum
- Water: tap water, via automatic watering devices, ad libitum
- Acclimation period: at least 14 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21.1 ± 5
- Humidity (%): 40 - 60
- Photoperiod (hrs dark / hrs light): 12 / 12

Route:
epicutaneous, occlusive
Vehicle:
other: (Squibb) Mineral Oil
Concentration / amount:
- Induction: 0.4 mL of a 50.0% (w/w) test substance solution in Squibb Mineral Oil
Day(s)/duration:
6 h
No.:
#1
Route:
epicutaneous, occlusive
Vehicle:
other: (Squibb) Mineral Oil
Concentration / amount:
- Challenge: 0.4 mL of a 25.0% (w/w) test substance solution in Squibb Mineral Oil
Day(s)/duration:
6 h
No.:
#2
Route:
epicutaneous, occlusive
Vehicle:
other: (Squibb) Mineral Oil
Concentration / amount:
Rechallenge: 0.4 mL of a 20.0% (w/w) or 12.5% test substance solution in Squibb Mineral Oil
Day(s)/duration:
6 h, 6 days after first exposure
No. of animals per dose:
- 4 animals for range-finding of primary irritation of the test substance (Irritation group)
- 10 test animals (Induction group)
- 10 control animals (Control group)
Details on study design:
RANGE FINDING TESTS:
- Primary irritation:
To determine the highest non-irritating concentration of the test material to be used in both the challenge and rechallenge phases of the test, a group of guinea pigs was treated with various concentrations of the test article.
Hair was removed from the entire back of 3 uncommitted guinea pigs using electric clippers. On the following day, patches were applied using a Hill Top Chamber System with a 25 mm Webril swatch moistened with 0.4 mL of either 100.0 (neat) or 75.0, 50.0, and 25.0% (w/w) test substance in Squibb Mineral Oil.
An irritant response was elicited by the 100.0, 75.0, 50.0, and 25.0% concentrations. Since even the lowest concentration of 25.0% (w/w) in mineral oil caused an irritant response, an additional group of 4 animals was used for a second primary irritation test. These animals were treated according to the procedure mentioned above. The concentrations of the test substance used were 50.0, 25.0, 10.0, and 5.0% (w/w) in Squibb Mineral oil.

The positive control material (DNCB) was administered in the same manner as for the test substance irritation groups. DNCB was administered at a concentration of 0.5, 0.1, or 0.05% (w/v) in acetone. These positive control irritation animals were also administered acetone via the chamber system.

The guinea pigs were wrapped with a piece of rubber dental dam (approx. 3"x4") that was placed over the patch site and secured with Elastoplast in order to ensure occlusive conditions. After an exposure period of approx. 6 h, the patches were removed and the treated sites wiped with cotton gauze wet with saline.
On the day following application of the test material, the clipped areas were depilated with Neet Cream Hair Remover. The depilatory was allowed to remain on the sites for 5 - 10 min and then wiped with cotton towels moistened with warm tap water. The patch sites were scored for erythema approx. 2 hours later (24-h reading) and approx. 24 h later (48-h reading) using the Draize scoring system.

MAIN STUDY
A. INDUCTION EXPOSURE
- No. of exposures: 3 exposures
- Exposure period: 6 h
- Control group: not treated
- Positive control group: DNCB was administered at a concentration of 0.1% (w/v) in 70% ethanol.
- Site: entire back
- Frequency of applications: once weekly
- Concentrations: 0.4 mL of 50.0% (w/w) in Squibb Mineral Oil
- Application: The patches were applied using a Hill Top Chamber with a 25 mm Webril swatch moistened with the substance. Then, the animals were wrapped with a piece of rubber dental dam (approx. 3"x4") that was placed over the patch site and secured with Elastoplast in order to ensure occlusive conditions.

