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Diss Factsheets

Administrative data

Description of key information

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records

Referenceopen allclose all

Endpoint:
skin sensitisation: in vivo (LLNA)
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
June - November 2018
Reliability:
1 (reliable without restriction)
Justification for type of information:
Study was perfomed for the notification in non-EU regions not accepting in vitro studies nor read-across data.
Qualifier:
according to guideline
Guideline:
OECD Guideline 429 (Skin Sensitisation: Local Lymph Node Assay)
Version / remarks:
July 22, 2010
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Type of study:
mouse local lymph node assay (LLNA)
Species:
mouse
Strain:
other: CBA/CaOlaHsd
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Enviigo, 5800 AN Vebray, The Netherlands
- Females (if applicable) nulliparous and non-pregnant: yes
- Microbiological status of animals, when known: SPF
- Age at study initiation: 8 to 9 weeks
- Weight at study initiation: 17 to 19.9 g
- Housing: IVC cages, type II L, polysophone cages on Altromin saw fibre bedding
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: at least 5 days
- Indication of any skin lesions: no

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 3 °C
- Humidity (%): 55 +/- 10 %
- Air changes (per hr): at least 10
- Photoperiod (hrs dark / hrs light) 12/12:
- IN-LIFE DATES: From: September 19, 2018 To: September 26, 2018
Vehicle:
acetone/olive oil (4:1 v/v)
Concentration:
25, 50, 100 %
No. of animals per dose:
5
Positive control substance(s):
other: Phenylendiamine in AOO
Positive control results:
SI = 7.2 (+/- 1.0)
Parameter:
SI
Value:
3.5
Variability:
+/- 0.9
Test group / Remarks:
25 %
Parameter:
SI
Value:
6.4
Variability:
+/- 1.1
Test group / Remarks:
50 %
Parameter:
SI
Value:
6.6
Variability:
+/- 0.2
Test group / Remarks:
100 %
Key result
Parameter:
EC3
Value:
22.18
Cellular proliferation data / Observations:
DETAILS ON STIMULATION INDEX CALCULATION
The proliferative response of lymph node cells was expressed as the number of radioactive disintegrations per minute per lymph node (DPM/NODE) and as the ratio of 3H-methyl thymidine - incorporation into lymph node cells of test group animals relative to that recorded for control group animals (STIMULATION INDEX). Before DPM/NODE values were determined, background values were subtracted.

EC3 CALCULATION
EC3 values were determined by linear interpolation, EC3=c+[(3-d)/(b-d)]x(a-c), between two points of the stimulation indices axis, one above (a,b) and one below (c,d) the stimulation index of three [11], [12]. If all measured points are above or below the stimulation index of three, no EC3 value can be stated.
In certain situations where the dose response does not incorporate a data point lying below the SI value of three, provided the data are of good quality (relatively close to an SI of three and evidence of a dose response), an EC3 value may be estimated by using the two doses closest to the SI value of three. The EC3 value is estimated by log-linear interpolation between these two points on a plane where the x-axis represents the dose level and the y-axis represents the SI. The point with the higher SI is denoted (a,b) and the point with the lower SI is denoted (c,d). The formula for the EC3 estimate is as follows: EC3=2^{(log2(c)+(3-d)/(b-d)*[(log2(a)-log2(c)]}, by log-transforming the doses, EC3 estimates will never fall below zero.

CLINICAL OBSERVATIONS:
All animals survived throughout the study period without showing any clinical signs.

