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EC number: 242-833-4 | CAS number: 19139-31-2
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Endpoint summary
Administrative data
Description of key information
Key value for chemical safety assessment
Skin sensitisation
Link to relevant study records
- Endpoint:
- skin sensitisation: in vivo (LLNA)
- Type of information:
- experimental study
- Adequacy of study:
- key study
- 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)
- Deviations:
- yes
- Remarks:
- During the acclimation phase the relative humidity in the animal room was between approximately 25 - 65 % instead of 45 - 65% for several hours. This deviation to the study plan, however, does not affect the validity of the study.
- GLP compliance:
- yes (incl. QA statement)
- Type of study:
- mouse local lymph node assay (LLNA)
- Specific details on test material used for the study:
- Identity: Dihexyl Fumarate
Batch No.: VE00180024
Purity: 98.1 % dose calculation not adjusted to purity
Stability in solvent: Not indicated by the sponsor
Storage: At room temperature, light protected
Expiration Date: January 07, 2014 - Species:
- mouse
- Strain:
- CBA/Ca
- Remarks:
- CBA/CaOlaHsd
- Sex:
- female
- Details on test animals and environmental conditions:
- Test system: Mice, CBA/CaOlaHsd
Rationale: Recognised as the recommended test system
Source: Harlan Laboratories B.V. Postbus 6174
5960 AD Horst / The Netherlands
Number of animals for
the pre-tests: 2 females
Number of animals for the main study:
25 females
Number of animals per group 5 females (nulliparous and non-pregnant) Number of test groups: 3
Number of control (vehicle) groups: 1
Number of positive control groups: 1
Age: 1st pre-test: 10 - 11 weeks (beginning of treatment) 2nd pre-test: 11 - 12 weeks (beginning of treatment) Main study: 9 – 10 weeks (beginning of treatment)
Body weight: See Annex 1
Identification: The animals were distributed into the test groups at random. All animals belonging to the same experimental group were kept in one cage. In the main experiment, the animals were identified by tail tags. In the pre-experiment, animals were identified by cage number.
Acclimatisation: At least 5 days prior to the start of dosing under test conditions after health examination. Only animals without any visible signs of illness were used for the study.
Husbandry
The animals were kept conventionally. The experiment was conducted under standard laboratory conditions.
Housing: group
Cage Type: Makrolon Type II / III, with wire mesh top (EHRET GmbH, 79302 Emmendingen, Germany)
Bedding: granulated soft wood bedding
(Rettenmaier & Söhne GmbH + Co. KG, 73494 Rosenberg, Germany)
Feed: pelleted standard diet, ad libitum
(Harlan Laboratories B.V. 5960 AD Horst / Netherlands)
Water: tap water, ad libitum
(Gemeindewerke, 64380 Rossdorf, Germany)
Environment:
temperature 22 + 2°C relative humidity 25-65%
artificial light 6.00 a.m. - 6.00 p.m. - Vehicle:
- acetone/olive oil (4:1 v/v)
- Concentration:
- 1, 10, 25%
- No. of animals per dose:
- 5
- Details on study design:
-
Allocation
The animals were distributed as follows:
Control Group: 0%(vehicle only), 5 animals
Low Dose Group: 1%, 5 animals
Mid Dose Group: 10 %, 5 animals
High Dose Group: 25%, 5 animals
Positive control Group: 25%, 5 animals - Positive control substance(s):
- hexyl cinnamic aldehyde (CAS No 101-86-0)
- Key result
- Parameter:
- SI
- Value:
- 0.99
- Test group / Remarks:
- 1% Dihexyl Fumarate
- Key result
- Parameter:
- SI
- Value:
- 1.25
- Test group / Remarks:
- 10% Dihexyl Fumarate
- Key result
- Parameter:
- SI
- Value:
- 2.28
- Test group / Remarks:
- 25% Dihexyl Fumarate
- Interpretation of results:
- GHS criteria not met
- Conclusions:
- The test item Dihexyl Fumarate was not a skin sensitiser under the test conditions of this study.
Reference
RESULTS
Table 1: Calculation and Results of Individual Data
Vehicle for the test item and positive control: acetone:olive oil
Test item concentration |
Group No. |
Animal No. |
DPM values measured |
DPM-BG per animal (2 lymph nodes)a) |
S.I.b) |
% (w/w) |
|||||
--- |
BG I |
16 |
--- |
--- |
|
--- |
BG II |
16 |
--- |
--- |
|
0 |
1 |
1 |
2065 |
2049 |
--- |
0 |
2 |
1483 |
1467 |
--- |
|
0 |
3 |
1301 |
1285 |
--- |
|
0 |
4 |
1324 |
1308 |
--- |
|
0 |
5 |
946 |
930 |
--- |
|
1 |
2 |
6 |
733 |
717 |
0.5 |
1 |
7 |
1464 |
1448 |
1.0 |
|
1 |
8 |
2354 |
2338 |
1.7 |
|
1 |
9 |
929 |
913 |
0.6 |
|
1 |
10 |
1573 |
1557 |
1.1 |
|
10 |
3 |
11 |
814 |
798 |
0.6 |
10 |
12 |
1980 |
1964 |
1.4 |
|
10 |
13 |
2491 |
2475 |
1.8 |
|
10 |
14 |
1138 |
1122 |
0.8 |
|
10 |
15 |
2421 |
2405 |
1.7 |
|
25 |
4 |
16 |
3046 |
3030 |
2.2 |
25 |
17 |
1713 |
1697 |
1.2 |
|
25 |
18 |
3265 |
3249 |
2.3 |
|
25 |
19 |
4871 |
4855 |
3.4 |
|
25 |
20 |
3237 |
3221 |
2.3 |
|
25 (HCA) |
5 |
21 |
3922 |
3906 |
2.8 |
25 (HCA) |
22 |
12200 |
12184 |
8.7 |
|
25 (HCA) |
23 |
12672 |
12656 |
9.0 |
|
25 (HCA) |
24 |
10954 |
10938 |
7.8 |
|
25 (HCA) |
25 |
10545 |
10529 |
7.5 |
BG = Background (1 ml 5% trichloroacetic acid) in duplicate
1 = Control Group for the test item and for the positive control item
2-4 = Test Groups (w/w)
5 = Positive Control Group (w/v)
HCA= 25% -α-Hexyl cinnamaldehyde, tech. 85%
S.I. = Stimulation Index
a) = values corrected for mean background value (BGI andBGII).
