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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:
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 condi ti ons
Expiry date : January 5, 1990
Stability in vehicles : Unknown in methyl cellulose 1%.
Safety precautions : Gloves, goggles and face mask were considered to be 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 stuciy.
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 artificial 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:
Inducti on
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).
0n day 3, the dressing covering the window was removed, the application site
clipped, 0.2 ml of the test substarice 50 % (w/w) in methyl cellulose 1%
applied and the window reclosed with the same dressirig.
0n 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 received two intradermal
injections of 0,1 ml 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.
Challenge
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 dioxicie
asphyxiati on.
IcI
Cranial
IbI
idl
Caudal
al
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
Sensitisation 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
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.