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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:
Jul 20, 1983 to Sep 08, 1983
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Remarks:
no data on positive controls (but clearly positive results), no data on impurities of the test substance (but analytical grade), high concentration for intradermal induction

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1983
Report date:
1983

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
OECD Guideline 406 (Skin Sensitisation)
Version / remarks:
May 12, 1981
Deviations:
yes
Remarks:
intradermal induction with high concentration
Qualifier:
according to guideline
Guideline:
other: EEC Directive 79-831, Annex V, Part B: Methods For The Determination Of Toxicity 4.1.7 Skin Sensitization
GLP compliance:
yes
Type of study:
guinea pig maximisation test
Justification for non-LLNA method:
The LLNA method was not available yet by the time the study was conducted.

Test material

Constituent 1
Chemical structure
Reference substance name:
Formaldehyde
EC Number:
200-001-8
EC Name:
Formaldehyde
Cas Number:
50-00-0
Molecular formula:
CH2O
IUPAC Name:
formaldehyde
Details on test material:
- Name of test material (as cited in study report): formaldehyde
Specific details on test material used for the study:
TEST MATERIAL
- Source: Riedel del Haen, Germany
- Purity: analytical grade, at least 35 % formaldehyde in aqueous solution
- Physical appearance: colourless, liquid

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: in the dark at ca. 22°C

In vivo test system

Test animals

Species:
guinea pig
Strain:
other: Pirbright White, Hoe: DHPK(SPFLac)
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Hoechst AG, Kastengrund, Germany
- Weight at study initiation: 247 g (219 - 279 g)
- Housing: in groups of 5 in Makrolon cages type IV
- Diet: ERKA 8300 (Robert Koch OHG, 47 Hamm), ad libitum
- Water: tap water, ad libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature: 20 - 24°C
- Humidity: 45 - 65 %
- Fully air-conditioned rooms
- Photoperiod: 12 hours / 12 hours

Study design: in vivo (non-LLNA)

Inductionopen allclose all
Route:
intradermal
Vehicle:
other: 50 % Freund`s adjuvant or 0.9 % NaCl
Concentration / amount:
5 % / 0.1 mL
Day(s)/duration:
study day 1 / once
Adequacy of induction:
highest concentration used causing mild-to-moderate skin irritation and well-tolerated systemically
Route:
epicutaneous, occlusive
Vehicle:
physiological saline
Concentration / amount:
5 % / 0.5 mL
Day(s)/duration:
study day 9 / 48 hours
Adequacy of induction:
highest concentration used causing mild-to-moderate skin irritation and well-tolerated systemically
Challengeopen allclose all
No.:
#1
Route:
epicutaneous, occlusive
Vehicle:
physiological saline
Concentration / amount:
4 % (left flank) and 2 % (right flank) / 0.5 mL
Day(s)/duration:
study day 22 / 24 hours
Adequacy of challenge:
highest non-irritant concentration
No.:
#2
Route:
epicutaneous, occlusive
Vehicle:
physiological saline
Concentration / amount:
4 % (left flank) and 2 % (right flank) / 0.5 mL
Day(s)/duration:
study day 36 / 24 hours
Adequacy of challenge:
highest non-irritant concentration
No. of animals per dose:
20
Details on study design:
RANGE FINDING TESTS
The following test concentrations were applied to the right flank of two guinea pigs each dermal-occlusive for primary skin irritation: 10 % in 0.9 % NaCl, 6 % in 0.9 % NaCl and 1.2 % in 0.9 % NaCl. The right flank of the test animals was mechanically depilated, 0.5 mL of the test substance preparation was applied to a 2 x 2 cm cellulose swab, fixed to the flank and occluded (with foil and bandage) for 24 hours. The treated skin site was checked 24 hours after removal of the patch.
After treatment with the 1.2 % test substance solution, no irritation effects occurred. The dermal application of the 6 % solution resulted in hardly perceptible erythema, while the 10 % solution led to the formation of well-defined erythema. The results of this preliminary test led to the use of a 4 and 2 % test substance solution for dermal re-treatment in the main experiment.
To determine tolerability, the following 3 x 2 preparations were injected intradermally into two guinea pigs each:
1. site 1: 2 x 0.1 mL 50 % Freund's adjuvans, site 2: 2 x 0.1 mL 5 % test substance in 0.9 % NaCl, site 3: 2 x 0.1 mL 5 % test substance in 50 % Freund's adjuvans
2. site 1: 2 x 0.1 mL 50 % Freund's adjuvans, site 2: 2 x 0.1 mL 1 % test substance in 0.9 % NaCl, site 3: 2 x 0.1 mL 1 % test substance in 50 % Freund's ddjuvans
3. site 1: 2 x 0.1 ml 50 % Freund's adjuvans, site 2: 2 x 0.1 mL 0.2 % test substance in 0.9 % NaCl, site 3: 2 x 0.1 mL 0.2 % test substance in 50 % Freund's adjuvans
The injection sites were located within an area of 2 x 4 cm in the dorsal region near the shoulders of the animals.
Intradermal injections of 0.2, 1, and 5 % test substance in 0.9 % NaCl led to hardening, crusting and browning of the injection sites within 12 days. For the intradermal injections in the main experiment, the use of a 5 % preparation was used for the intradermal injections in the main experiment in order to compare the results of this with the results of studies conducted under these conditions published in the literature.

