Registration Dossier

Administrative data

Description of key information

Reliable, adequate and relevant studies from various analogue substances, demonstrate a lack of irritation/corrosion potential of the substance zind ditetradecanoate.

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records

Referenceopen allclose all

Endpoint:
skin irritation: in vivo
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
Not reported
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study well documented, meets generally accepted scientific principles, acceptable for assessment
Reason / purpose:
reference to same study
Reason / purpose:
reference to other study
Qualifier:
no guideline followed
Principles of method if other than guideline:
Macroscopic skin reactions, skin histological changes and epidermal keratin binding of the test material were observed after 5 d application of test material to skin using open patch test.
GLP compliance:
not specified
Species:
guinea pig
Strain:
Dunkin-Hartley
Details on test animals and environmental conditions:
TEST ANIMALS
- Sex: Male
- Source: Harlan-Porcellus (Heathfield, Sussex, UK)
- Weight at study initiation: 250-400 g
- Diet: RGP diet (Biosure) (zinc content 65 mg/kg, w/w)

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22±2
- Humidity (%): 55
- Photoperiod (h dark/h light): 12/12


Type of coverage:
open
Preparation of test site:
shaved
Vehicle:
other: 0.1 % Tween 80
Controls:
yes, concurrent vehicle
Amount / concentration applied:
TEST SOLUTION
- Concentration (if solution): 20 % (w/v) zinc oxide suspension in 0.1 % Tween 80
- pH: 7.4


Duration of treatment / exposure:
5 d
Observation period:
Observed during and after 5 d exposure period
Number of animals:
Eight animals both in control and test groups
Details on study design:
Test suspension or vehicle was applied daily for 5 successive days to three test sites on dorsal skin. The animals were restrained until the test sites had dried. Skin sites were observed during and after 5 d exposure period.

24 h after the fifth daily treatment, animals were killed and representative samples of each test and control skin sites were preserved in 10 % phosphate buffered formalin for histology. Thin sections cut along the anterior-posterior axis were stained with haematoxylin and eosin, or with morin dye, which fluoresces blue-green in the presence of zinc ions and ultraviolet light (to demonstrate zinc binding to epidermal keratin histologically).

SCORING SYSTEM: Not reported
Irritation parameter:
other: Score not reported
Remarks on result:
no indication of irritation
Irritant / corrosive response data:
No obvious reactions were observed in both control and test groups after 5 d exposure.
Other effects:
Histological changes: No evidence of damage was observed.

Morin fluorescence for zinc on skin: No obvious reaction was observed.



None

Interpretation of results:
not irritating
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Based on these results, 20 % w/v zinc oxide was found to be non-irritating to guinea-pig skin.
Executive summary:

A study was conducted to evaluate the skin irritation potential of zinc oxide in Dunkin-Hartley white guinea-pigs.

20 % w/v zinc oxide suspension in 0.1 % Tween 80 or vehicle was applied to shaved sites (5 cm2) of groups of eight animals for 5 consecutive days. Skin sites were observed during and after 5 d exposure period. 24 h after the fifth daily treatment, animals were killed and representative samples of each test and control skin sites were analysed histologically and stained with morin dye to study epidermal keratin binding of zinc.

No obvious reactions were observed in both control and test groups after 5 d exposure. No evidence of damage was observed upon histological examination. No morin fluorescence was observed in skin sections.

Based on these results, 20 % w/v zinc oxide was found to be non-irritating to guinea-pig skin.

 

Endpoint:
skin irritation: in vivo
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
Not reported
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Reason / purpose:
reference to same study
Reason / purpose:
reference to other study
Qualifier:
no guideline followed
Principles of method if other than guideline:
Macroscopic skin reactions, skin histological changes and epidermal keratin binding of the test material were observed in TO mice after 5 d application of test material to skin using open patch test.
GLP compliance:
not specified
Species:
mouse
Strain:
other: TO (outbred) strain
Details on test animals and environmental conditions:
TEST ANIMALS
- Sex: Male
- Source: Charing Cross and Westminster Medical School, London, UK
- Age at study initiation: 8-10 wk
- Diet: Complete rodent diet (CRM, Biosure, Cambridge, UK) (zinc content 65 mg/kg, w/w), ad libitum
- Water: Deionized water, ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22±2
- Humidity (%): 55
- Photoperiod (h dark/h light): 12/12