- Rest period: 19 days

B. CHALLENGE EXPOSURE
- No. of exposures: 2 exposures (challenge and rechallenge after a 6-day rest period)
- Exposure period: 6 h
- Test group: treated as described
- Control group: treated as test group
- Positive control group: DNCB at 0.05% (w/v) in acetone
- Site: the lower right quadrant of the back for challenge; lower left and upper right quadrants of the back for rechallenge
- Concentrations: 0.4 mL of 25.0% (w/w) in Squibb Mineral Oil for challenge; 0.4 mL of 20.0% or 12.5% (w/w) in Squibb Mineral Oil for rechallenge
- Evaluation (hr after challenge): 24 h (after depilation for 5 - 10 min) and 48 h (without additional depilation)
- Application: The patches were applied using a Hill Top Chamber with a 25 mm Webril swatch moistened with the substance. Then, the animals were wrapped with a piece of rubber dental dam (approx. 3"x4") that was placed over the patch site and secured with Elastoplast in order to ensure occlusive conditions.

Challenge controls:
The control animals were maintained without treatment until primary challenge.
Positive control substance(s):
yes
Remarks:
2,4-Dinitrochlorobenzene (DNCB)
Reading:
1st reading
Hours after challenge:
24
Group:
negative control
Dose level:
induction: 0%; challenge: 25%
No. with + reactions:
4
Total no. in group:
10
Key result
Reading:
1st reading
Hours after challenge:
24
Group:
test chemical
Dose level:
induction: 50%; challenge: 25%
No. with + reactions:
9
Total no. in group:
10
Reading:
1st reading
Hours after challenge:
24
Group:
positive control
Dose level:
induction: 0.1%; challenge: 0.05%
No. with + reactions:
10
Total no. in group:
10
Reading:
2nd reading
Hours after challenge:
48
Group:
negative control
Dose level:
induction: 0%; challenge: 25%
No. with + reactions:
2
Total no. in group:
10
Key result
Reading:
2nd reading
Hours after challenge:
48
Group:
test chemical
Dose level:
induction: 50%; challenge: 25%
No. with + reactions:
9
Total no. in group:
10
Reading:
2nd reading
Hours after challenge:
48
Group:
positive control
Dose level:
induction: 0.1%; challenge: 0.05%
No. with + reactions:
10
Total no. in group:
10
Reading:
rechallenge
Hours after challenge:
24
Group:
other: challenge control
Dose level:
induction: 0%; challenge: 12.5%
No. with + reactions:
0
Total no. in group:
5
Key result
Reading:
rechallenge
Hours after challenge:
24
Group:
test chemical
Dose level:
induction: 50%; challenge: 12.5%
No. with + reactions:
3
Total no. in group:
10
Reading:
rechallenge
Hours after challenge:
24
Group:
other: challenge control
Dose level:
Induction: 0%; challenge: 20%
No. with + reactions:
0
Total no. in group:
5
Key result
Reading:
rechallenge
Hours after challenge:
24
Group:
test chemical
Dose level:
induction: 50%; rechallenge: 20%
No. with + reactions:
4
Total no. in group:
10
Reading:
rechallenge
Hours after challenge:
48
Group:
other: challenge control
Dose level:
induction: 0%; challenge: 12.5%
No. with + reactions:
0
Total no. in group:
5
Reading:
rechallenge
Hours after challenge:
48
Group:
other: challenge control
Dose level:
induction: 0%; challenge: 20%
No. with + reactions:
0
Total no. in group:
5
Key result
Reading:
rechallenge
Hours after challenge:
48
Group:
test chemical
Dose level:
induction: 50%; rechallenge: 12.5%
No. with + reactions:
2
Total no. in group:
10
Key result
Reading:
rechallenge
Hours after challenge:
48
Group:
test chemical
Dose level:
induction: 50%; rechallenge: 20%
No. with + reactions:
4
Total no. in group:
10

Primary Irritation Tests:

 

1. Test:

In the evaluation of the primary irritation potential of the test substance, the 100.0% (neat) as well as the 75.0, 50.0, and 25.0% (w/w) concentrations produced significant irritant responses.