b) = Stimulation Indices relative to the mean of the control group (Group1)
Table 2: Calculation of Stimulation Indices per Dose Group
Test item concentration |
Group Calculation |
SD |
S.I. |
Mean DPM per animal (2 lymph nodes)a) |
|||
Vehicle Control Group for the Test Item (acetone:olive oil) |
1407.8 |
408.6 |
1.00 |
1% Dihexyl Fumarate |
1394.6 |
634.5 |
0.99 |
10% Dihexyl Fumarate |
1752.8 |
758.5 |
1.25 |
25% Dihexyl Fumarate |
3210.4 |
1121.3 |
2.28 |
Positive Control Group (25%α-HCA) |
10042.6 |
3539.5 |
7.13 |
a) Mean DPM/animal was determined by dividing the sum of the measured valuesfromlymphnodesofallanimalswithinagroupbythenumberofanimalsinthatgroup(5animals)
The EC3 value could not be calculated, since all S.I.´s, for the test item, are below the threshold value of 3.
Viability /Mortality
No deaths occurred during the study period.
ClinicalSigns
From day 3 to 6 the animals treated with a test item concentration of 25% showed an erythema of the ear skin (Score 1). On day 4 also the animals treated with 10% test item concentration showed an erythema of the ear skin (Score 1). Animals treated with 1% test item concentration did not show any signs of local skin irritation.
BodyWeights
The body weight of the animals, recorded prior to the first application and prior to treatment with3HTdR, was within the range commonly recorded for animals of this strain and age.
EarWeight
The measured ear weight of all animals treated was recorded on the day of preparation. An increase in ear weight was observed in the groups treated with 10 and 25% test item concentration in comparison to the vehicle control group. A dose-dependance was not observed. A statistically significant increase in ear weights was observed in all dose groups in comparison to the vehicle control group(p<0.05).
EarThickness
The measured ear thickness of all animals treated was recorded prior to the 1st application, on study day 3 and prior to necropsy (day 6). A statistically significant increase in ear thickness was observed in the high dose group in comparison to the vehicle control group (p<0.05).
DISCUSSION
In order to study a possible skin sensitising potential of Dihexyl Fumarate, three groups each of five female mice were treated once daily with the test item at a concentrations of 1, 10 and 25% (w/w) in acetone:olive oil (4:1 v/v) by topical application to the dorsum of each ear for three consecutive days. The highest concentration tested was the highest concentration that could be achieved whilst avoiding systemic toxicity and excessive local skin irritation as confirmed by the two pre-experiments. One further group of five mice was treated with the vehicle for the test item and positive control (acetone:olive oil (4+1 v/v)) and another group of five mice was treated with the positive control at 25%. 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 animal. 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 of3H-methyl thymidine measured in ab-scintillationcounter.
From day 3 to day 6, the animals treated with a test item concentration of 25% showed an erythema of the ear skin (Score 1). Animals treated with 10% test item concentration showed an erythema of the ear skin (Score 1) on day 4. The animals treated with 1% did not show any signs of local skin irritation. Animal 24 belonging to the positive control group showed ruffled fur on day 2 and 3. A statistically significant increase in ear weights was observed in all dose groups in comparison to the vehicle control group (p<0.05). A statistically significant increase in ear thickness was observed in the high dose group in comparison to the vehicle control group (p<0.05).
A test item is regarded as a sensitiser in the LLNA if the exposure to one or more test concentration resulted in a 3-fold or greater increase in incorporation of 3HTdR compared with concurrent controls, as indicated by the Stimulation Index (S.I.). The estimated concentration of test item required to produce a S.I. of 3 is referred to as the EC3 value.
In this study Stimulation Indices of 0.99, 1.25 and 2.28 were determined with the test item at concentrations of 1, 10 and 25% (w/w) in acetone:olive oil (4:1 v/v). A clear dose response was observed.
The S.I. determined for the positive control was 7.13, demonstrating the validity of the study. An outlier was identified in the positive control group (DPM value determined for animal number 21). However, the exclusion of the outlier did not change the overall test result and the value in question was not excluded from calculation.
CONCLUSION
The test item Dihexyl Fumarate was not a skin sensitiser under the test conditions of this study.
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed (not sensitising)
Respiratory sensitisation
Endpoint conclusion
- Endpoint conclusion:
- no study available
Justification for classification or non-classification
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