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Toxicological information

Skin irritation / corrosion

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Administrative data

Endpoint:
skin irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2003-10-27 to 2004-01-19
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2004
Report Date:
2004

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Version / remarks:
2002
Deviations:
yes
Remarks:
Deviations from the minimum level of temperature occurred. Based on laboratory historical data these deviations were considered not to have affected the study integrity.
Qualifier:
according to
Guideline:
EU Method B.4 (Acute Toxicity: Dermal Irritation / Corrosion)
Version / remarks:
1992
Deviations:
yes
Remarks:
Deviations from the minimum level of temperature occurred. Based on laboratory historical data these deviations were considered not to have affected the study integrity.
Qualifier:
according to
Guideline:
EPA OPPTS 870.2500 (Acute Dermal Irritation)
Version / remarks:
1998
Deviations:
yes
Remarks:
Deviations from the minimum level of temperature occurred. Based on laboratory historical data these deviations were considered not to have affected the study integrity.
GLP compliance:
yes (incl. certificate)

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
impurity

Test animals

Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
Species
Albino Rabbit, New Zealand White, (SPF-Quality)
Recognised by international guidelines as the recommended test system (e.g. EC, OECD)
Number of animals
3 Males.
Age and body weight
Animals used within the study were at least 6 weeks old and body weights were at least 1.0 kg.
Identification
Earmark.

Animal husbandry
Conditions
Animals were housed in a controlled environment, in which optimal conditions were considered to be approximately 15 air changes per hour, a temperature of 21.0 ± 3.0°C (actual range: 17.9
- 21.2°C), a relative humidity of 30-70% (actual range: 41 - 74%) and 12 hours artificial fluorescent light and 12 hours darkness per day. Cleaning procedures in the room might have caused the temporary fluctuations above the optimal maximum level of 70% for relative humidity. Based on laboratory historical data, these fluctuations were considered not to have affected the study integrity.

Accommodation
Individually in labelled cages with perforated floors (Scanbur, Denmark, dimensions 56x44x37.5 cm).
Acclimatisation period was at least 5 days before start of treatment under laboratory conditions.

Diet
Standard laboratory rabbit diet (Charles River Breeding and Maintenance Diet for Rabbits, Altromin, Lage, Germany) approx. 100 g. per day. Certificates of analysis were examined and retained in the NOTOX archives. In addition, pressed hay (BMI, Helmond, the Netherlands) was provided twice a week.

Water
Free access to tap-water. Certificates of quarterly analysis were examined and retained in the
NOTOX archives.

Test system

Type of coverage:
semiocclusive
Preparation of test site:
clipped
Vehicle:
water
Controls:
not required
Amount / concentration applied:
Each animal was treated by dermal application of 0.5 grams of the test substance. The test substance was moistened with 1 ml Milli U water and applied to the skin of one flank, using a metalline patch* of 2x3 cm. The patch was mounted on Micropore tape*, which was wrapped around the abdomen and secured with Coban elastic bandage*.

*Suppliers: Lohmann GmbH, Neuwied. Germany (Metalline) and 3M. St. Paul. Minnesota. U.S.A. (Micropore and Coban).
Duration of treatment / exposure:
Four hours after the application, the dressing was removed and the skin cleaned of residual test substance using water and ethanol.
Observation period:
Mortality/Viability
Twice daily.
Toxicity
At least once daily.
Body Weight
Day of treatment (prior to application) and at termination.
Irritation
The skin reactions were assessed at approximately 1, 24, 48 and 72 hours (all animals) and 7 days (two animals) after the removal of the dressings and test substance. The irritation scores and a description of all other (Iocal) effects were recorded. Adjacent areas of the untreated skin of each animal served as controls.
Number of animals:
3 males.
Details on study design:
All available data relevant to the potential dermal irritationlcorrosivity of the substance indicated that no severe effects were to be expected. An in-vitro test was considered, but a negative test result was anticipated that still would have to be confirmed in an in-vivo study. Since no severe harm for the animals was to be expeeted, this in-vivo skin irritation study was performed and was started by treatment of a single rabbit (sentinel). The two other animals were treated in a similar manner 7 days later, after considering the degree of skin irritation observed in the first animaI.
Approximately 24 hours before treatment, the dorsal fur was clipped with electric clippers, exposing an area of approximately 150 square centimeters (10x15 cm2).
Whenever considered necessary the treated skin areas were re-clipped at least 3 hours before the observations, to facilitate scoring.
A health inspection was performed prior to the commencement of treatment, to ensure that the animals were in a good state of health. Special attention was paid to the skin to be treated, which was intact and free from abnormalities.

Each animal was treated by dermal application of 0.5 grams of the test substance. The test substance was moistened with 1 ml Milli U water and applied to the skin of one flank, using a metalline patch* of 2x3 cm. The patch was mounted on Micropore tape*, which was wrapped around the abdomen and secured with Coban elastic bandage*.
Four hours after the application, the dressing was removed and the skin cleaned of residual test substance using water and ethanol.

*Suppliers: Lohmann GmbH, Neuwied. Germany (Metalline) and 3M. St. Paul. Minnesota. U.S.A. (Micropore and Coban).

Observations
Mortality/Viability
Twice daily.
Toxicity
At least once daily.
Body Weight
Day of treatment (prior to application) and at termination.
Irritation
The skin reactions were assessed at approximately 1, 24, 48 and 72 hours (all animals) and 7 days (two animals) after the removal of the dressings and test substance. The irritation scores and a description of all other (Iocal) effects were recorded. Adjacent areas of the untreated skin of each animal served as controls.

