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Toxicological information

Skin sensitisation

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Administrative data

Endpoint:
skin sensitisation: in vivo (non-LLNA)
Type of information:
experimental study
Adequacy of study:
key study
Study period:
13 May 2002 - 8 July 2002.
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
other company data
Title:
Unnamed
Year:
2002
Report date:
2002

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
EU Method B.6 (Skin Sensitisation)
Deviations:
no
Qualifier:
according to guideline
Guideline:
OECD Guideline 406 (Skin Sensitisation)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.2600 (Skin Sensitisation)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Type of study:
guinea pig maximisation test
Justification for non-LLNA method:
The study was conducted before the LLNA was in force

Test material

Constituent 1
Reference substance name:
1,4-cyclohexanedimethanol (CHDM)
IUPAC Name:
1,4-cyclohexanedimethanol (CHDM)
Constituent 2
Chemical structure
Reference substance name:
Cyclohex-1,4-ylenedimethanol
EC Number:
203-268-9
EC Name:
Cyclohex-1,4-ylenedimethanol
Cas Number:
105-08-8
Molecular formula:
C8H16O2
IUPAC Name:
cyclohexane-1,4-diyldimethanol
Constituent 3
Reference substance name:
[4-(hydroxymethyl)cyclohexyl]methanol
IUPAC Name:
[4-(hydroxymethyl)cyclohexyl]methanol
Details on test material:
- Name of test material (as cited in study report): 1,4-cyclohexanedimethanol
- Substance type: pure active substance
- Physical state: White waxy solid
- Analytical purity: Min 99.0%
- Impurities (identity and concentrations): not available
- Composition of test material, percentage of components: 99%
- Isomers composition: not applicable
- Purity test date: not available
- Lot/batch No.: 0090
- Expiration date of the lot/batch: 31 March 2003
- Stability under test conditions: not determined
- Storage condition of test material: room temperature

In vivo test system

Test animals

Species:
guinea pig
Strain:
Dunkin-Hartley
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: D. Hall, Newchurch, Staffordshire, UK
- Age at study initiation: Four to five weeks of age
- Weight at study initiation: 348-409g
- Housing: housed in groups of five in suspended metal cages with wire mesh floors in Building 5 Room 515A (preliminary investigations) and 507B (main study investigation), Eye Research Centre, Eye, Suffolk, IP23 7PX.
- Diet (e.g. ad libitum): A vitamin C enriched guinea-pig diet (SDS FD1 MOD SQC)
- Water (e.g. ad libitum): drinking water ad libitum
- Acclimation period: 7 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 +/- 3
- Humidity (%): 40 to 70
- Photoperiod (hrs dark / hrs light): 12/12

Study design: in vivo (non-LLNA)

Inductionopen allclose all
Route:
other: intradermal injection and topical application
Vehicle:
water
Concentration / amount:
Preliminary test: control, 0.05, 0.1, 0.5, 1.0, 5.0, 10, 25, 50 % w/v
main test
- induction intradermal injection : 1% w/v in water for irrigation
- induction topical application : as supplied
- topical challenge : as supplied and 50% w/v in water for injection
Challengeopen allclose all
Route:
other: topical application
Vehicle:
water
Concentration / amount:
Preliminary test: control, 0.05, 0.1, 0.5, 1.0, 5.0, 10, 25, 50 % w/v
main test
- induction intradermal injection : 1% w/v in water for irrigation
- induction topical application : as supplied
- topical challenge : as supplied and 50% w/v in water for injection
No. of animals per dose:
preliminary test:
- Intradermal injection: 2 animals (control, 0.05, 0.1, 0.5, 1.0, 5.0, 10, 25, 50 % w/v per each animal)
-Topical application: 4 animals( 25, 50, 75% w/v, as supplied per each animal)

main test
test : 10 animals, control: 5 animals
Details on study design:

The intradermal and topical irritancy of a range of dilutions of CHDM was investigated to identify where possible (a) the minimum irritant test substance concentrations suitable for the induction phase of the main study and (b) a maximum nonirritant concentration by the topical route of administration and a dilution of this for the challenge phase.

