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Diss Factsheets

Administrative data

Endpoint:
skin sensitisation: in vivo (non-LLNA)
Type of information:
experimental study
Adequacy of study:
key study
Study period:
From 1989, october 17th to 1989, november 23rd
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP study performed according to the Test Guidelines described in the EEC Directive 84/449/EEC

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1989
Report date:
1990

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
OECD Guideline 406 (Skin Sensitisation)
Qualifier:
according to guideline
Guideline:
EU Method B.6 (Skin Sensitisation)
GLP compliance:
yes
Type of study:
Freund's complete adjuvant test

Test material

Constituent 1
Chemical structure
Reference substance name:
3',5'-dichloro-4'-ethyl-2'-hydroxypalmitanilide
EC Number:
406-200-8
EC Name:
3',5'-dichloro-4'-ethyl-2'-hydroxypalmitanilide
Cas Number:
117827-06-2
Molecular formula:
C24H39Cl2NO2
IUPAC Name:
N-(3,5-dichloro-4-ethyl-2-hydroxyphenyl)hexadecanamide
Details on test material:
Identification UC—136
Description White powder
Purity 98.5%
Instructions for test article storage At room temperature in the dark in a tightly sealed container
Stability of test article Stable for one year maximal under storage conditions
Expiry date January 5, 1990
Stability in vehicles Unknown in methyl cellulose 1%.
Safety precautions Gloves, goggles and face mask were considered tobe sufficient to ensure personnel health and safety.

In vivo test system

Test animals

Species:
guinea pig
Strain:
Dunkin-Hartley
Sex:
female
Details on test animals and environmental conditions:
Test system
Species Dunkin—Hartley albino guinea pigs (SPF—quality)
Rationale Recognised by international guidelines as the recommended test system, (e.g. EPA, OECO, EEC).
Source Charles River Wiga, Sulzfeld / West Germany
Total number of animals 35 females
Age at start of treatment Approx. 10 weeks
Body Weight at the end of acclimatisation 348 — 431 gram
Identification Tattoo
Acclimatisation At least five days under test conditions after physical examination.
The animals were distributed as follows:
Ten females for the control group and twenty females for the experimental group. The five remaining animals were used for the primary irritation test,
one week before the main study.
A positive control experiment is carried out once a year as a sensitivity check of the test system. The most recent test was carried out in August 1989
HUSBANDRY
Room No.: 7
Conditions
Standard Laboratory Conditions. Air—conditioned with 15 air changes per hour and hourly monitored environment with temperature set at 21 ± 3°C, the relative humidity at 30—70%, (actual ranges were 17—20°C and 35—79%) and 12 hours artif’icial fluorescent light / 12 hours dark per day.
Accommodation
Group housing of 2 animals per cage with wire—mesh floors (ITL, Bergen / The Netherlands).
Diet
Free access to standard guinea pig diet, including ascorbic acid (1600 mg/kg); LC 23—B, pellet diameter 4mm. (Hope Farms, Woerden, The Netherlands). In addition, once a week hay was provided (Broekman Institute, Someren / The Netherlands). Certificates of diet analysis are examined and retained in the RCC NOTOX archives.
Water
Free access to tapwater, diluted with decalcified water.
Certificates analysis are examined and retained in the RCC NOTOX archives.

Study design: in vivo (non-LLNA)

