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Skin sensitisation

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Endpoint:
skin sensitisation: in vivo (non-LLNA)
Type of information:
read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Study period:
2009
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Justification for type of information:
See attached document with the justification for the category/read-across approach.
Qualifier:
according to guideline
Guideline:
OECD Guideline 406 (Skin Sensitisation)
Version / remarks:
Magnusson and Kligman Test
GLP compliance:
yes (incl. QA statement)
Type of study:
guinea pig maximisation test
Justification for non-LLNA method:
This study was already available and considered to be the key study.
Specific details on test material used for the study:
Test Substance / Item : COASOL
Code by test facility : D08-11
Lot No. : 50046869
Manufactured by: Dow Haltermann Custom Processing, Middlesbrough, UK
Date of receipt at test facility : October 5, 2009
Purity as per Certificate of Analysis: 99% total diester content
Physical appearance : Colorless liquid
Storage conditions : Ambient (+18 to +30°C)
Species:
guinea pig
Strain:
Dunkin-Hartley
Sex:
male/female
Route:
intradermal and epicutaneous
Vehicle:
DMSO
Concentration / amount:
Intradermal Induction: 5% v/v in DMSO
Epicutaneous induction and Challenge: 100% undiluted test material
Route:
epicutaneous, occlusive
Vehicle:
DMSO
Concentration / amount:
Intradermal Induction: 5% v/v in DMSO
Epicutaneous induction and Challenge: 100% undiluted test material

Dosing solutions:
Control group:

Solution-1: 20 mL of 50% v/v CFA mixture (10 mL of CFA + 10 mL of distilled water) with 20 mL of DMSO was mixed as a 1:1 mixture and vortexed.
Solution-2: Undiluted DMSO.
Solution-3: 10 mL of solution 1 with 10 mL of solution 2 was mixed as a 1:1 mixture and vortexed.

Treatment group:
Solution-4: 5% v/v of test substance in Dimethyl Sulphoxide : 1 mL of test substance was made up to 20 mL and vortexed.
Solution-5: 1 mL of test substance made up to 10 mL with Dimethyl Sulphoxide (i.e., 10% v/v) and added to 10 mL of solution 1 (10 mL of 1 : 1 mixture of solution-1 and solution-2) to achieve the final concentration of 5 % v/v and vortexed.

No. of animals per dose:
10 per sex per dose in treatment group
5 per sex per dose in control group
Positive control substance(s):
yes
Remarks:
2-mercaptobenzothiazole
Key result
Reading:
1st reading
Hours after challenge:
24
Group:
test chemical
Dose level:
100%
No. with + reactions:
0
Total no. in group:
20
Clinical observations:
none
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 24.0. Group: test group. Dose level: 100%. No with. + reactions: 0.0. Total no. in groups: 20.0. Clinical observations: none.
Key result
Reading:
2nd reading
Hours after challenge:
48
Group:
test chemical
Dose level:
100%
No. with + reactions:
0
Total no. in group:
20
Clinical observations:
none
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: test group. Dose level: 100%. No with. + reactions: 0.0. Total no. in groups: 20.0. Clinical observations: none.
Key result
Reading:
1st reading
Hours after challenge:
24
Group:
negative control
Dose level:
0%
No. with + reactions:
0
Total no. in group:
10
Clinical observations:
none
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 24.0. Group: negative control. Dose level: 0%. No with. + reactions: 0.0. Total no. in groups: 10.0. Clinical observations: none.
Key result
Reading:
2nd reading
Hours after challenge:
48
Group:
negative control
Dose level:
0%
No. with + reactions:
0
Total no. in group:
10
Clinical observations:
none
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: negative control. Dose level: 0%. No with. + reactions: 0.0. Total no. in groups: 10.0. Clinical observations: none.
Key result
Reading:
1st reading
Hours after challenge:
24
Group:
positive control
Dose level:
100%
No. with + reactions:
6
Total no. in group:
10
Remarks on result:
positive indication of skin sensitisation
Key result
Reading:
2nd reading
Hours after challenge:
48
Group:
positive control
Dose level:
100%
No. with + reactions:
5
Total no. in group:
10
Remarks on result:
positive indication of skin sensitisation

There were no toxic signs during the study nor any pre-terminal deaths. All animals gained weight throughout the observation period. There were no signs of irritation or sensitisation during the study.