The animals for the topical irritancy investigations were pre-treated with an intradermal injection of Freund's Complete Adjuvant, 50:50 with water for irrigation (Ph.Eur.), approximately one week prior to the start of the preliminary investigations.

Intradermal injections
- No. of exposures: 2
- Test groups: 2 animals (931,932)
- Control group: 2 animals (931,932)
- Site: dorsal skin on the scapular region
- Frequency of applications: once treated
- Duration: assessed approximately 24 and 72 hours later
- Concentrations: 0.05, 0.1, 0.5, 1.0, 5.0, 10, 25, 50 % w/v of 0.1ml/site

Topical application - No. of exposures: 4
- Test groups: 4 animals(933, 934, 935, 936)
- Control group: 0
- Site: dorsal skin on the scapular region
- Frequency of applications:
- Duration: assessed approximately 24 and 48 hours after removal of the dressing
- Concentrations: 25% of neat test material (0.2ml/patch)

Based on the results of the preliminary investigations, the following concentrations of CHDM were selected for the main study:
Induction intradermal injection-1% w/v in water for irrigation (This was the highest concentration that caused irritation but did not cause necrosis or give signs of toxicity).



A. INDUCTION EXPOSURE
- No. of exposures: 10
- Test groups: 10 animals (260, 261, 262, 263, 264, 265, 266, 267, 268, 269)
- Control group: 5 animals (255, 256,257,258, 259)
- Site: an approximately 4x6 cm area of dorsal skin on the scapular region
- Frequency of applications: once treated
- Duration: 22 days (6 days for intradermal injection and 16 days for topical application)
- Concentrations
for intradermal injection
1) Freund's Complete Adjuvant 50:50 with water for irrigation (Ph.Eur.).
2) CHDM, 1% w/v in water for irrigation.
3) CHDM, 1% w/v in a 50:50 mixture of Freund's Complete Adjuvant and water for irrigation.
for topical application
: approximated 0.4 ml , as supplied

B. CHALLENGE EXPOSURE
- No. of exposures: 10
- Test groups: 10 animals (260, 261, 262, 263, 264, 265, 266, 267, 268, 269)
- Control group: 5 animals (255, 256,257,258, 259)
- Site: the left flank of guinea-pig
- Frequency of applications: once treated
- Duration: evaluated approximately 24 and 48 hours after removal of the patches
- Concentrations: as supplied (0.2ml of CHDM) and 50% w/v in water for injection
RANGE FINDING TESTS:
The intradermal and topical irritancy of a range of dilutions of CHDM was investigated to identify where possible (a) the minimum irritant test substance concentrations suitable for the induction phase of the main study and (b) a maximum nonirritant concentration by the topical route of administration and a dilution of this for the challenge phase.

The animals for the topical irritancy investigations were pre-treated with an intradermal injection of Freund's Complete Adjuvant, 50:50 with water for irrigation (Ph.Eur.), approximately one week prior to the start of the preliminary investigations.

Intradermal injections: Intradermal injections (0.1ml/site) were made into the clipped and shaved flank of two guinea-pigs, using a range of concentrations (0.05% w/v to 50% w/v) of CHDM in water for irrigation. The resulting dermal responses were assessed approximately 24 and 72 hours later.

Topical application - Patches of Whatman No. 4 paper (2cm * 2cm) were saturated (volume approximately 0.2 ml per patch) with a range of concentrations (25% w/v to neat test material) of CHDM in water for irrigation and applied to the clipped and shaved flanks of each of four guinea-pigs. The patches were covered by a strip of "Blenderm" and firmly secured by "Elastoplast" wound round the trunk and fixed with an impervious plastic adhesive tape. The dressings were removed after an exposure period of approximately 24 hours and the reaction sites were assessed for erythema and oedema. Further examination of the sites was carried out approximately 24 and 48 hours after removal of the dressings.

