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Description of key information

An acute in vivo skin irritation / corrosion test according to OECD 404 (Hansen, 2013) was performed with vanadium dioxide, and results indicate that it is not irritant to skin. 
An acute in vivo eye irritation / corrosion test according to OECD 405 (Hansen, 2013) was performed with vanadium dioxide, and results indicate that it is not irritant to eyes.

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records
Reference
Endpoint:
skin irritation: in vivo
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
2013-03-04 to 2013-03-14
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Version / remarks:
adopted 2002-04-24
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Remarks:
signed 2009-11-12
Species:
rabbit
Strain:
Himalayan
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: LPT Laboratory of Pharmacology and Toxicology GmbH & Co. KG, Branch Löhndorf, 24601 Löhndorf/Post Wankendorf, Germany
- Age at study initiation: approximately 8 months
- Weight at study initiation: 2.63 - 2.97 kg
- Housing: before and after the 4-hour exposure period, the animals were kept singly in cages measuring 380 mm x 425 mm x 600 mm (manufacturer: Dipl. Ing. W. EHRET GmbH, 16352 Schönwalde, Germany). During the exposure period, the animals were kept singly in restrainers which allowed free movement of the head but prevented a complete body turn. The cages excluded irritation of the skin by excrements and urine.
- Diet (ad libitum; before and after exposure period): commercial diet, ssniff® K-H V2333 (ssniff Spezialdiäten GmbH, 59494 Soest, Germany)
- Water (ad libitum; before and after exposure period): drinking water
- Acclimation period: at least 20 adaptation days

ENVIRONMENTAL CONDITIONS
- Temperature: 20°C ± 3°C (maximum range)
- Relative humidity: 30% - 70% (maximum range)
- Photoperiod (hrs dark / hrs light): 12/12
Type of coverage:
semiocclusive
Preparation of test site:
shaved
Vehicle:
water
Controls:
no
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 500 mg of the test item moistened with the vehicle was applied to the test site.
Duration of treatment / exposure:
4 hours
Observation period:
prior to the administration and 60 minutes, 24, 48 and 72 hours after the exposure period
Number of animals:
3 female rabbits
Details on study design:
TEST SITE
- Area of exposure: approximately 24 hours before the test, the fur was removed by closely clipping the dorsal area of the trunk of the animals. Care was taken to avoid abrading the skin. Only animals with healthy intact skin were used.
The test item moistened with the vehicle was applied to the test site (area: approx. 6 cm^2) and then covered with a gauze patch. The patch was held in contact with the skin with non-irritating tape for the duration of the exposure period. The surrounding untreated skin served as a control.

INITIAL TEST AND CONFIRMATORY TEST
As it was expected that the test item would not produce any severe irritancy or corrosion, the test was started using at first only one animal, receiving a single patch for an exposure period of 4 hours.
As neither a corrosive effect nor a severe irritant effect was observed after a four-hour exposure, the test was completed using two additional animals, each with one patch only, for an exposure period of 4 hours.

SCORING SYSTEM: according to the Draize scale
Irritation parameter:
erythema score
Basis:
mean
Remarks:
animal #1
Time point:
other: 24, 48 and 72 hours
Score:
0
Max. score:
4
Irritation parameter:
edema score
Basis:
mean
Remarks:
animal #1
Time point:
other: 24, 48 and 72 hours
Score:
0
Max. score:
4
Irritation parameter:
erythema score
Basis:
mean
Remarks:
animal #2
Time point:
other: 24, 48 and 72 hours
Score:
0
Max. score:
4
Irritation parameter:
edema score
Basis:
mean
Remarks:
animal #2
Time point:
other: 24, 48 and 72 hours
Score:
0
Max. score:
4
Irritation parameter:
erythema score
Basis:
mean
Remarks:
animal #3
Time point:
other: 24, 48 and 72 hours
Score:
0
Max. score:
4
Irritation parameter:
edema score
Basis:
mean
Remarks:
animal #3
Time point:
other: 24, 48 and 72 hours
Score:
0
Max. score:
4
Irritant / corrosive response data:
None of the three rabbits exposed for 4 hours to 500 mg vanadium dioxide/animal showed any skin reactions 60 minutes, 24, 48 and 72 hours after the application.
Other effects:
There were not any systemic intolerance reactions.
Interpretation of results:
not irritating
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Vanadium dioxide is not irritating to the skin.
According to the EC-Commission directive 67/548/EEC, vanadium dioxide is not classified as irritating to the skin.
According to the EC-Regulation 1272/2008, vanadium dioxide is not classified as irritating to the skin.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Eye irritation