Interpretation of results:
not sensitising
Remarks:
Migrated information
Conclusions:
The test material was not sensitising under the circumstances of this study at the highest doses possible (100%) for topical induction and challenge.
Endpoint:
skin sensitisation: in vivo (non-LLNA)
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
Study period:
1989
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 406 (Skin Sensitisation)
Qualifier:
according to guideline
Guideline:
EU Method B.6 (Skin Sensitisation)
Principles of method if other than guideline:
not applicable
GLP compliance:
yes
Type of study:
guinea pig maximisation test
Species:
guinea pig
Strain:
Dunkin-Hartley
Sex:
male/female
Route:
intradermal and epicutaneous
Vehicle:
water
Concentration / amount:
Test substance:
10 % (v/v, in water) and 100 %
Positive control:
3% and 30% (v/v, in water)
Route:
epicutaneous, open
Vehicle:
water
Concentration / amount:
Test substance:
10 % (v/v, in water) and 100 %
Positive control:
3% and 30% (v/v, in water)
No. of animals per dose:
5 males and 5 females
Positive control substance(s):
yes
Remarks:
1,4-benzenediamine
Reading:
1st reading
Hours after challenge:
24
Group:
test chemical
Dose level:
both 10 and 100 %
No. with + reactions:
0
Total no. in group:
10
Clinical observations:
none
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 24.0. Group: test group. Dose level: both 10 and 100 %. No with. + reactions: 0.0. Total no. in groups: 10.0. Clinical observations: none.
Reading:
2nd reading
Hours after challenge:
48
Group:
test chemical
Dose level:
both 10 and 100 %
No. with + reactions:
0
Total no. in group:
10
Clinical observations:
none
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: test group. Dose level: both 10 and 100 %. No with. + reactions: 0.0. Total no. in groups: 10.0. Clinical observations: none.
Reading:
1st reading
Hours after challenge:
24
Group:
negative control
Dose level:
all 4 groups (10 and 100% test item and 3 and 30% positive control substance)
No. with + reactions:
0
Total no. in group:
5
Clinical observations:
none
Remarks on result:
other: see Remark
Remarks:
Reading: 1st reading. . Hours after challenge: 24.0. Group: negative control. Dose level: all 4 groups (10 and 100% test item and 3 and 30% positive control substance). No with. + reactions: 0.0. Total no. in groups: 5.0. Clinical observations: none.
Reading:
2nd reading
Hours after challenge:
48
Group:
negative control
Dose level:
all 4 groups (10 and 100% test item and 3 and 30% positive control substance)
No. with + reactions:
0
Total no. in group:
5
Clinical observations:
none
Remarks on result:
other: see Remark
Remarks:
Reading: 2nd reading. . Hours after challenge: 48.0. Group: negative control. Dose level: all 4 groups (10 and 100% test item and 3 and 30% positive control substance). No with. + reactions: 0.0. Total no. in groups: 5.0. Clinical observations: none.
Reading:
1st reading
Hours after challenge:
24
Group:
positive control
Dose level:
3%
No. with + reactions:
6
Total no. in group:
10
Clinical observations:
none
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 24.0. Group: positive control. Dose level: 3%. No with. + reactions: 6.0. Total no. in groups: 10.0. Clinical observations: none.
Reading:
1st reading
Hours after challenge:
24
Group:
positive control
Dose level:
30%
No. with + reactions:
9
Total no. in group:
10
Clinical observations:
none
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 24.0. Group: positive control. Dose level: 30%. No with. + reactions: 9.0. Total no. in groups: 10.0. Clinical observations: none.
Reading:
2nd reading
Hours after challenge:
48
Group:
positive control
Dose level:
3%
No. with + reactions:
4
Total no. in group:
10
Clinical observations:
none
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: positive control. Dose level: 3%. No with. + reactions: 4.0. Total no. in groups: 10.0. Clinical observations: none.
Reading:
2nd reading
Hours after challenge:
48
Group:
positive control
Dose level:
30%
No. with + reactions:
9
Total no. in group:
10
Clinical observations:
none
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: positive control. Dose level: 30%. No with. + reactions: 9.0. Total no. in groups: 10.0. Clinical observations: none.

None

Interpretation of results:
not sensitising
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
DBE was tested for its sensitizing potential in a guinea pig maximization test according to OECD TG 406.
During the challenge phase, no dermal irritation was observed in the test or negative control animals treated with DBE. No to moderate erythema was observed in the positive control animals, showing the sensitivity and validity of the test system. No dermal irritation was observed in the negative control animals treated with the positive control substance.
Under the conditions of this study, DBE did not produce delayed hypersensitivity or allergic reactions in guinea pigs.
Executive summary:

DBE has been tested for its sensitizing potential in a guinea pig maximization test according to OECD no. 406 and EU guideline no. B.6 tris in compliance with Good Laboratory Practice.