Based on the results of the preliminary investigations, the following concentrations of CHDM were selected for the main study:
Induction intradermal injection-1% w/v in water for irrigation (This was the highest concentration that caused irritation but did not cause necrosis or give signs of toxicity).


MAIN STUDY
A. INDUCTION EXPOSURE
- No. of exposures: 10 animals
- Exposure period: 24 hours
- Test groups: An approximately 4*6cm area of dorsal skin on the scapular region of the guinea-pig was clipped free of hair with electric clippers. On Day 1, three pairs of intradermal injections (0.1 ml/site) were made into an approximately 2*4 cm area within the clipped area.
The topical induction application as supplied did not produce skin irritation.
- Control group: 5 animals, During the induction phase, the control animals were treated similarly to the test animals with the exception that the test substance was omitted from the intradermal injections and topical application.

- Site: dorsal skin on the scapular region
- Frequency of applications: intradermal injection,
tropical application- six days following the injections the same scapular area was clipped and shaved free of hair and the site was pre-treated by gentle rubbing with 0.5 ml per site of 10% w/w sodium lauryl sulphate in petrolatum.
- Concentrations:
Freund's Complete Adjuvant 50:50 with water for irrigation (Ph. Eur.)
CHDM, 1 % w/v in water for irrigation.
CHDM 1 % w/v in a 50:50 mixture of Freund/s Complete Adjuvant and water for irrigation.


B. CHALLENGE EXPOSURE
- No. of exposures: 10 animals
- Day(s) of challenge: two weeks after the topical induction application (Day 22)
- Exposure period: 24 hours
- Control group and test groups: The control and test animals were challenged topically two weeks after the topical induction application (Day 22) using CHDM, as supplied and 50 % w/v in water for irrigation.
- Site: anterior site on the flank
- Concentrations: 0.2 ml of CHDM as supplied, 50% w/v in water
- Evaluation (hr after challenge): approximately 24 and 48 hours after removal of the patches.




Positive control substance(s):
yes
Remarks:
Hexyl cinnamic aldehyde

Results and discussion

Positive control results:
In this study, HCA produced evidence of skin sensitization (delayed contact hypersensitivity) in eight of the ten animals, thus confirming the sensitivity of the strain of animals and reliability of the experimental technique.

In vivo (non-LLNA)