Type of coverage:
open
Preparation of test site:
other: clipped
Vehicle:
other: 0.1 % Tween 80
Controls:
yes, concurrent vehicle
Amount / concentration applied:
TEST SOLUTION
- Amount(s) applied (volume): 0.5 mL
- Concentration (if solution): 20 % (w/v) zinc oxide suspension in 0.1 % Tween 80
- pH: 7.4

Duration of treatment / exposure:
5 d
Observation period:
Observed during and after 5 d exposure period
Number of animals:
Six animals both in test and control group
Details on study design:
Sites of 5 cm2 were treated with the test suspension or vehicle for 5 consecutive days. Animals were gently anaesthetized with ether until the test sites had dried. Skin sites were observed during and after 5 d exposure period.

24 h after the fifth daily treatment, animals were killed and representative samples of each test and control skin sites were preserved in 10 % phosphate buffered formalin for histology. Thin sections cut along the anterior-posterior axis were stained with haematoxylin and eosin, or with morin dye, which fluoresces blue-green in the presence of zinc ions and ultraviolet light (to demonstrate zinc binding to epidermal keratin histologically).

SCORING SYSTEM: Not reported
Irritation parameter:
other: Score not reported
Remarks on result:
no indication of irritation
Irritant / corrosive response data:
No obvious reactions were observed in both control and test groups after 5 d exposure.
Other effects:
Histological changes: No evidence of damage was observed.

Morin fluorescence for zinc on skin: No obvious reaction was observed.



None

Interpretation of results:
not irritating
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Based on these results, 20 % w/v zinc oxide was found to be non-irritating to mouse skin.
Executive summary:

A study was conducted to evaluate the skin irritation potential of zinc oxide in TO (outbred) strain mice.

0.5 mL of 20 % w/v zinc oxide suspension in 0.1 % Tween 80 or vehicle was applied to clipped sites (5 cm2) of groups of six animals for 5 consecutive days. Skin sites were observed during and after 5 d exposure period. 24 h after the fifth daily treatment, animals were killed and representative samples of each test and control skin sites were analysed histologically and stained with morin dye to study epidermal keratin binding of zinc.

No obvious reactions were observed in both control and treatment groups after 5 d exposure. No evidence of damage was observed upon histological examination. No morin fluorescence was observed in skin sections.

Based on these results, 20 % w/v zinc oxide was found to be non-irritating to mouse skin.

 

Endpoint:
skin irritation: in vivo
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
Not reported
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Reason / purpose:
reference to same study
Reason / purpose:
reference to other study
Qualifier:
no guideline followed
Principles of method if other than guideline:
Macroscopic skin reactions, skin histological changes and epidermal keratin binding of test material were observed in New Zealand White rabbits after 5 d application of test material to skin using both open and occlusive patch methods.
GLP compliance:
not specified
Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
TEST ANIMALS
- Sex: Male
- Source: Charing Cross and Westminster Medical School, London, UK
- Weight at study initiation: 2.5-4.0 kg
- Housing: Housed singly
- Diet: R14 pellets (Biosure) (zinc content 74 mg/kg, w/w)
- Water: Tap water
- Acclimation: Acclimatized to conventional restraining boxes before open patch test


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18±2
- Humidity (%): 45
- Photoperiod (h dark/h light): 12/12


Type of coverage:
other: Both open and occlusive in two different tests
Preparation of test site:
other: Clipped
Vehicle:
other: 0.1 % Tween 80
Controls:
yes, concurrent vehicle
Amount / concentration applied:
TEST SOLUTION
- Amount(s) applied (volume): 0.5 mL
- Concentration (if solution): 20 % (w/v) zinc oxide suspension in 0.1 % Tween 80
- pH: 7.4
Duration of treatment / exposure:
5 d
Observation period:
Open patch test: Observed during and after 5 d exposure period
Occlusive patch test: On Day 3 and Day 5
Number of animals:
Four animals each for control and test groups in both open and occlusive patch test
Details on study design:
Open patch test: Eight test sites (5 cm2) were designated, four on each side of the mid-dorsal line. Test suspension or vehicle was applied daily for 5 successive days. The animals were restrained for 30 min to allow test sites to dry. Skin sites were observed during and after 5 d exposure period. Rabbits were killed 24 h after the fifth daily treatment.