The test item was administered epicutaneously (open, once) and intradermally (4 times, once a week) at doses of 100 % and 10 % (v/v in water) following the standard procedure of OECD 406. The challenge was conducted 2 weeks after the last induction epicutaneous (open) at 100 % and 10 % (v/v in water). Positive (1,4 benzenediamine) and negative controls were conducted following OECD 406.

Erythema and edema were scored according to the Draize scoring system.

No mortality was recorded during the study. Body weight gain of the treated animals was not affected by treatment.

During the challenge phase, no dermal irritation was observed in the test or negative control animals treated with DBE. No to moderate erythema was observed in the positive control animals, showing the sensitivity and validity of the test system. No dermal irritation was observed in the negative control animals treated with the positive control substance. Under the conditions of this study, DBE did not produce delayed hypersensitivity or allergic reactions in guinea pigs.

Based on this results DBE is not classified according to Annex VI of the Directive 67/548/CEE and according to EU Regulation 1272/2008 (CLP).

Endpoint:
skin sensitisation: in vivo (LLNA)
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
Study period:
March 09 to June 06, 2005
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)
Principles of method if other than guideline:
not applicable
GLP compliance:
yes (incl. QA statement)
Type of study:
mouse local lymph node assay (LLNA)
Species:
mouse
Strain:
CBA
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Harlan, NL-5960 AD Horst, The Netherlands
- Age at study initiation: 8-12 weeks
- Weight at study initiation: 16-24 g
- Housing:cage
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum):ad libitum
- Acclimation period:under test conditions
Vehicle:
acetone/olive oil (4:1 v/v)
Concentration:
0.0% (Control), 5, 10, 25, 50, 100% (w/v)
No. of animals per dose:
4 female animals per dose
Details on study design:
RANGE FINDING TESTS:
- Lymph node proliferation response: at 10, 25, 50 and 100% (w/v)
Positive control substance(s):
hexyl cinnamic aldehyde (CAS No 101-86-0)
Positive control results:
As positive control for the current LLNA test, three groups each of four female mice were treated daily with alpha-hexylcinnamaldehyde at concentrations of 5 %, 10 % and 25 % (w/v) in acetone:olive oil, 4:1 (v/v) by topical application to the dorsum of each ear lobe (left and right) for three consecutive days. A control group of four mice was treated with the vehicle (acetone:olive oil, 4:1 (v/v).

The results obtained (STIMULATION INDEX (S.I.) for this positive test are reported as follows:.

Group 2 5* % (w/v) 2.4 * (S.I.)
Group 3 10 * % (w/v) 3.6 * (S.I.)
Group 4 25 % (w/v) 11.2 (S.I.)

A clear dose-response relationship was observed. * This value was used in calculation of EC3. The estimated concentration of test item required to produce a S.I. of 3 is referred to as the EC3 value and found to be EC3 = 7.5 % (w/v),
Parameter:
SI
Remarks on result:
other: 0.6, minimum 1.0, maximum
Parameter:
other: disintegrations per minute (DPM)
Remarks on result:
other: 4'890 minimum; 2'589 maximum;

Calculation and results of individual data -

The proliferative capacity of pooled lymph node cells was determined by the incorporation of 3H-methyl thymidine measured on a 13-scintillation counter See in text table below for stimulation index (S.I.).

Test item concentration

% (w/v)

S.I.

Group 2

5

0.6

Group 3

10

0.6

Group 4

25

1.0

Group 5

50

0.6

Group 6

100 (undiluted)

0.5

No dose-response relationship was observed.

Calculation of the EC 3 value was not performed because no test concentrations produced a STIMULATION INDEX (S.I.) of 3 or higher.

The radioactive disintegration values for the individual treatment groups are included in table below.

Viability / Mortality - No deaths occurred during the study period.

Clinical Signs -

No clinical signs were observed in any animals of the control group, Group 2 (5 %), Group 3 (10 %) or Group 4 (25 %). On the second application day, a slight to moderate ear erythema was observed at both dosing sites in all mice of Group 5 (50 %) and Group 6 (100 %,  undiluted), persisting for a total of two days. The individual clinical were graded in severity of the symptoms into four grades: slight (1), moderate (2), severe (3) and very severe (4).

Body weights -

The body weight of the animals, recorded prior to the first application and prior to necropsy, was within the range commonly recorded for animals of the strain and age.