Inductionopen allclose all
Route:
epicutaneous, occlusive
Vehicle:
CMC (carboxymethyl cellulose)
Concentration / amount:
Epicutaneous induction:
50 % (w/w) in methyl cellulose 1%.
Challenge:
a = 25 % (w/w) in methyl cellulose 1%.
b = 10 % (w/w) in methyl cellulose 1%.
c = 5 % (w/w) in methyl cellulose 1%.
d = methyl cellulose 1%.
Challengeopen allclose all
Route:
epicutaneous, occlusive
Vehicle:
CMC (carboxymethyl cellulose)
Concentration / amount:
Epicutaneous induction:
50 % (w/w) in methyl cellulose 1%.
Challenge:
a = 25 % (w/w) in methyl cellulose 1%.
b = 10 % (w/w) in methyl cellulose 1%.
c = 5 % (w/w) in methyl cellulose 1%.
d = methyl cellulose 1%.
No. of animals per dose:
test group 20 animals all at 0, 5, 10, 25 and 50%
control group 10 animals all at 0, 5, 10 and 25%
Details on study design:
Induction
EXPERIMENTAL GROUP
On day 1, the experimental animals were clipped over an area of skin on the back behind the right shoulder. The area clipped was delimited by a cloth
frame whose square centre measured 2 x 2 cm. The clipped patch was then closely shaved. The ariimal was wrapped in a “window dressing” which consisted of an elastic bandage with a previously prepared 2 x 2 cm opening cut in the dressing. This opening was placed over the sensitization site. The dressing was fixed with adhesive tape. Dry ice was applied for approximately 5 seconds with firm pressure to the test site. The test substance: 50 % (w/w) in methyl cellulose 1% (0.2 ml) was applied and was covered with a Metalline patch. The area was then covered with occiusive tape (Sleek).
On day 3, the dressing covering the window was removed, the application site clipped, 0.2 ml of the test substance 50 % (w/w) in methyl cellulose 1%
applied and the window reclosed with the same dressirig.
On day 5, the window was again opened the application site clipped and 0.1 ml Freunds Complete Adjuvant (FCA, Difco, Detroit, U.S.A.) injected intradermally on either side of the sensitization site. This was followed by a further application of 0.2 ml of the test substance 50 % (w/w) in methyl cellulose 1% and the window closed.
On day 8, the dressing covering the window was removed, the application site clipped and the test substance 50 % (w/w) in methyl cellulose 1% was applied again.
On day 10, all wrappings were removed and the skin reactions of’ the induction applications observed immediately after bandage removal, according to the grading system for erythema described previously.
CONTROL GROUP
On day 5, the control animals were clipped and recieved two intradermal Freunds complete adjuvant in the right shoulder to exclude interpretation difficulties in the challenge caused by non—specific lowering of the skin irritation threshold by this substance.
Chal lenge
The test and control guinea pigs were challenged two weeks after the epidermal
induction application.
Hair was clipped and shaved from a 5 x 5 cm area on the left flank of each guinea—pig.
The following series of 3 test substance concentrations and the vehicle were applied using Square chambers attached to Micropore tape:
a = 25 % in methyl cellulose 1%.
b = 10 % in methyl cellulose 1%.
c = 5 % in methyl cellulose 1%.
d = methyl cellulose 1%.
Of each concentratjon and the vehicle, 0.05 ml was placed into a Square chamber. The patches were placed on the shaved area, the Micropore tape firmly secured around the trunk of the animals and held in place by Coban elastic bandage.
The location of the 4 Square chambers was as follows:
c b
Cranial caudal
d a
The dressings and residual test substance were removed after approximately 24 hours.
The sites were assessed for redness and swelling 24 and 48 hours after removal of the dressings, using the numerical grading system described below (modified from Kligman A.M., J. Invest. Oermatol. 47, 1966).
The test sites were shaved with an electric razor after the first reading.
no skin reaction 0
Red spots (scattered reactions) 1
Moderate but confluerit redness 2
Redness and swelling 3
Intense reddening and swelling 4
All animals were killed at the end of the test period by carbon dioxide asphyxiation.
Positive control substance(s):
yes
Remarks:
formaldehyde