2. Test:

In the second test, significant dermal responses were observed at the highest concentration of 50.0%, but not at the lower concentrations. Based on these data, the 25.0% (w/w) concentration was determined to be the highest non-irritating concentration for challenge.

 

Challenge:

 

 

Number of animals showing indicated erythema score

 

Score

0

1

2

3

4

24-h reading

induced

1

4

5

0

0

 

control

6

2

2

0

0

 

positive control

0

0

4

5

1

48-h reading

induced

1

6

3

0

0

 

control

8

2

0

0

0

 

positive control

0

1

4

5

0

 

Rechallenge:

 

 

Number of animals showing indicated erythema score

 

Score

0

1

2

3

4

24-h reading

induced 12.5%     

7

3

0

0

0

 

induced 20.0%

6

3

0

1

0

 

control

10

0

0

0

0

48-h reading

induced 12.5%

8

1

1

0

0

 

induced 20.0%

6

1

3

0

0

 

control

10

0

0

0

0
Interpretation of results:
other: Skin Sens. 1, H317. Classification according to Regulation (EC) No. 1272/2008 (CLP/EU GHS)
Endpoint:
skin sensitisation: in vivo (LLNA)
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
06 Sep - 05 Oct 2016
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 429 (Skin Sensitisation: Local Lymph Node Assay)
Version / remarks:
adopted 23 Jul 2010
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Remarks:
Health Care Inspectorate of the Ministry of Health, Welfare and Sport, Utrecht, The Netherlands
Type of study:
mouse local lymph node assay (LLNA)
Species:
mouse
Strain:
CBA:J
Remarks:
SPF quality
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Janvier, Le Genest-Saint-Isle, France
- Females (if applicable) nulliparous and non-pregnant: Yes
- Age at study initiation: Approximately 10 weeks
- Weight at study initiation: 17.5 - 21.5 g (Group 1); 20.8 - 22.7 g (Group 2); 19.5 - 23.3 g (Group 3); 22.0 - 26.3 g (Group 4)
- Housing: 5 females per group were housed in labeled Makrolon Cages (MIII type; height 18 cm) containing sterilised sawdust as bedding material. Paper and shelters were supplied as cage-enrichment.
- Diet: SM R/M-Z, pelleted rodent diet (SSNIFF Spezialdiäten GmbH, Soest, Germany), ad libitum
- Water: Tap water, ad libitum
- Acclimation period: At least 5 days
- Indication of any skin lesions: Animals were healthy and the ears were intact and free from any abnormality.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18 - 24
- Humidity (%): 40 - 70
- Air changes (per hr): At least 10
- Photoperiod (hrs dark / hrs light): 12/12
Vehicle:
dimethylformamide
Concentration:
10, 25 and 50% (w/w)
No. of animals per dose:
5
Details on study design:
PRE-SCREEN TESTS: 2 female mice per concentration were treated by daily application of a 50% solution in dimethylformamide or undiluted test substance to the dorsal surface of the ear, for 3 consecutive days. Very slight erythema (Grade 1) and/or scaliness were noted for the animals treated with the undiluted test substance between Days 2 - 6. Hunched posture and/or piloerection were observed for the animals treated with the undiluted test substance on Days 2 and 3. With a 50% test substance concentration no signs of systemic toxicity were noted and no erythema were observed, but scaliness was noted for one animal between Days 4 and 6.
- Irritation: The animals were observed for local skin irritation to the application site once daily on Day 1 (pre-dose) to Day 6 (prior to necropsy). On Days 1 - 3 observation was performed within 1 h after dosing.
- Systemic toxicity: The animals were observed for mortality twice daily. The body weight was recorded on Day 1 prior to dosing and on Day 6. Signs of toxicity were recorded on Days 1 - 6 (on Days 1 - 3 between 3 - 4 h after dosing).
- Ear thickness measurements: Ear thickness measurements of both ears were performed using a digital thickness gauge prior to dosing on Days 1 and 3, and on Day 6.
- Erythema scores: Draize scoring system