Table 1

Test item

Measurement

Calculation

Result

concentration

dpm

dpm -

number of

dpm per

S.I.

% (w/v)

BGa)

lymph nodes

lymph nodeb)

--

BG I

10

--

--

--

--

--

BGII

14

--

--

--

--

--

CG 1

4902

4890

8

611

--

5

TG 2

2978

2966

8

371

0.6

10

TG 3

2898

2886

8

361

0.6

25

TG4

4846

4834

8

604

1.0

50

TG5

2726

2714

8 **

339

0.6

100 *

TG6

2601

2589

8 **

324

0.5

*, undiluted as delivered by sponsor;

**, the size of the draining lymph nodes of this group was obviously small compared to those of the control group;

BG, background (1 ml 5% trichloroacetic acid) in duplicate;

CG, control group;

TG, test group;

S.I., simulation index

Interpretation of results:
not sensitising
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
A test item is regarded as a sensitizer in the LLNA if the exposure to one or more test concentrations resulted in 3-fold or greater increase in incorporation of 3HTdR compared with concurrent controls, as indicated by the STIMULATION INDEX (S.I.).

RHODIASOLV RPDE was found to be a non-sensitizer when tested at up to the concentration of 100 % (undiluted).

Executive summary:

In order to study a possible contact allergenic potential of RHODIASOLV RPDE,  a local lymph node assay (LLNA) was performed according to the OECD Guideline 429 and und GLP Regulations. Five groups each of four female mice were treated daily with the test item at concentrations of 5 %, 10 %, 25 %, 50 % (w/v) in acetone/olive oil (4/1, v/v) and 100 % (undiluted) by topical application to the dorsum of each ear lobe (left and right) for three consecutive days. A control group of four mice was treated with the vehicle (acetone/olive oil (4/1, v/v)) only. Five days after the first topical application the mice were injected intravenously into a tail vein with radio-labelled thymidine 3H-methyl thymidine. Approximately five hours after intravenous injection, the mice were sacrificed, the draining auricular lymph nodes excised and pooled per group. Single cell suspensions of lymph node cells were prepared from pooled lymph nodes which were subsequently washed and incubated with trichloroacetic acid overnight. The proliferative capacity of pooled lymph node cells was determined by the incorporation of 3H-methyl thymidine measured. All treated animals survived the scheduled study period. No clinical signs were observed in any animals of the control group, Group 2 (5 %), Group 3 (10 %) or Group 4 (25 %). On the second application day, a slight to moderate ear erythema was observed at both dosing sites in all mice of Group 5 (50 %) and Group 6 (100 %, undiluted), persisting for a total of two days.

The results obtained (Stimulation Index (S.I.)) for each group of animals and exposure were as follows: group 2 (5% (w/v)), S.I. 0.6; group 3 (10% (w/v)), S.I. 0.6; group 4 (25% (w/v)), S.I. 1.0; group 5 (50% (w/v)), S.I.  0.6; group 6 (100% (w/v)), S.I. 0.5.

A test item is regarded as a sensitizer in the LLNA if the exposure to one or more test concentrations resulted in 3-fold or greater increase in incorporation of 3HTdR compared with concurrent controls, as indicated by the stimulation index (S.I.). In this study S.I. of 0.6, 0.6, 1.0, 0.6 and 0.5 were determined with the test item at concentrations of 5 %, 10 %, 25 %, 50 % (w/v) in acetone/olive oil (4/1, v/v) and 100 % (undiluted), respectively.

RHODIASOLV RPDE was therefore found to be a non-sensitizer when tested at up to the concentration of 100 % (i.e., undiluted).