Occlusive patch test: Animals were prepared similar to open patch test. Test suspension or vehicle was applied to the skin on a sterile gauze pad that was secured by a hypoallergenic adhesive tape. The trunks of these animals were wrapped in rubberized fabric and impermeable dressing for 3 d. At this stage, dressings were removed and skin sites were evaluated for irritancy. Two rabbits were killed at this stage. The remaining animals were redressed with freshly impregnated gauze pads and then re-examined and killed after a further 2 d.

In both tests, representative samples of each test and control skin sites of killed animals were preserved in 10 % phosphate buffered formalin for histology. Thin sections cut along the anterior-posterior axis were stained with haematoxylin and eosin, or with morin dye, which fluoresces blue-green in the presence of zinc ions and ultraviolet light (to demonstrate zinc binding to epidermal keratin histologically).

SCORING SYSTEM: Not reported
Irritation parameter:
other: Score not reported
Remarks on result:
no indication of irritation
Irritant / corrosive response data:
No obvious reactions were observed in both control and treatment groups in any of the performed tests after 5 d exposure.

Other effects:
Histological changes: No evidence of damage was observed.

Morin fluorescence for zinc on skin: No obvious reaction was observed.



None

Interpretation of results:
not irritating
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Based on these results, 20 % w/v zinc oxide was found to be non-irritating to rabbit skin.
Executive summary:

A study was conducted to evaluate the skin irritation potential of zinc oxide in New Zealand White rabbits by both open and occlusive patch methods.

In open patch test, 0.5 mL of 20 % w/v zinc oxide suspension in 0.1 % Tween 80 or vehicle was applied to clipped sites (5 cm2) of groups of four animals for 5 d. Skin sites were observed during and after 5 d exposure period. Animals were killed 24 h after the fifth daily treatment.

In occlusive patch test, groups of four animals were treated similarly to open patch test, but the test suspension or vehicle was applied to the skin using occlusive dressing for 3 d. After 3 d, dressings were removed and skin sites evaluated for irritancy. Two rabbits were killed at this stage. The remaining animals were redressed with freshly impregnated gauzes and then re-examined and killed after a further 2 d.

In both tests, representative samples of each test and control skin site of killed animals were analysed histologically and stained with morin dye to study epidermal keratin binding of zinc.

No obvious reactions were observed in both control and treatment groups in any of the performed tests after 5 d exposure. No evidence of damage was observed upon histological examination. No morin fluorescence was observed in skin sections.

Based on these results, 20 % w/v zinc oxide was found to be non-irritating to rabbit skin.

 

Endpoint:
skin irritation: in vivo
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Used in EU risk assessment for zinc oxide 2004, although not compliant with current guidlelines, considered reliable
Qualifier:
no guideline followed
Principles of method if other than guideline:
although not compliant with current guideline studies, considerd acceptable for assessment
GLP compliance:
not specified
Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
no further information
Type of coverage:
occlusive
Preparation of test site:
other: ear
Vehicle:
not specified
Controls:
not specified
Amount / concentration applied:
500 mg ZnO/animal
Duration of treatment / exposure:
24 hours
Observation period:
7 days
Number of animals:
2
Details on study design:
no further information
Irritation parameter:
overall irritation score
Basis:
mean
Time point:
other: 24 h
Score:
0
Irritant / corrosive response data:
none
Other effects:
none

none

Interpretation of results:
not irritating
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
No signs of irritation observed.
Executive summary:

In a skin irritation test, no dermal reactions were noted following the application of 500 mg ZnO/animal during 24 hours under occlusion to the ears of 2 New-Zealand white rabbits. The observation period was for 7 days.