Link to relevant study records
Reference
Endpoint:
eye irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2013-03-04 to 2013-03-19
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Version / remarks:
adopted 2012-10-02
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Remarks:
signed 2009-11-12
Species:
rabbit
Strain:
Himalayan
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Source: LPT Laboratory of Pharmacology and Toxicology GmbH & Co. KG, Branch Löhndorf, 24601 Löhndorf/¬Post Wankendorf, Germany
- Age at study initiation: approximately 8 months
- Weight at study initiation: 2.48 - 2.83 kg
- Housing: for 8 hours following test item application, the animals were kept singly in restrainers which allowed free movement of the head but prevented a complete body turn, wiping of the eyes with the paws and excluded irritation of the eye by excrements and urine. During the acclimatisation period and after the 8-hour period in restrainers, the animals were kept singly in cages with dimensions of 380 mm x 425 mm x 600 mm (manufacturer: Dipl.Ing. W. EHRET GmbH, 16352 Schönwalde, Germany).
- Diet (ad libitum; before and after the exposure period): commercial diet, ssniff® K-H V2333 (ssniff Spezialdiäten GmbH, 59494 Soest, Germany)
- Water (ad libitum; before and after exposure period): tap water
- Acclimation period: at least 20 adaptation days

ENVIRONMENTAL CONDITIONS
- Temperature: 20°C ± 3°C (maximum range)
- Relative humidity: 30% - 70% (maximum range)
- Photoperiod (hrs dark / hrs light): 12/12
Vehicle:
unchanged (no vehicle)
Controls:
no
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 100 mg of the test item were administered into one eye each of three animals.
The test item was placed into the conjunctival sac of the right eye of each animal after gently pulling the lower lid away from the eyeball. The lids were then gently held together for about one second in order to prevent loss of the material. The left eye, which remained untreated, served as a control.
Duration of treatment / exposure:
One hour
Observation period (in vivo):
Prior to the administration and 1, 24, 48, 72 hours after the administration
Number of animals or in vitro replicates:
3 female rabbits
Details on study design:
USE OF TOPICAL ANAESTHETICS AND SYSTEMIC ANALGESICS
Sixty minutes prior to test item administration, 0.01 mg Buprenovet®/kg bw were administered by subcutaneous injection to all animals.
Five minutes prior to the test item administration, one or two drops of Ophtocain®, a topical anaesthetic, was applied to each eye of all animals.
In addition, 8 hours after administration of the test item all animals were treated with 0.01 mg Buprenovet®/kg bw in conjunction with 0.5 mg Metacam®/kg b.w., subcutaneously.

INITIAL TEST AND CONFIRMATORY TEST
The test was performed initially using one animal. As no corrosive or severe irritant effects were observed in this animal, 2 further animals were employed 24 hours after start of the initial test.

REMOVAL OF TEST SUBSTANCE
- Washing: each eye was rinsed with 20 mL of 0.9% aqueous NaCl solution.
- Time after start of exposure: one hour after instillation

SCORING SYSTEM: according to the Draize scale
Any further lesions are listed.

TOOL USED TO ASSESS SCORE: the eyes were examined ophthalmoscopically with a slit lamp prior to the administration and 1, 24, 48, 72 hours after the administration. The eye reactions were observed and registered.
24 hours after administration, fluorescein (Fluorescein SE Thilo drops (ALCON PHARMA GmbH, 79108 Freiburg, Germany)) was applied to the eyes before being examined to aid evaluation of the cornea for possible lesions.