BODY WEIGHTS
all animals showed expected weight development.
 POS  CPM  Test item  Animal number  DPM  DPM mean background  DPM/Node  Stimulation index

 56

 1925.0* Negative control 101 3883.0* n.d. n.d.  
 57  263.0 Negative control 102  528.0  514.8  257.4  
 58  763.0 Negative control  103  1532.0  1518.8  759.4  
 59  345.0 Negative control  104  692.0  678.8 339.4   
 60  576.0 Negative control  105  1162.0  1148.8  574.4  
 MV  486.8 Negative control  MV  978.5  965.3  482.7  1.0
 SD  196.5 Negative control  SD  395.3  395.3  197.7  
 41  2011.0  25% test substance in AOO  1  4063.0  4049.8  2024.9  4.2
 42 2219.0  25% test substance in AOO  2  4468.0  4454.8  2227.4  4.6
 43  1838.0 25% test substance in AOO  3  3691.0  3677.8  1838.9  3.8
 44  1087.0 25% test substance in AOO  4  2183.0  2169.8  1084.9 2.2 
 45  1176.0 25% test substance in AOO  5  2370.0  2356.8  1178.4  2.4
 MV  1666.2 25% test substance in AOO  MV  3355.0  3341.8  1670.9  3.5
 SD  453.8 25% test substance in AOO  SD  916.2  916.2  458.1  0.9
 46  2382.0 50 % test substance in AOO  6  4788.0  4774.8  2387.4  4.9
47   3389.0 50 % test substance in AOO  7  6838.0  6824.8  3412.4  7.1
 48  3798.0 50 % test substance in AOO  8  7646.0  7632.8  3816.4  7.9
 49  3353.0 50 % test substance in AOO  9  6732.0  6718.8  3359.4  7.0
 50  2492.0 50 % test substance in AOO  10  5065.0  5051.8  2525.9 5.2
 MV  3082.8 50 % test substance in AOO  MV  6213.8  6200.6  3100.3 6.4
 SD  551.1 50 % test substance in AOO  SD  1101.1  1101.1  550.5  1.1
 51  3073.0 100 % test substance in AOO  11  6223.0  6209.8  3104.9 6.4
 52  3332.0 100 % test substance in AOO  12  6728.0  6714.8  3357.4  7.0
 53  1612.0* 100 % test substance in AOO  13  3246.0*  n.d.  n.d.  n.d.
 54  3240.0 100 % test substance in AOO  14  6540.0  6526.8  3263.4  6.8
 55  3088.0 100 % test substance in AOO  15  6212.0  6198.8  3099.4  6.4
 MV  3183.3 100 % test substance in AOO  MV  6425.8  6412.6  3206.3  6.6
 SD  107.9 100 % test substance in AOO  SD  218.6  218.6  109.3 0.2 
 66  9.0  Background Szinti and TCA    18.0      
 67  5.0  Background Szinti and TCA    10.0      
 68  6.0  Background Szinti and TCA    10.0      
 69  6.0  Background Szinti and TCA    12.0      
 70  8.0  Background Szinti and TCA    16.0      
 MV  6.8  Background Szinti and TCA  MV  13.2  0.0  0.0  0.0
 SD  1.5  Background Szinti and TCA  SD  3.2      

  POS = position in counter; CPM = counts per minute; Conc. = concentration; DPM = disintegrations per minute; * = outlier, failed Grubbs, Nalimov and Dixon; n.d. = not determined; MV = mean value; SD = standard deviation; Szinti = scintillation fluid; TCA = trichloroacetic acid

Interpretation of results:
Category 1B (indication of skin sensitising potential) based on GHS criteria
Conclusions:
The EC3 value (estimated by linear interpolation) was calculated to be at a test item concentration of 22.18%.
Executive summary:

The test item was assessed for sensitising properties in the LLNA at concentrations of 25% (v/v), 50% (v/v) , each diluted with AOO 4:1 (v/v) and 100% (undiluted test item). Each of the three tested concentrations exceeded the stimulation index of 3 [SI (25%) = 3.5; SI (50%) = 6.4; SI (100%) = 6.6].

The EC3 value (estimated by linear interpolation) was calculated to be at a test item concentration of 22.18%. The substance is therefore considered to be a weak sensitizer.

Endpoint:
skin sensitisation: in vivo (non-LLNA)
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
January - August 2019
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Justification for type of information:
Study was perfomed for the notification in non-EU regions not accepting in vitro studies nor read-across data.