MAIN STUDY

ANIMAL ASSIGNMENT AND TREATMENT
- Name of test method: ³H-methyl thymidine incorporation determined by β-scintillation and γ-counting
- Criteria used to consider a positive response: DPM values are presented for each animal and for each dose group. A Stimulation Index (SI) is calculated for each group using the individual SI values. The individual SI is the ratio of the DPM/animal compared with the DPM/vehicle control group mean. If the results indicate a SI ≥ 3, the test item is regarded as a skin sensitizer.
- Other: The animals were observed for mortality twice daily. The body weight was recorded on Day 1 prior to dosing and on Day 6. Signs of toxicity were recorded on Days 1 - 6 (on Days 1 - 3 between 3 - 4 h after dosing).

TREATMENT PREPARATION AND ADMINISTRATION:
25 µL of the test material was applied to the entire dorsal surface of each ear of each mouse on Day 1, 2 and 3 in concentrations of 10, 25 and 50% in dimethylformamide. The local irritation effects on the treatment site were assessed daily. On Day 6 an injection of 250 µL phosphate buffered saline (PBS) containing 20 µCi of ³H-methyl thymidine (³H-TdR) was made into the tail vein of each mouse. Five hours later, the draining auricular lymph node of each ear was excised into PBS and pooled per group. A single cell suspension of pooled lymph node cells was prepared by gentle separation through a 200-mesh stainless steel gauze and rinsed with PBS. The precipitates were incubated in the refrigerator until the next day, centrifuged, resuspended in 1 mL trichloroacetic acid and transferred to 10 mL scintillation fluid before β-scintillation counting.
Positive control substance(s):
hexyl cinnamic aldehyde (CAS No 101-86-0)
Positive control results:
For both scientific and animal welfare reasons, no concurrent positive control group was included in the study. An extensive data base is available with reliability checks performed at half-yearly intervals during at least the past 9 years, showing reproducible and consistent positive results with hexyl cinnamic aldehyde. The SI values calculated for the positive control concentrations 5, 10 and 25% were 1.4, 1.5 and 4.3, respectively. An EC3 value of 18.0% was calculated using linear interpolation (Test facility study number: 513924, May 2016).
Based on the results, the positive control was considered to demonstrate the appropriate performance of the assay, with adequate and reproducible sensitivity to a known sensitising test substance.
Key result
Parameter:
SI
Value:
0.9
Test group / Remarks:
10% (w/w)
Key result
Parameter:
SI
Value:
1.1
Test group / Remarks:
25% (w/w)
Key result
Parameter:
SI
Value:
1.4
Test group / Remarks:
50% (w/w)
Cellular proliferation data / Observations:
DETAILS ON STIMULATION INDEX CALCULATION: The SI of the 10, 25 and 50% treatment group was 0.9, 1.1 and 1.4, respectively. None of the test substance concentrations produced a 3-fold increase in ³HTdR incorporation.

EC3 CALCULATION: None of the SI values were above 3 and it is therefore not possible to determine a EC3 concentration.

CLINICAL OBSERVATIONS: No mortality occured and no signs of systemic toxicity were observed in any of the animals. Very slight erythema (Grade 1) was observed in 3/5 females treated with a 50% test substance concentration (w/w) on Day 2, 3 and 4, respectively.

BODY WEIGHTS: The body weights and body weight gain remained with the same range as controls during the study period.

Table 1: Irritation scores and clinical signs of toxicity recorded in the pre-screen test

Test substance concentration Day 1 Day 2 Day 3 Day 4 Day 5 Day 6
left right left right left right left right left right left right
50% 0 0 0 0 0 0 0 0 0 0 0 0
0 0 0 0 0 0 0 S 0 0 S 0 0 S 0
100% 0 0 0 H 1 1 HP 1 0 S 0 0 S 0 0 S 0 S
0 0 0 HP 0 1 HP 1 0 S 0 S 0 S 0 S 0 S 0 S