The irritation was assessed according to the following numerical scoring system. At each observation, the highest scores given were recorded:
Erythema and eschar formation:
No erythema .......................................................................................................................... 0
Very slight erythema (barely perceptible) ............................................................................... 1
Well-defined erythema ........................................................................................................... 2
Moderate to severe erythema ................................................................................................ 3
Severe erythema (beet redness)· ......................................................................................... 4
-. Where signs of necrosis or corrosion (injuties in depth) prevent erythema scoring. The maximum grade for erythema (= 4) is given.
Oedema formation:
No oedema ............................................................................................................................ 0
Very slight oedema (bBrely perceptible) ................................................................................. 1
Slight oedema (edges of area well-defined by definite raising) .............................................. 2
Moderate oedema (raised approximately 1 millimeter) ........................................................... 3
Severe oedema (raised more than 1 millimeter and extending beyond the area of exposure) 4
Histopathology
No histopathology was performed, since the skin reactions were not masked by test substance staining.
Interpretation
The results were evaluated according to the OECD Harmonized Integrated Hazard Classification System for Human Health and Environmental Effects of Chemical Substances (OECD, 1998) and the EC criteria for classification and labelling of dangerous substances and preparations (Council Directive 67/548/EEC and all adaptations to technical progress and amendments of this Directive published in the Official Journal of the European Communities).

Results and discussion

In vivo

Resultsopen allclose all
Irritation parameter:
erythema score
Basis:
animal: 718
Time point:
24/48/72 h
Score:
0
Max. score:
4
Irritation parameter:
erythema score
Basis:
animal: 732
Time point:
24/48/72 h
Score:
1.7
Max. score:
4
Irritation parameter:
erythema score
Basis:
animal: 734
Time point:
24/48/72 h
Score:
0
Max. score:
4
Irritation parameter:
edema score
Basis:
animal: 718
Time point:
24/48/72 h
Score:
0
Max. score:
4
Irritation parameter:
edema score
Basis:
animal: 732
Time point:
24/48/72 h
Score:
1
Max. score:
4
Irritation parameter:
edema score
Basis:
animal: 734
Time point:
24/48/72 h
Score:
0
Max. score:
4
Irritant / corrosive response data:
Irritation
Four hours exposure to 0.5 g of naphthalene-1,5-diol resulted in well-defined erythema and slight oedema in the treated skin-area of one rabbit. Scaliness was noted in this animal 7 days after treatment. Signs of irritation were absent in the other rabbits.
Corrosion
There was no evidence of a corrosive effect on the skin.
Colouration I Remnants
Yellow staining of the treated skin by the test substance was observed in all animals between 1 and 72 hours after exposure, which did not hamper the scoring of the skin reactions. No test substance remnants were seen.
Other effects:
Toxicity I Mortality
No symptoms of systemic toxicity were observed in the animals during the test period and no mortality occurred.

Applicant's summary and conclusion

Interpretation of results:
GHS criteria not met
Conclusions:
The difference in responses observed in the animals tend to be related to the difference in hair density observed prior to treatment. The animaI with the lower hair density showed irritation.
Based on these results and according to the:
- OECD Harmonized Integrated Hazard Classification System for Human Health and Environmental Effects of Chemical Substances (OECD, 1998), naphthalene-1,5-diol does not have to be classified for skin irritation.
- EC criteria for classification and labelling requirements for dangeraus substances and preparations (Council Directive 67/548/EEC), naphthalene-1,5-diol does not have to be classified and has no obligatory labelling requirement for skin irritation.
Executive summary:

Primary skin irritation/corrosion study with naphthalene-1,5 -diol in the rabbit (4-hour semiocclusive application).

The study was carried out based on the guidelines described in: OECD No.404, "Acute Dermal Irritation/Corrosion" (2002); EC Commission Directive 92169/EEC, B.4, "Acute Toxicity – Skin irritation" (1992); US EPA, OPPTS 870.2500, Acute Dermal Irritation (1998) and JMAFF, Japanese Test Guidelines (2000).

Three rabbits were exposed to 0.5 grams of naphthalene-1,5-diol, applied onto clipped skin for 4 hours using a semi-occlusive dressing. Observations were made 1, 24, 48 and 72 hours and/or 7 days aftn System for Human Health and

Environmental Effects of Chemical Substances (OECD, 1998), naphthalene-1,5-diol does not have to be classified for skin irritation.

- EC criteria for classification and labelling requirements for dangerous substances and preparations (Council Directive 67/548/EEC), naphthalene-1,5-diol does not have to be classified and has no obligatory labelling requirement for skin irritation. er exposure. Exposure to naphthalene-1,5 -diol resulted in well-defined erythema and slight oedema in the treated skin-area of one rabbit. Scaliness was noted in this animal 7 days after treatment. Signs of irritation were absent in the other rabbits. Yellow staining of the treated skin by the test substance was observed in all animals between 1 and 72 hours after exposure, which did not hamper the scoring of the skin reactions. No test substance remnants were seen. The difference in responses observed in the animals tend to be related to the difference in hair density observed prior to treatment. The anima I with the lower hair density showed irritation. Based on these results and according to the: - OECD Harmonized Integrated Hazard Classificatio