As data on structurally related substances showed no skin sensitizing effects in guinea pig tests the result of the LLNA test showing only a weak sensitising potential was questioned. Experiences with the LLNA showed some limitations in the applicability domain of some substance groups therefore it was considered possible that the LLNA is not suitable for the reliable detection of skin sensitizing properties of dialkyl ethers. Hence an additional Magnusson & Kligman sensitisation test according to OECD Guideline 429 was performed in guinea pigs.
Qualifier:
according to guideline
Guideline:
OECD Guideline 406 (Skin Sensitisation)
Version / remarks:
July 17, 1992
Deviations:
no
GLP compliance:
yes
Type of study:
guinea pig maximisation test
Justification for non-LLNA method:
Test was done based on an authority study request from another region.
Species:
guinea pig
Strain:
Hartley
Sex:
male/female
Route:
intradermal
Vehicle:
other: ethanol
Concentration / amount:
5 %
Route:
epicutaneous, occlusive
Vehicle:
unchanged (no vehicle)
No.:
#1
Route:
epicutaneous, occlusive
Vehicle:
other: acetone
Concentration / amount:
50%
No.:
#2
Route:
epicutaneous, occlusive
Vehicle:
other: acetone
Concentration / amount:
50 %
No. of animals per dose:
20
Details on study design:
according to guideline
Challenge controls:
undiluted negative control (acetone)
Positive control substance(s):
yes
Remarks:
historical control
Reading:
1st reading
Hours after challenge:
48
Group:
test chemical
Dose level:
50%
No. with + reactions:
8
Total no. in group:
20
Clinical observations:
Grade 1 erythema reactions
Reading:
1st reading
Hours after challenge:
48
Group:
test chemical
Dose level:
vehicle acetone
No. with + reactions:
1
Total no. in group:
20
Clinical observations:
Grade 1 erythema reactions
Reading:
1st reading
Hours after challenge:
48
Group:
negative control
Dose level:
50 %
No. with + reactions:
0
Total no. in group:
10
Reading:
1st reading
Hours after challenge:
48
Group:
negative control
Dose level:
vehicle acetone
No. with + reactions:
1
Total no. in group:
10
Clinical observations:
Grade 1 erythema reactions
Reading:
2nd reading
Hours after challenge:
72
Group:
test chemical
Dose level:
50%
No. with + reactions:
3
Total no. in group:
20
Clinical observations:
Grade 1 erythema reactions
Reading:
2nd reading
Hours after challenge:
72
Group:
test chemical
Dose level:
vehicle acetone
No. with + reactions:
0
Total no. in group:
20
Reading:
2nd reading
Hours after challenge:
72
Group:
negative control
Dose level:
50%
No. with + reactions:
0
Total no. in group:
10
Reading:
2nd reading
Hours after challenge:
72
Group:
negative control
Dose level:
vehicle acetone
No. with + reactions:
0
Total no. in group:
10
Reading:
rechallenge
Hours after challenge:
48
Group:
test chemical
Dose level:
50%
No. with + reactions:
10
Total no. in group:
20
Clinical observations:
9 Grade 1 reaction; 1 Grade 2 reactions
Reading:
rechallenge
Hours after challenge:
48
Group:
test chemical
Dose level:
vehicle acetone
No. with + reactions:
3
Total no. in group:
20
Clinical observations:
Grade 1 reactions
Reading:
rechallenge
Hours after challenge:
48
Group:
negative control
Dose level:
50%
No. with + reactions:
4
Total no. in group:
10
Clinical observations:
3 Grade 1 reactions; 1 Grade 2 reaction
Reading:
rechallenge
Hours after challenge:
48
Group:
negative control
Dose level:
vehicle acetone
No. with + reactions:
1
Total no. in group:
10
Clinical observations:
Grade 1 reaction
Reading:
rechallenge
Hours after challenge:
72
Group:
test chemical
Dose level:
50%
No. with + reactions:
5
Total no. in group:
20
Clinical observations:
Grade 1 reactions
Reading:
rechallenge
Hours after challenge:
72
Group:
test chemical
Dose level:
vehicle acetone
No. with + reactions:
0
Total no. in group:
20
Reading:
rechallenge
Hours after challenge:
72
Group:
negative control
Dose level:
50 % test substance
No. with + reactions:
3
Total no. in group:
10
Clinical observations:
Grade 1 reactions
Reading:
rechallenge
Hours after challenge:
72
Group:
negative control
Dose level:
vehicle acetone
No. with + reactions:
0
Total no. in group:
10
Reading:
1st reading
Hours after challenge:
48
Group:
positive control
Dose level:
10% in 70/30 Acetone/PEG400
No. with + reactions:
17
Total no. in group:
20
Remarks on result:
positive indication of skin sensitisation
Reading:
2nd reading
Hours after challenge:
72
Group:
positive control
Dose level:
10% in 70/30 (v/v) Acetone/PEG 400
No. with + reactions:
13
Total no. in group:
20
Remarks on result:
positive indication of skin sensitisation
Interpretation of results:
Category 1B (indication of skin sensitising potential) based on GHS criteria
Conclusions:
8 out of 20 treated animals exhibited weak erythemal reactions 48 hours post challenge application. The substance is therefore considered to be a weak sensitizer.
Executive summary:

A test according to the Magnusson and Kligman method was performed with the test article to investigate the sensitizing potential with female guinea pigs, strain Hartley albino. The test substance was applied as a 5% dilution in ethanol for the intracutaneous and undiluted for the epicutaneous induction. The challenge application was performed undiluted 14 days following completion of the epicutaneous induction. Concentration for the challenge was 50% in acteone. 8 out of 20 treated animals exhibited weak erythemal reactions 48 hours post challenge application. Concurrent negative controls showed no skin reaction (0/10). Each one vehicle control of the test and control groupd showed weak erythemal reactions. Following rechallenge with 50 % test substance in acetone in the treastment group 9 animals showed weak and one animal moderate erythemal reactions. In the concurrent negative control group three animals showed weak and one animal moderate erythemal reactions. For the vehicle control three animals in the treatment group and one animal in the control group showed weak erythemal reactions. The substance is therefore considered to be a weak sensitizer.

Endpoint:
skin sensitisation: in vivo (non-LLNA)
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: guideline study, klimisch criteria
Qualifier:
according to guideline
Guideline:
OECD Guideline 406 (Skin Sensitisation)
Deviations:
no
GLP compliance:
yes
Type of study:
guinea pig maximisation 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:
Pirbright-Hartley
Sex:
female
Details on test animals and environmental conditions:
according to guideline
Route:
intradermal and epicutaneous
Vehicle:
paraffin oil
Concentration / amount:
intracutaneous induction: 2%
epicutanous induction: 10%
challenge: 5%
rechallenge: 3%
Route:
epicutaneous, occlusive
Vehicle:
paraffin oil
Concentration / amount:
intracutaneous induction: 2%
epicutanous induction: 10%
challenge: 5%
rechallenge: 3%
No. of animals per dose:
20
Details on study design:
according to guideline
Positive control substance(s):
no
Reading:
1st reading
Hours after challenge:
24
Group:
test chemical
Dose level:
5%
No. with + reactions:
14
Total no. in group:
20
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 24.0. Group: test group. Dose level: 5%. No with. + reactions: 14.0. Total no. in groups: 20.0.
Reading:
1st reading
Hours after challenge:
24
Group:
negative control
Dose level:
vehicle
No. with + reactions:
10
Total no. in group:
10
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 24.0. Group: negative control. Dose level: vehicle. No with. + reactions: 10.0. Total no. in groups: 10.0.
Reading:
2nd reading
Hours after challenge:
48
Group:
test chemical
Dose level:
5%
No. with + reactions:
9
Total no. in group:
20
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: test group. Dose level: 5%. No with. + reactions: 9.0. Total no. in groups: 20.0.
Reading:
2nd reading
Hours after challenge:
48
Group:
negative control
Dose level:
vehicle
No. with + reactions:
5
Total no. in group:
10
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: negative control. Dose level: vehicle. No with. + reactions: 5.0. Total no. in groups: 10.0.
Reading:
rechallenge
Hours after challenge:
24
Group:
test chemical
Dose level:
3%
No. with + reactions:
10
Total no. in group:
20
Remarks on result:
other: Reading: rechallenge. . Hours after challenge: 24.0. Group: test group. Dose level: 3%. No with. + reactions: 10.0. Total no. in groups: 20.0.
Reading:
rechallenge
Hours after challenge:
24
Group:
negative control
Dose level:
vehicle
No. with + reactions:
3
Total no. in group:
10
Remarks on result:
other: Reading: rechallenge. . Hours after challenge: 24.0. Group: negative control. Dose level: vehicle. No with. + reactions: 3.0. Total no. in groups: 10.0.
Reading:
rechallenge
Hours after challenge:
48
Group:
test chemical
Dose level:
3%
No. with + reactions:
3
Total no. in group:
20
Remarks on result:
other: Reading: rechallenge. . Hours after challenge: 48.0. Group: test group. Dose level: 3%. No with. + reactions: 3.0. Total no. in groups: 20.0.
Reading:
rechallenge
Hours after challenge:
48
Group:
negative control
Dose level:
vehicle
No. with + reactions:
1
Total no. in group:
10
Remarks on result:
other: Reading: rechallenge. . Hours after challenge: 48.0. Group: negative control. Dose level: vehicle. No with. + reactions: 1.0. Total no. in groups: 10.0.
Interpretation of results:
GHS criteria not met
Remarks:
Migrated information
Conclusions:
Both controls and treated animals exhibited weak reactions that were attributed to irritation. Following rechallenge, no distinct dermal effects were observed.
Executive summary:

A test according to the Magnusson and Kligman method was performed with the test article to investigate the sensitizing potential with female guinea pigs, strain Pirbright White. The test substance was applied as a 2% dilution in paraffin perliquid for the intracutaneous and as a 10% dilution for the epicutaneous induction. Concentration for the challenge was 5%. 24 hours after the removal of the challenge patches the test substance solution did not cause any dermal reactions, which could be attributed to allergic reactions. The substance is therefore not considered to be a sensitizer.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (sensitising)
Additional information:

For the assessment of the sensitising properties of dihexyl ether a local lymph node assay (LLNA) was performed according to OECD Guideline 429 at concentrations of 25% (v/v), 50% (v/v), each diluted with AOO 4:1 (v/v) and 100% (undiluted test item). For each of the three tested concentrations the stimulation index of 3 was exceeded [SI (25%) = 3.5; SI (50%) = 6.4; SI (100%) = 6.6]. The EC3 value (estimated by linear interpolation) was calculated to be at a test item concentration of 22.18%.

As data on structurally related substances showed no skin sensitizing effects in guinea pig tests the result of this test showing only a weak sensitising potential was questioned. Experiences with the LLNA showed some limitations in the applicability domain of some substance groups therefore it was considered possible that the LLNA is not suitable for the reliable detection of skin sensitizing properties of dialkyl ethers. Hence a Magnusson & Kligman sensitisation test according to OECD Guideline 406 was performed in guinea pigs.

In the maximasation test dihexyl ether was applied as a 5% dilution in ethanol for the intracutaneous and undiluted for the epicutaneous induction. The challenge application was performed undiluted 14 days following completion of the epicutaneous induction. Concentration for the challenge was 50% in acteone. 8 out of 20 treated animals exhibited weak erythemal reactions 48 hours post challenge application. Concurrent negative controls showed no skin reaction (0/10). Each one vehicle control of the test and control group showed weak erythemal reactions. Following rechallenge with 50 % test substance in acetone in the treatment group 9 animals showed weak and one animal moderate erythemal reactions. In the concurrent negative control group three animals showed weak and one animal moderate erythemal reactions. For the vehicle control three animals in the treatment group and one animal in the control group showed weak erythemal reactions.

Based on these results the substance dihexyl ether is considered to be a weak sensitizer.

Respiratory sensitisation

Endpoint conclusion
Endpoint conclusion:
no study available

Justification for classification or non-classification

Animal studies performed according to the OECD Guidelines show that dihexyl ether is a weak sensitiser.