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Diss Factsheets

Toxicological information

Skin sensitisation

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Administrative data

Endpoint:
skin sensitisation: in vivo (LLNA)
Type of information:
other: Data sharing dispute
Adequacy of study:
key study
Study period:
13 Sep - 02 Oct 2006
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Cross-referenceopen allclose all
Reason / purpose for cross-reference:
assessment report
Reference
Endpoint:
skin sensitisation: in vivo (LLNA)
Type of information:
other: Data Sharing Dispute
Adequacy of study:
key study
Study period:
29 Nov - 20 Dec 2011
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Reason / purpose for cross-reference:
assessment report
Reason / purpose for cross-reference:
assessment report
Qualifier:
according to guideline
Guideline:
OECD Guideline 429 (Skin Sensitisation: Local Lymph Node Assay)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.42 (Skin Sensitisation: Local Lymph Node Assay)
Deviations:
no
GLP compliance:
yes
Remarks:
The department of health of the government of the United Kingdom
Type of study:
mouse local lymph node assay (LLNA)
Specific details on test material used for the study:
Physical state: yellow liquid
- Analytical purity: not given
- Lot/batch No.: OE10817
- Expiration date of the lot/batch: 21.10.2016
- Storage condition of test material: room temperature in the dark
Species:
mouse
Strain:
other: CBA/Ca (CBA/CaOlaHsd)
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Harlan Laboratories UK Ltd., Oxon, UK
- Age at study initiation: 8 to 12 weeks
- Weight at study initiation: 15 to 23 g
- Housing: individually housed in suspended solid-floor polypropylene cages furnished with softwood woodflakes
- Diet: 2014C Teklad Global Rodent diet, ad libitum (Harlan Laboratories UK Ltd., Oxon, UK)
- Water: tap water, ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 - 25
- Humidity (%): 30 - 70
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12
Vehicle:
acetone/olive oil (4:1 v/v)
Concentration:
25, 50, 100 % (v/v)
No. of animals per dose:
4
Details on study design:
RANGE FINDING TESTS:
- Compound solubility: solution in acetone/olive oil 4:1 prepared because it produced the most suitable formulation at required concentration
- Irritation: no visual local irritation or irritation by an equal to or greater than 25% increase in mean ear thickness

MAIN STUDY
ANIMAL ASSIGNMENT AND TREATMENT
- Name of test method: ³H-Methyl Thymidine
- Criteria used to consider a positive response: the test item will be regarded as a sensitizer if at least on concentration of the test item results in a threefold or greater increase in 3HTdR incorporation compared to control values. Any test item failing to produce a threefold or greater increase in 3HTdR incorporation will be classified as "non-sensitizer".

TREATMENT PREPARATION AND ADMINISTRATION:
Groups of 4 mice were treated with the undiluted test item or the test item at concentrations of 50% or 25% v/v in acetone/olive oil 4:1 by daily application of 25 µl to the dorsal surface of each ear for three consecutive days (Day 1, 2, 3). Five days following the first topical application of the test item or vehicle (Day 6) all mice were injected via the tail vein with 250 µl of phosphate buffered saline (PBS) containing ³H-methyl thymidine. Five hours later the draining auricular lymph nodes were excised and pooled for each treatment group. To precipitate out the radioactive material, the pellet was resuspended in 3 mL of 5 % trichloracetic acid (TCA).
Positive control substance(s):
hexyl cinnamic aldehyde (CAS No 101-86-0)
Positive control results:
The positive control Hexylcinnamaldehyde 25 % (v/v) in acetone/olive oil 4:1 a positive result in 5 animals with a SI value of 4.05.
Parameter:
SI
Remarks on result:
other: The stimulation index for 25, 50 and 100 % test item was calculated as 2.45, 1.49 and 1.68, respectively.
Parameter:
other: disintegration per minute (DPM)
Remarks on result:
other: Disintegrations per minute were slightly increased by the test item, however no dose dependent increase was seen (see table1).