Endpoint:
skin sensitisation: in vivo (non-LLNA)
Type of information:
read-across based on grouping of substances (category approach)
Adequacy of study:
supporting study
Study period:
1981
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Qualifier:
no guideline followed
Principles of method if other than guideline:
Weekly Intradermal induction using 0.1ml of a 1% solution in dimethyl phthalate for 4 weeks. 15 days later challenge (topical)
GLP compliance:
not specified
Type of study:
intracutaneous test
Species:
guinea pig
Strain:
Dunkin-Hartley
Sex:
male
Route:
intradermal
Vehicle:
other: dimethylphalate
Concentration / amount:
Intradermal induction: 0.1 ml of a 1% solution of the test material in Dimethylpthalate
Topical challenge: 0.05ml of 100% solution of test material AND 0.05ml of 10% solution of test material in Dimethylpthalate
Route:
epicutaneous, open
Vehicle:
other: dimethylphalate
Concentration / amount:
Intradermal induction: 0.1 ml of a 1% solution of the test material in Dimethylpthalate
Topical challenge: 0.05ml of 100% solution of test material AND 0.05ml of 10% solution of test material in Dimethylpthalate
No. of animals per dose:
10 test and 10 control
Reading:
1st reading
Hours after challenge:
24
Group:
test chemical
Dose level:
100%
No. with + reactions:
9
Total no. in group:
10
Clinical observations:
mild erythema
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 24.0. Group: test group. Dose level: 100%. No with. + reactions: 9.0. Total no. in groups: 10.0. Clinical observations: mild erythema.
Reading:
2nd reading
Hours after challenge:
48
Group:
test chemical
Dose level:
100%
No. with + reactions:
1
Total no. in group:
10
Clinical observations:
slight erythema in 1 animal
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: test group. Dose level: 100%. No with. + reactions: 1.0. Total no. in groups: 10.0. Clinical observations: slight erythema in 1 animal.
Reading:
1st reading
Hours after challenge:
24
Group:
test chemical
Dose level:
10% in DMA
No. with + reactions:
0
Total no. in group:
10
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 24.0. Group: test group. Dose level: 10% in DMA. No with. + reactions: 0.0. Total no. in groups: 10.0.
Reading:
2nd reading
Hours after challenge:
48
Group:
test chemical
Dose level:
10% in DMA
No. with + reactions:
0
Total no. in group:
10
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: test group. Dose level: 10% in DMA. No with. + reactions: 0.0. Total no. in groups: 10.0.
Reading:
1st reading
Hours after challenge:
24
Group:
negative control
Dose level:
100%
No. with + reactions:
9
Total no. in group:
10
Clinical observations:
mild erythema
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 24.0. Group: negative control. Dose level: 100%. No with. + reactions: 9.0. Total no. in groups: 10.0. Clinical observations: mild erythema.
Reading:
2nd reading
Hours after challenge:
48
Group:
negative control
Dose level:
100%
No. with + reactions:
0
Total no. in group:
10
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: negative control. Dose level: 100%. No with. + reactions: 0.0. Total no. in groups: 10.0.
Reading:
1st reading
Hours after challenge:
24
Group:
negative control
Dose level:
10% in DMA
No. with + reactions:
0
Total no. in group:
10
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 24.0. Group: negative control. Dose level: 10% in DMA. No with. + reactions: 0.0. Total no. in groups: 10.0.
Reading:
2nd reading
Hours after challenge:
48
Group:
negative control
Dose level:
10% in DMA
No. with + reactions:
0
Total no. in group:
10
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: negative control. Dose level: 10% in DMA. No with. + reactions: 0.0. Total no. in groups: 10.0.

At the first challenge in the 100% dose group there was evidence of some mild irritation consistent with that observed in the skin irritation studies. However by 48 hours all evidence of irritation ahd gone in all but 1 animal. The Uninduced control group also showed the same pattern of results. Therefore this erythema (mild) is considered local irritation rather than evidence of a sensitising response.

Interpretation of results:
not sensitising
Remarks:
Migrated information
Conclusions:
Not sensitising.
Endpoint:
skin sensitisation: in vitro
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not sensitising)
Additional information:

Two assays were conducted on this mix of isobutyl esters. In a non-standard guideline study in guinea pigs, animals were induced using 4 weekly intradermal injections of 1% of the test material in dimethylphthalate followed by a challenge 15 days later of a 100% solution and a 10% solution in Dimethylphthalate. This study was negative with some minor signs of irritation that were observed in both test and control animals. A second Guinea pig study, a full guideline GPMT assay, was also negative. The intradermal induction was done with a 5% solution and 100% solutions were used for the topical induction and challenge. No animals were sensitised in this assay. In a LLNA and a GPMT conducted using the reaction mass of methyl esters of adipic acid, glutaric acid and succinic acid

Based on the above information it is concluded that the these dibasic esters are not sensitisers to humans. Therefore it is also concluded that the dibutyl esters would not be sensitising in humans.

Respiratory sensitisation

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not sensitising)
Additional information:

There is no direct link between the ability of something to induce an immune response via the skin in an animal study such as the LLNA or GPMT and the ability to sensitise via inhalation. Therefore it is not possible to conclusively state that this substance is or is not a respiratory sensitiser. Considering that the overall weight of evidence suggest this substance is not a human sensitiser it is unlikely it would be a respiratory sensitiser.

Migrated from Short description of key information:

No data available

Justification for classification or non-classification

No classification required.