H: Hunched posture

P: Piloerection

S: Scaliness

0: no erythema; 1: very slight erythema

Table 2: Results of the main test

Test substance DPM/animal mean DPM ± SEM mean SI ± SEM
Solvent control 1256 748 ± 205 1.0 ± 0.4
74
537
1020
851
10% 668 704 ± 48 0.9 ± 0.3
809
573
647
822
25% 845 790 ± 57 1.1 ± 0.3
905
88
619
694
50% 871 1070 ± 225 1.4 ± 0.5
879
490
1809
1302
Interpretation of results:
other: CLP/EU GHS criteria not met, no classification required according to Regulation(EC) No. 1272/2008
Endpoint:
skin sensitisation: in vivo (LLNA)
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Justification for type of information:
refer to analogue justification provided in IUCLID section 13
Reason / purpose for cross-reference:
read-across source
Key result
Parameter:
SI
Value:
0.9
Test group / Remarks:
10% (w/w)
Remarks on result:
other: source: CAS 92969-90-9
Key result
Parameter:
SI
Value:
1.1
Test group / Remarks:
25% (w/w)
Remarks on result:
other: source: CAS 92969-90-9
Key result
Parameter:
SI
Value:
1.4
Test group / Remarks:
50% (w/w)
Remarks on result:
other: source: CAS 92969-90-9
Interpretation of results:
other: CLP/EU GHS criteria not met, no classification required according to Regulation(EC) No. 1272/2008
Conclusions:
In a study according to OECD 406, the source substance was found to have no skin sensitising potential. Based on a weight of evidence approach on all available data for the target and source substances, it was concluded that the target substance Fatty acids, C18 -unsaturated, 1,6 Hexanediol Diester (EC 947-912-3) does also not have a skin sensitising potential (please refer to the endpoint summary of sensitisation for further details).
Endpoint:
skin sensitisation: in vivo (non-LLNA)
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
refer to analogue justification provided in IUCLID section 13
Reason / purpose for cross-reference:
read-across source
Reading:
1st reading
Hours after challenge:
24
Group:
negative control
Dose level:
induction: 0%; challenge: 25%
No. with + reactions:
4
Total no. in group:
10
Remarks on result:
other: source: CAS 16958-92-2
Key result
Reading:
1st reading
Hours after challenge:
24
Group:
test chemical
Dose level:
induction: 50%; challenge: 25%
No. with + reactions:
9
Total no. in group:
10
Remarks on result:
other: source: CAS 16958-92-2
Reading:
1st reading
Hours after challenge:
24
Group:
positive control
Dose level:
induction: 0.1%; challenge: 0.05%
No. with + reactions:
10
Total no. in group:
10
Remarks on result:
other: source: CAS 16958-92-2
Reading:
2nd reading
Hours after challenge:
48
Group:
negative control
Dose level:
induction: 0%; challenge: 25%
No. with + reactions:
2
Total no. in group:
10
Remarks on result:
other: source: CAS 16958-92-2
Key result
Reading:
2nd reading
Hours after challenge:
48
Group:
test chemical
Dose level:
induction: 50%; challenge: 25%
No. with + reactions:
9
Total no. in group:
10
Remarks on result:
other: source: CAS 16958-92-2
Reading:
2nd reading
Hours after challenge:
48
Group:
positive control
Dose level:
induction: 0.1%; challenge: 0.05%
No. with + reactions:
10
Total no. in group:
10
Remarks on result:
other: source: CAS 16958-92-2
Reading:
rechallenge
Hours after challenge:
24
Group:
other: challenge control
Dose level:
induction: 0%; challenge: 12.5%
No. with + reactions:
0
Total no. in group:
5
Remarks on result:
other: source: CAS 16958-92-2
Key result
Reading:
rechallenge
Hours after challenge:
24
Group:
test chemical
Dose level:
induction: 50%; challenge: 12.5%
No. with + reactions:
3
Total no. in group:
10
Remarks on result:
other: source: CAS 16958-92-2
Reading:
rechallenge
Hours after challenge:
24
Group:
other: challenge control
Dose level:
Induction: 0%; challenge: 20%
No. with + reactions:
0
Total no. in group:
5
Remarks on result:
other: source: CAS 16958-92-2
Key result
Reading:
rechallenge
Hours after challenge:
24
Group:
test chemical
Dose level:
induction: 50%; rechallenge: 20%
No. with + reactions:
4
Total no. in group:
10
Remarks on result:
other: source: CAS 16958-92-2
Reading:
rechallenge
Hours after challenge:
48
Group:
other: challenge control
Dose level:
induction: 0%; challenge: 12.5%
No. with + reactions:
0
Total no. in group:
5
Remarks on result:
other: source: CAS 16958-92-2
Reading:
rechallenge
Hours after challenge:
48
Group:
other: challenge control
Dose level:
induction: 0%; challenge: 20%
No. with + reactions:
0
Total no. in group:
5
Remarks on result:
other: source: CAS 16958-92-2
Key result
Reading:
rechallenge
Hours after challenge:
48
Group:
test chemical
Dose level:
induction: 50%; rechallenge: 12.5%
No. with + reactions:
2
Total no. in group:
10
Remarks on result:
other: source: CAS 16958-92-2
Key result
Reading:
rechallenge
Hours after challenge:
48
Group:
test chemical
Dose level:
induction: 50%; rechallenge: 20%
No. with + reactions:
4
Total no. in group:
10
Remarks on result:
other: source: CAS 16958-92-2
Interpretation of results:
other: CLP/EU GHS criteria not met, no classification required according to Regulation(EC) No. 1272/2008
Conclusions:
In a study according to OECD 406, the source substance was found to have skin sensitising potential. However, based on a weight of evidence approach on all available data for the target and source substances, it was concluded that the target substance Fatty acids, C18 -unsaturated, 1,6 Hexanediol Diester (EC 947-912-3) does not have a skin sensitising potential (please refer to the endpoint summary of sensitisation for further details).
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not sensitising)
Additional information:

Justification for read-across

There are no experimental data on skin sensitisation available for Fatty acids, C18-unsaturated, 1,6 Hexanediol Diester (EC 947 -912 -3). To fulfil the standard data requirements defined in Regulation (EC) No. 1907/2006, Annex VII, 8.3, read-across from appropriate substances is conducted in accordance with Regulation (EC) No. 1907/2006, Annex XI, 1.5 in addition to a QSAR analysis by means of the OECD toolbox v4.1 for the target substance.

According to 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) “to avoid the need to test every substance for every endpoint”.

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 substances are the basis of read-across. A detailed justification for the analogue read- across approach is provided in the technical dossier (see IUCLID Section 13).

As no experimental data are available on sensitisation, read-across of reliable data on the analogue substances Ditridecyl adipate (CAS 16958-92-2) and Hexanedioic acid, di-C16-18 (even numbered)-alkyl esters (CAS 92969-90-9) was conducted in addition to a QSAR analysis by means of the OECD toolbox for the target substance.

Fatty acids, C18 -unsaturated, 1,6 Hexanediol Diester (EC 947-912-3)

QSAR predictions based on the OECD QSAR Toolbox v4.1 were performed with the target substance Fatty acids, C18 -unsaturated, 1,6 Hexanediol Diester (Dr. Knoell Consult, 2017, WoE). The predicted skin sensitisation potential based on protein binding potential was modelled in the OECD QSAR Toolbox v4.1 for 2 representative constituents of the target substance as it is an UVCB. No alerts for protein binding were found according to Protein binding by OASIS, Protein binding by OECD, Protein binding alerts for skin sensitisation and Respiratory sensitisation. Based on these results, especially considering the results of the skin sensitising relevant profiler, OASIS (endpoint specific), the test substance is not expected to exhibit skin sensitising properties.