Table1: results of LLNA

test item 
[% v/v] dpm SI
vehicle 9652.68 na
25 23618.86 2.45
50 14422.08 1.49
100 16232.34 1.68

na = Not applicable

Interpretation of results:
GHS criteria not met
Conclusions:
CLP: not classified
Reason / purpose for cross-reference:
assessment report
Reference
Endpoint:
skin sensitisation, other
Remarks:
Skin sensitization in silico
Type of information:
(Q)SAR
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
accepted calculation method
Justification for type of information:
Guidance on registration Reference: ECHA-16-G-06-EN Publ.date:November 2016
Practical guide 2: How to report weight of evidence - Reference: ECHA-10-B-05-EN Publ.date: 24/03/2010
Reason / purpose for cross-reference:
assessment report
Reason / purpose for cross-reference:
assessment report
Qualifier:
according to guideline
Guideline:
other: GUIDANCE : REACH Guidance on Qsars and grouping of chemicals R.6 year 2008
GLP compliance:
not specified
Run / experiment:
other:
Parameter:
other: QSAR
Remarks on result:
other: no indication of skin sensitization
Interpretation of results:
GHS criteria not met
Conclusions:
Overall remarks : the model is recognized scientifically valid; the substance is included in the applicability domain of the model; results are adequate for classification and labelling and for risk assessment;
adequate documentation of the methods provided
Executive summary:

no indication of skin sensitization

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2006
Report date:
2006

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
OECD Guideline 429 (Skin Sensitisation: Local Lymph Node Assay)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.42 (Skin Sensitisation: Local Lymph Node Assay)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.2600 (Skin Sensitisation)
Deviations:
no
GLP compliance:
yes
Type of study:
mouse local lymph node assay (LLNA)

Test material

Constituent 1
Reference substance name:
Fatty acids, coco, 2,2-dimethyl-1,3-propanediyl esters
EC Number:
292-990-8
EC Name:
Fatty acids, coco, 2,2-dimethyl-1,3-propanediyl esters
Cas Number:
91031-85-5
IUPAC Name:
91031-85-5
Specific details on test material used for the study:
- Name of test material (as cited in study report): only trade name given
- Physical state: yellow liquid
- Analytical purity: 98%
- Lot/batch No.: OE40323
- Stability under storage conditions: stable
- Storage condition of test material: at room temperature in the dark
- Expiration date of the lot/batch: 01 Jan 2008

In vivo test system

Test animals

Species:
mouse
Strain:
other: CBA strain, inbred, SPF-Quality
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River France, L´Arbresle Cedex, France
- Age at study initiation: approx. 11 weeks old
- Weight at study initiation: 20-25 g (females)
- Housing: individual housing in labelled Macrolon cages (MI type) containing sterilized sawdust as bedding material
- Diet: pelleted rodent diet, ad libitum
- Water: tap water, ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 ± 3
- Humidity (%): 30 - 70 (relative humidity); 40 – 70 (actual range)
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12 / 12

IN-LIFE DATES: From: 13 Sept 2006 To: 02 October 2006

Study design: in vivo (LLNA)

Vehicle:
acetone/olive oil (4:1 v/v)
Concentration:
25, 50 and 100%
No. of animals per dose:
5
Details on study design:
RANGE FINDING TESTS:
- Irritation: a preliminary irritation study (range-finding study) was run in order to select the highest test substance concentration to be used in the main study.
A series of two test substances concentrations was tested, selected from the series: 100% (undiluted), 50%, 25%, 10%, 5%, 2.5%, and 1% and if needed further lower concentrations using the same steps. The test system, procedures and techniques were identical to those used during days 1 to 3 of the main study unless otherwise specified.
2 young adult animals were selected (5-14 weeks old). Each animal was treated with one concentration on 3 consecutive days.
Approximately 4 hours after the last exposure, the ear was cleaned of residual test substance with tap water and the irritation was assessed. Body weight were recorded on day 3.