Results and discussion

Positive control results:
This positive control experiment was carried out in accordance to check the sensitivity of the test system as used by RCC NOTOX.
The positive control substance FORMALDEHYDE was obtained from Lamers & Pleuger, ‘s—Hertogenbosch, The Netherlands. It was fabricated under No. C 22500 and the purity was 35—37%.
Concentrations selected for this study were:
Epidermal induction: 2% (w/w) in milli—RO water.
Challenge:
a = 1% (w/w) in milli—RO water.
b = 0.5% (wiw) in milli—RO water.
c = 0.25% (wiw) in milli—RO water.
d = milli—RO water.
Clearly positive results were observed in the experimental animals after the challenge with 1% (w/w) FORMALDEHYDE in milli—RO water.
POSITIVE SKIN REACTIONS TO THE CHALLENGE
FORMALDEHYDE Concentration
1% 0.5% 0.25% 0%
EXPERIMENTAL GROUP Number of animals with positive reaction 10 7 2 0
Sensitization rate 50 35 10 0
CONTROL GROUP Number of animals with positive reaction 0 0 0 0

The raw data and report from this study are kept in the RCC NOTOX archives.
The test described above was performed under GLP—conditions with a QA—check.

In vivo (non-LLNA)

Resultsopen allclose all
Reading:
1st reading
Hours after challenge:
576
Group:
test chemical
Dose level:
25%
No. with + reactions:
8
Total no. in group:
20
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 576.0. Group: test group. Dose level: 25%. No with. + reactions: 8.0. Total no. in groups: 20.0.
Reading:
1st reading
Hours after challenge:
576
Group:
test chemical
Dose level:
10%
No. with + reactions:
5
Total no. in group:
20
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 576.0. Group: test group. Dose level: 10%. No with. + reactions: 5.0. Total no. in groups: 20.0.
Reading:
1st reading
Hours after challenge:
576
Group:
test chemical
Dose level:
5%
No. with + reactions:
5
Total no. in group:
20
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 576.0. Group: test group. Dose level: 5%. No with. + reactions: 5.0. Total no. in groups: 20.0.
Reading:
1st reading
Hours after challenge:
576
Group:
test chemical
Dose level:
0
No. with + reactions:
0
Total no. in group:
20
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 576.0. Group: test group. Dose level: 0. No with. + reactions: 0.0. Total no. in groups: 20.0.
Reading:
2nd reading
Hours after challenge:
625
Group:
test chemical
Dose level:
25%
No. with + reactions:
7
Total no. in group:
20
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 625.0. Group: test group. Dose level: 25%. No with. + reactions: 7.0. Total no. in groups: 20.0.
Reading:
2nd reading
Hours after challenge:
625
Group:
test chemical
Dose level:
10%
No. with + reactions:
6
Total no. in group:
20
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 625.0. Group: test group. Dose level: 10%. No with. + reactions: 6.0. Total no. in groups: 20.0.
Reading:
2nd reading
Hours after challenge:
625
Group:
test chemical
Dose level:
5%
No. with + reactions:
6
Total no. in group:
20
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 625.0. Group: test group. Dose level: 5%. No with. + reactions: 6.0. Total no. in groups: 20.0.
Reading:
2nd reading
Hours after challenge:
625
Group:
test chemical
Dose level:
0%
No. with + reactions:
0
Total no. in group:
20
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 625.0. Group: test group. Dose level: 0%. No with. + reactions: 0.0. Total no. in groups: 20.0.

Applicant's summary and conclusion

Interpretation of results:
not sensitising
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Under the conditions used in this study, UC—136 resulted in a sensitization rate of 5 per cent after epicutaneous appilcation to the guinea pig.
Applying the general classificatjon and labelling requirements for dangerous substances as laid down in Annex VI of the EEC Council Directjve 67/548/EEC (amended by Directive 83/467/EEC), the test substance need not be labelled as a skin sensitizer.
SENSITIZATION
These results lead to a sensitization rate of 5 per cent, which indicates that UC—136 has sensitizing properties in this test.
TOXICITY SYMPTOMS / MORTALITY
No symptoms of systemic toxicity were observed in the animals during the study.
One animal was found dead on day 19, without abnormal symptoms noted before.
At necropsy this animal showed white/yellow/greenish substance at the medial abdominal muscie and at the surface of the heart, dark red coloured medial abdominal subcutis, light brown/red fluid in thoracic cavity and red spotted areas in the lungs.
BODY WEIGHTS
The average body weight gain of experimental and control animals was similar.