Resultsopen allclose all
Reading:
other: main study : intradermal injection
Group:
negative control
Dose level:
0.1 ml per each concentration
No. with + reactions:
0
Total no. in group:
5
Clinical observations:
No erythema or oedema was seen
Remarks on result:
other: Reading: other: main study : intradermal injection. Group: negative control. Dose level: 0.1 ml per each concentration. No with. + reactions: 0.0. Total no. in groups: 5.0. Clinical observations: No erythema or oedema was seen.
Reading:
other: main study : intradermal injection
Group:
test chemical
Dose level:
0.1 ml per each concentration
No. with + reactions:
10
Total no. in group:
10
Clinical observations:
erythema grade : 1 for all animals, a false indication of ioedema for all animals
Remarks on result:
other: see Remark
Remarks:
Reading: other: main study : intradermal injection. Group: test group. Dose level: 0.1 ml per each concentration. No with. + reactions: 10.0. Total no. in groups: 10.0. Clinical observations: erythema grade : 1 for all animals, a false indication of ioedema for all animals.
Reading:
other: main study : topical application
Hours after challenge:
48
Group:
negative control
Dose level:
0.4 ml of CHDM
No. with + reactions:
0
Total no. in group:
5
Clinical observations:
No erythema or oedema was observed in the test animals.
Remarks on result:
other: see Remark
Remarks:
Reading: other: main study : topical application. . Hours after challenge: 48.0. Group: negative control. Dose level: 0.4 ml of CHDM. No with. + reactions: 0.0. Total no. in groups: 5.0. Clinical observations: No erythema or oedema was observed in the test animals..
Reading:
other: main study: topical application
Hours after challenge:
48
Group:
test chemical
Dose level:
0.4 ml of CHDM
No. with + reactions:
0
Total no. in group:
10
Clinical observations:
No erythema or oedema was observed in the test animals.
Remarks on result:
other: see Remark
Remarks:
Reading: other: main study: topical application. . Hours after challenge: 48.0. Group: test group. Dose level: 0.4 ml of CHDM. No with. + reactions: 0.0. Total no. in groups: 10.0. Clinical observations: No erythema or oedema was observed in the test animals..
Reading:
other: challenge test
Hours after challenge:
24
Group:
negative control
Dose level:
0.2 ml of CHDM
No. with + reactions:
0
Total no. in group:
5
Clinical observations:
There was no dermal reaction.
Remarks on result:
other: Reading: other: challenge test. . Hours after challenge: 24.0. Group: negative control. Dose level: 0.2 ml of CHDM. No with. + reactions: 0.0. Total no. in groups: 5.0. Clinical observations: There was no dermal reaction..
Reading:
other: challenge test
Hours after challenge:
48
Group:
negative control
Dose level:
0.2 ml of CHDM
No. with + reactions:
0
Total no. in group:
5
Clinical observations:
There was no dermal reaction.
Remarks on result:
other: Reading: other: challenge test. . Hours after challenge: 48.0. Group: negative control. Dose level: 0.2 ml of CHDM. No with. + reactions: 0.0. Total no. in groups: 5.0. Clinical observations: There was no dermal reaction..
Reading:
other: challenge test
Hours after challenge:
24
Group:
test chemical
Dose level:
0.2 ml of CHDM
No. with + reactions:
0
Total no. in group:
10
Clinical observations:
There was no dermal reaction.
Remarks on result:
other: Reading: other: challenge test. . Hours after challenge: 24.0. Group: test group. Dose level: 0.2 ml of CHDM. No with. + reactions: 0.0. Total no. in groups: 10.0. Clinical observations: There was no dermal reaction..
Reading:
other: challenge test
Hours after challenge:
48
Group:
test chemical
Dose level:
0.2 ml of CHDM
No. with + reactions:
0
Total no. in group:
10
Clinical observations:
There was no dermal reaction.
Remarks on result:
other: Reading: other: challenge test. . Hours after challenge: 48.0. Group: test group. Dose level: 0.2 ml of CHDM. No with. + reactions: 0.0. Total no. in groups: 10.0. Clinical observations: There was no dermal reaction..
Reading:
1st reading
Hours after challenge:
24
Group:
positive control
Dose level:
0
No. with + reactions:
8
Total no. in group:
10
Clinical observations:
none
Remarks on result:
positive indication of skin sensitisation
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:
no indication of skin sensitisation

Applicant's summary and conclusion

Interpretation of results:
GHS criteria not met
Conclusions:
In this study, CHDM did not produce evidence of skin sensitization (delayed contact hypersensitivity) in any of the ten test animals.
Therefore, CHDM is no considered to have the potential to cause skin sensitization.
Executive summary:

This study was performed to assess the skin sensitization potential of CHDM (1,4-cyclohexanedimethanol) using the guinea-pig.

The guinea-pigs were dosed by intradermal injection and topical application, as these are the routes of exposure required by the test guidelines and method.

Based on the results of a preliminary study and in compliance with the guidelines, the following dose levels were selected:

- Intradermal injection : 1% w/v in water for irrigation

- Topical application : as supplied

- Chanllenge application : as supplied and 50% w/v in water for irrigation

Ten test and five control guinea-pigs were used in the main study

In this study CHDM(1,4-cyclohexanedimethanol) did not produce evidence of skin sensitization (delayed contact hypersensitivity) in any of the ten test animals. CHDM(1,4 -cyclohexanedimethanal) is not considered to have the potential to cause skin sensitization.