At 50% dose concentration a grade 2 erythema (well defined erythema) was observed in 1 animal on the left and right dorsal surface ear. At 100% dose concentration a grade 1 erythema (slight erythema) was observed in the other animal on the left and right dorsal surface area. Based on the results, the highest test substance concentration selected for the main study was 100% concentration.

MAIN STUDY
ANIMAL ASSIGNMENT AND TREATMENT
- Name of test method: ³H-methyl thymidine incorporation determined by ß-scintillation
- Criteria used to consider a positive response: DPM (disintegration per minutes) values were presented for each animal and for each dose group. A stimulation index (SI, ratio of the DPM/ treated group compared to DPM/vehicle control group) was calculated for each group. If the results indicate a SI ≥ 3, the test substance was regarded as a skin sensitizer.

TREATMENT PREPARATION AND ADMINISTRATION: 25 µL of test substance was applied to the dorsal surface of each ear of each mouse. The application was repeated on Days 2 and 3. 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 experimental mouse. Five hours later, the draining auricular lymph node of each ear was excised in PBS. A single cell suspension of lymph node cells (LNC) was prepared in PBS by gentle separation through stainless steel gauze (diameter 125 µm). LNC were washed twice with an excess of PBS by centrifugation at 200 g for 10 minutes at 4 °C. To precipitate the DNA, the LNC were exposed to 5% trichloroacetic acid (TCA) at 4 °C during the night.
Positive control substance(s):
hexyl cinnamic aldehyde (CAS No 101-86-0)

Results and discussion

In vivo (LLNA)

Resultsopen allclose all
Parameter:
SI
Remarks on result:
other: see remark
Remarks:
The SI values calculated for the substance concentrations 25, 50 and 100% were 1.1, 0.9 and 2.3 respectively. The SI value calculated for the control group (vehicle) was 1.0. These results indicate that the test substance could not elicit an SI of 3.
Parameter:
other: disintegrations per minute (DPM)
Remarks on result:
other: see Remark
Remarks:
No significant increase in isotope incorporation was detected after repeated application in treated animals compared with controls. Mean DPM/animal values for the experimental groups treated with test substance concentrations of 25, 50 and 100% were 256, 213, and 553 respectively. The mean DPM/animal value for the control group (vehicle group) was 241.

Any other information on results incl. tables

Slight irritation was noted among the animals of the control group and in all animals treated at 25%. Slight or well-defined irritation was noted among the animals of the higher dose groups.

 

Table 1: Skin reactions, body weights and relative size auricular lymph nodes

Group

%Test substance

Animal

Day 3

Day 6

 

 

 

Skin reactions dorsal surface ear

Size nodes

 

 

 

left

right

 

 

 

 

erythema

oedema

erythema

oedema

left

right

1

0% (vehicle)

1

0

0

0

0

n

n

 

 

2

0

0

1

0

n

n

 

 

3

0

0

1

0

n

n

 

 

4

0

0

0

0

n

n

 

 

5

0

0

1

0

n

n

 

25%

6

1

0

1

0

n

n

 

 

7

0

0

1

0

n

n

 

 

8

0

0

1

0

n

n

 

 

9

0

0

1

0

n

n

 

 

10

1

0

1

0

n

n

 

50%

11

1

0

2

0

n

n

 

 

12

1

0

1

0

n

n

 

 

13

1

0

2

0

n

-

 

 

14

1

0

1

0

n

n

 

 

15

1

0

1

0

-

n

 

100%

16

0

0

1

0

n

-

 

 

17

1

0

2

0

n

n

 

 

18

1

0

1

0

n

n

 

 

19

1

0

1

0

n

n

 

 

20

1

0

2

0

n

n

n= considered to be normal

Applicant's summary and conclusion

Interpretation of results:
GHS criteria not met
Conclusions:
CLP: not classified