OBSERVATIONS:
General criteria: body weight of all animals was measured at the beginning and at the end of the study. Behaviour and food consumption were monitored.
Irritation parameter:
cornea opacity score
Basis:
mean
Remarks:
animal #1
Time point:
other: 24, 48 and 72 hours
Score:
0
Max. score:
4
Remarks on result:
other: Fluorescein test: no pathological findings
Irritation parameter:
iris score
Basis:
mean
Remarks:
animal #1
Time point:
other: 24, 48 and 72 hours
Score:
0
Max. score:
2
Irritation parameter:
conjunctivae score
Basis:
mean
Remarks:
animal #1
Time point:
other: 24, 48 and 72 hours
Score:
0.67
Max. score:
3
Reversibility:
fully reversible within: 72 hours
Remarks on result:
other: Some blood vessels hyperaemic (injected) at the 60 minute observation.
Irritation parameter:
chemosis score
Basis:
mean
Remarks:
animal #1
Time point:
other: 24, 48 and 72 hours
Score:
0.67
Max. score:
4
Reversibility:
fully reversible within: 48 hours
Irritation parameter:
cornea opacity score
Basis:
mean
Remarks:
animal #2
Time point:
other: 24, 48 and 72 hours
Score:
0
Max. score:
4
Remarks on result:
other: Fluorescein test: no pathological findings
Irritation parameter:
iris score
Basis:
mean
Remarks:
animal #2
Time point:
other: 24, 48 and 72 hours
Score:
0
Max. score:
2
Irritation parameter:
conjunctivae score
Basis:
mean
Remarks:
animal #2
Time point:
other: 24, 48 and 72 hours
Score:
0.33
Max. score:
3
Reversibility:
fully reversible within: 48 hours
Remarks on result:
other: Some blood vessels hyperaemic (injected) at the 60 minute observation.
Irritation parameter:
chemosis score
Basis:
mean
Remarks:
animal #2
Time point:
other: 24, 48 and 72 hours
Score:
0
Max. score:
4
Irritation parameter:
cornea opacity score
Basis:
mean
Remarks:
animal #3
Time point:
other: 24, 48 and 72 hours
Score:
0
Max. score:
4
Remarks on result:
other: Fluorescein test: no pathological findings
Irritation parameter:
iris score
Basis:
mean
Remarks:
animal #3
Time point:
other: 24, 48 and 72 hours
Score:
0
Max. score:
2
Irritation parameter:
conjunctivae score
Basis:
mean
Remarks:
animal #3
Time point:
other: 24, 48 and 72 hours
Score:
0.33
Max. score:
3
Reversibility:
fully reversible within: 48 hours
Remarks on result:
other: Some blood vessels hyperaemic (injected) at the 60 minute observation.
Irritation parameter:
chemosis score
Basis:
mean
Remarks:
animal# 3
Time point:
other: 24, 48 and 72 hours
Score:
0
Max. score:
4
Irritant / corrosive response data:
A single instillation of 100 mg vanadium dioxide per animal into the conjunctival sac of the right eye of three rabbits caused the following changes:
Conjunctival redness (grade 1) was observed in all animals 60 minutes to 24 hours, in one animal until 48 hours after instillation. The effect was fully reversible in 2 animals within 48 hours and in 1 animal 72 hours after application of the test material.
Chemosis was observed in one animal: 24 hours (grade 2) after instillation but not anymore after 48 hours.
The cornea and irises were not affected by instillation of the test item.
Other effects:
There were not any systemic intolerance reactions concerning behaviour, body weight and food consumption.
Interpretation of results:
not irritating
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Vanadium dioxide is not irritating to the eyes.
According to the EC-Commission directive 67/548/EEC and its subsequent amendments, vanadium dioxide is not classified as irritating to the eyes.
According to the EC-Regulation 1272/2008 and subsequent regulations, vanadium dioxide is not classified as irritating to the eyes.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Additional information

Skin irritation: Three studies on skin irritation were conducted. An in vitro study on skin corrosion (OECD 435) with a negative outcome and a positive in vitro skin irritation study (OECD 439) which indicates an irritation potential of vanadium dioxide, since the mean relative absorbance decreased to 9.3% and this is below the threshold for irritancy of ≤ 50%.

However, long-term experience in manufacture and handling indicates that the substance is not a skin or eye irritant. Furthermore, vanadium dioxide did not cause an increase of the corneal permeability or opacity in thein vitroBCOP test according to OECD 437 (meanin vitroirritation core of 6.44) and thus is not corrosive and not a severe irritant to the eye.

Thus, a third study in skin irritation/corrosion was conducted in vivo (OECD 404). The study shows no irritation/corrosion potential of vanadium dioxide. The erythema and edema scores at all relevant time points were “0” (24, 48, 72 h). Fact is that results of in vivo studies should take precedence over in vitro studies. Hence, vanadium dioxide is considered to be non irritating to skin and should not be labelled as such.

Eye irritation:

Two studies on eye irritation / corrosion were conducted. The first study was initiated in vitro to show that vanadium dioxide has no corrosive potential. Since no fully validated in vitro eye irritation study exist at time of study initiation, an in vivo eye irritation study was conducted with the following results:

Conjunctival redness (grade 1) was observed in all animals 60 minutes to 24 hours, in one animal until 48 hours after instillation. The effect was fully reversible in 2 animals within 48 hours and in 1 animal 72 hours after application of the test material.

Chemosis was observed in one animal: 24 hours (grade 2) after instillation but not anymore after 48 hours.

The cornea and irises were not affected by instillation of the test item.

In conclusion, vanadium dioxide is considered to be neither corrosive nor irritant to eyes.


Justification for selection of skin irritation / corrosion endpoint:
The study selected is conducted in vivo. Since in vivo studies take presedence over in vitro studies, this study was selected for endpoint conclusion. For more information please refer to the discussion below.

Justification for selection of eye irritation endpoint:
This study is selected as key study, since the study was conducted in vivo. In vivo studies should take presedence over in vitro studies.

Justification for classification or non-classification

Skin and eye irritation:

Vanadium dioxide does not possess an irritation potential and does not require classification as skin or eye irritant according to Directive 67/548/EEC and Regulation (EC) 1272/2008.

Respiratory irritation:

Vanadium dioxide does not possess an irritation potential in the respiratory tract, hence it does not require classification as respiratory irritant according to Directive 67/548/EECandRegulation (EC) 1272/2008. For further information, please refer to the endpoint "acute toxicity: inhalation" and "repeated dose toxicity: inhalation" and the respective endpoint summaries.

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