MAIN STUDY
A. INDUCTION EXPOSURE
INTRADERMAL
An area of 4 x 6 cm in the dorsal region near the shoulders of the animals was mechanically depilated. Intradermal injection of a total of 3 x 2 preparations was carried out per test animal. The injection sites were within an area of 2 x 4 cm. The injection sites were not covered. The application area was examined for local tolerance. Systemic toxic effects were recorded.
Control group:
site 1: 2 x 0.1 mL 50 % Freund's adjuvans
site 2: 2 x 0.1 mL 0.9 % NaCl
site 3: 2 x 0.1 mL 50 % Freund's adjuvans
Test group:
site 1: 2 x 0.1 mL 50 % Freund's adjuvans
site 2: 2 x 0.1 mL 5 % test substance in 0.9 % NaCl
site 3: 2 x 0.1 mL 5 % test substance in 50 % Freund's adjuvans

EPICUTANOUS
0.5 mL of the test substance preparation or the vehicle was applied to a a 2 x 4 cm cellulose swab. This swab covered the area of the intradermal iniection sites. An occlusive impermeable film and elastic bandage closed the application site for 48 hours.
Control group: 0.9% NaCl
Test group: 5 % test substance in 0.9 % NaC

B. CHALLENGE EXPOSURE
Two areas of approximately 5 x 5 cm on the left and right flanks of the test animals were mechanically depilated. 0.5 mL of the test substance preparation was applied to a 2 x 2 cm cellulose swab. An occlusive dressing with impermeable film and elastic bandage sealed the application site for for 24 hours.
Control and Test group : left flank : 4 % test substance, right flank: 2 % test substance
The second re-treatment was carried out after the irritation caused by the first re-treatment had completely subsided.

ASSESSMENT OF THE SKIN REACTIONS ACCORDING TO DRAIZE
- Erythema and eschar formation:
0 = no erythema
1 = very slight erythema (barely perceptible)
2 = well-defined erythema
3 = moderate to severe erythema
4 = severe erythema (beet redness) to slight eschar formation (injuries in depth)
- Edema formation
0 = no edema
1 = very slight edema (barely perceptible)
2 = slight edema (edges of area well defined by definite raising)
3 = moderate edema (raised approximately 1 mm)
4 = severe edema (raised more than 1 mm and extending beyond the area of exposure)
Challenge controls:
yes
Positive control substance(s):
no

Results and discussion

In vivo (non-LLNA)

Resultsopen allclose all
Group:
positive control
Remarks on result:
not measured/tested
Reading:
1st reading
Hours after challenge:
48
Group:
negative control
Dose level:
0
No. with + reactions:
0
Total no. in group:
20
Clinical observations:
no
Reading:
1st reading
Hours after challenge:
48
Group:
test chemical
Dose level:
4 %
No. with + reactions:
20
Total no. in group:
20
Clinical observations:
erythema up to grade 3, edema up to grade 2
Remarks on result:
positive indication of skin sensitisation
Reading:
1st reading
Hours after challenge:
48
Group:
test chemical
Dose level:
2 %
No. with + reactions:
16
Total no. in group:
20
Clinical observations:
erythema up to grade 2, edema up to grade 1
Remarks on result:
positive indication of skin sensitisation
Reading:
2nd reading
Hours after challenge:
72
Group:
negative control
Dose level:
0
No. with + reactions:
3
Total no. in group:
20
Clinical observations:
erythema up to grade 1
Reading:
2nd reading
Hours after challenge:
72
Group:
test chemical
Dose level:
4 %
No. with + reactions:
20
Total no. in group:
20
Clinical observations:
erythema up to grade 3, edema up to grade 2
Remarks on result:
positive indication of skin sensitisation
Reading:
2nd reading
Hours after challenge:
72
Group:
test chemical
Dose level:
2 %
No. with + reactions:
18
Total no. in group:
20
Clinical observations:
erythema up to grade 3, edema up to grade 2
Remarks on result:
positive indication of skin sensitisation
Reading:
rechallenge
Hours after challenge:
48
Group:
negative control
Dose level:
0
No. with + reactions:
6
Total no. in group:
20
Clinical observations:
erythema up to grade 2
Reading:
rechallenge
Hours after challenge:
48
Group:
test chemical
Dose level:
4 %
No. with + reactions:
20
Total no. in group:
20
Clinical observations:
erythema up to grade 4, edema up to grade 2
Remarks on result:
positive indication of skin sensitisation
Reading:
rechallenge
Hours after challenge:
48
Group:
test chemical
Dose level:
2 %
No. with + reactions:
11
Total no. in group:
20
Clinical observations:
erythema up to grade 4, edema up to grade 1
Remarks on result:
positive indication of skin sensitisation

Applicant's summary and conclusion

Interpretation of results:
Category 1B (indication of skin sensitising potential) based on GHS criteria
Conclusions:
Sensitizing effects in the GPMT.
Executive summary:

In a reliable GLP conform study according to OECD TG 406, formaldehyde was tested for its potential to have a sensitizing effect with the help of the Guinea Pig Maximization Test based on the method of Magnusson and Kligman. Twenty females were induced by intradermal injection and topical application with 5 % formaldehyde solution, 10 female controls were shame treated. Challenge was performed with 2 or 4 % formaldehyde solution.


Controls gave valid results after both concentrations. In test animals 4 % formaldehyde solution resulted in positive reaction in all tested animals and 2 % formaldehyde solution in 80 % positive reactions in the first reading 48 hours after challenge application.


Under these test conditions and following the results described formaldehyde has a sensitizing effect on the skin of the guinea pig.