CAS 16958-92-2

A Buehler test was performed with the test substance according to OECD 406 (Exxon, 1986, WoE). 10 test and 10 control animals (Hartley white guinea pigs) were induced epicutaneously, once a week for 6 h using 50% test substance. The test substance was applied on the entire back and the procedure was repeated twice. The challenge was performed 19 days later using a 25% test substance dilution, which was applied on the lower right quadrant of the back and incubated for 6 h. 6 days later the re-challenge was performed using 20% or 12.5% test substance, which was applied to the upper right quadrants of the back for 6 h. Positive reactions were observed in 9/10 animals 24 h and 48 h after the challenge and in 3/10 and 4/10 animals 24 h after and in 2/10 and 4/10 animals 48 h after the re-challenge with 12.5% and 20% test substance, respectively. The control animals showed positive reactions in 4/10 animals 24 h after and in 2/10 animals 48h after the challenge, while no positive reactions were observed in any animal of the control group 24 and 48 h after the rechallenge using both concentrations.

Based on the results of the conducted study, the test substance is considered to exhibit sensitising properties towards the skin.

In addition, there is data from a Human Repeated Insult Patch Test (Exxon, 1987, WoE). The test substance was applied undiluted onto 19 male and 85 female subjects between 18 and 65 years in an occlusive (55 subjects) and a semi-occlusive (49 subjects) manner. After 3 weeks of induction (with 3 treatments per week) and 2 weeks of rest period the challenge patch was applied for 24 h to a virgin site and reactions were scored after 24 (removal of test substance), 48 and 72 h.

None of the persons that completed the study showed positive reactions under occlusive or semi-occlusive conditions.

Another Human Repeated Insult Patch Test was performed with the test substance (Exxon, 1987b, WoE) with 94 volunteers in an occlusive (43 subjects) and a semi-occlusive (51 subjects) manner. After 3 weeks of induction (with 3 treatments per week) and 10 or 13 days of rest period the challenge patch was applied for 24 h to a virgin site and reactions were scored after 24 (removal of test substance), 48 and 72 h.

None of the persons involved in this study showed positive reactions under occlusive or semi-occlusive conditions.

Although the non-adjuvant Buehler test in female guinea pigs revealed a positive result (Exxon,1986, WoE), there is strong evidence from the human sensitisation data to show that the test substance is not a sensitizer in humans.

 

CAS 92969-90-9

A LLNA was performed with the test substance according to OECD 429 and in compliance with GLP (Zschimmer and Schwarz, 2017, WoE). After treatment of 15 mice (CBA:J, SPF quality) with the test substance, stimulation indices of 0.9, 1.1 and 1.4 were calculated for concentrations of 10, 25 and 50%, respectively. No mortality occured and no signs of systemic toxicity were observed in any of the animals. Very slight erythema (grade 1) was observed in 3/5 females treated with 50% test substance on Day 2, 3 and 4, respectively.

Based on the available data the test substance is considered not to be a skin sensitiser.

Conclusion on skin sensitising properties

The available animal data for the read-across analogue substance Ditridecyl adipate (CAS 16958-92-2) revealed sensitising, whereas the human data indicate no sensitising potential. Therefore, there is strong evidence from the human sensitisation data that the test substance is not a sensitizer in humans.

The data for the other read-across analogue source substance Hexanedioic acid, di-C16-18 (even numbered)-alkyl esters (CAS 92969-90-9) showed non-sensitising properties.

As QSAR predictions for the target substance Fatty acids, C18 -unsaturated, 1,6 Hexanediol Diester (EC 947-912-3) revealed no alerts for protein binding indicative of skin sensitising properties and based on a weight of evidence approach on all available data for the target and source substances, it is concluded that the target substance Fatty acids, C18 -unsaturated, 1,6 Hexanediol Diester (EC 947 -912 -3) does not have a skin sensitising potential.

Respiratory sensitisation

Endpoint conclusion
Endpoint conclusion:
no study available

Justification for classification or non-classification

Based on QSAR analysis on the target substance and an analogue read-across approach, the available data on skin sensitisation do not meet the classification criteria according to Regulation (EC) No. 1272/2008, and are therefore conclusive but not sufficient for classification.