Endpoint:
skin irritation: in vivo
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
The study was peer-reviewed and rated reliable within the framework of the EU RAR “Zinc stearate (CAS# 91051-01-3, CAS# 557-05-1) Part II – Human Health. EUR 21168 EN. Institute for Health and Consumer Protection. ECB - Existing Substances. Final Report, 2004. In accordance with Section 1 (0.5), Annex I of Regulation (EC) No 1907/2006 (REACH), this study was considered reliable with restrictions.
Reason / purpose:
reference to same study
Qualifier:
according to
Guideline:
other: Draize et al. (1944) Methods for the study of irritation and toxicity of substances, applied topically to the skin and mucous membranes. J. Pharmacol. Exp. Ther. 82, 377.
Principles of method if other than guideline:
The test item was applied in a single dose under occlusive conditions for 4 hours. The method of Draize (Draize, J.H., Woodard, G., and Calvery, H.O. (1944). Methods for the study of irritation and toxicity of substances, applied topically to the skin and mucous membranes, J. Pharmacol. Exp. Ther. 82, 377.) was used.
GLP compliance:
not specified
Species:
rabbit
Strain:
not specified
Details on test animals and environmental conditions:
TEST ANIMALS
Albino rabbits were used.
No further infromation on the test animals was stated.
Type of coverage:
occlusive
Preparation of test site:
not specified
Vehicle:
not specified
Controls:
not specified
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.5 ml (0.5 g) of zinc stearate
- Concentration: 100 %
No further information on the amounts/concentration applied was stated.
Duration of treatment / exposure:
4 hours
Observation period:
not stated
Number of animals:
6 rabbits
Details on study design:
It was stated that the method of Draize was used.
Zinc stearate was applied in a single dose under occlusive conditions. The wrapping and test material were removed at 4 hours and the sites scored for erythema and oedema at 4 and 48 hours.
No further information on the study design was stated.
Irritation parameter:
other: Primary Irritation Index (PII)
Time point:
other: 4 and 48 hours
Score:
0
Max. score:
8
Remarks on result:
other: PII score of 0 translates into an overall irritation score of 0 according to OECD 404 (2002). Zinc stearate was not corrosive under 49 CFR 173.240(a)(1).
Irritant / corrosive response data:
Zinc stearate was not corrosive under 49 CFR 173.240(a)(1).
Interpretation of results:
other: neither corrosive nor irritating
Remarks:
Criteria used for interpretation of results: EU
Conclusions:
Within the EU RAR “Zinc stearate (CAS# 91051-01-3, CAS# 557-05-1) Part II – Human Health. EUR 21168 EN. Institute for Health and Consumer Protection. ECB - Existing Substances. Final Report, 2004, this study was used for classification and labelling with the following conclusion:
"Zinc distearate is not corrosive to skin."
Endpoint:
skin irritation: in vivo
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
The study was peer-reviewed and rated reliable within the framework of the EU RAR “Zinc stearate (CAS# 91051-01-3, CAS# 557-05-1) Part II – Human Health. EUR 21168 EN. Institute for Health and Consumer Protection. ECB - Existing Substances. Final Report, 2004. In accordance with Section 1 (0.5), Annex I of Regulation (EC) No 1907/2006 (REACH), this study was considered reliable with restrictions.
Reason / purpose:
reference to same study
Qualifier:
according to
Guideline:
other: Draize et al. (1944) Methods for the study of irritation and toxicity of substances, applied topically to the skin and mucous membranes. J. Pharmacol. Exp. Ther. 82, 377.
Principles of method if other than guideline:
The test item was applied under occlusive conditions to the abraded and intact skin of rabbits for 24 hours. The method of Draize (Draize, J.H., Woodard, G., and Calvery, H.O. (1944). Methods for the study of irritation and toxicity of substances, applied topically to the skin and mucous membranes, J. Pharmacol. Exp. Ther. 82, 377.) was used.
GLP compliance:
not specified
Species:
rabbit
Strain:
not specified
Details on test animals and environmental conditions:
TEST ANIMALS
Albino rabbits were used.
No further infromation on the test animals was stated.
Type of coverage:
occlusive
Preparation of test site:
not specified
Vehicle:
not specified
Controls:
not specified
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 500 mg/kg zinc distearate was applied undiluted
- Concentration: 100 %
No further information on the amount/concentration applied was stated.
Duration of treatment / exposure:
24 hours
Observation period:
not stated
Number of animals:
6 rabbits
Details on study design:
It was stated that the method of Draize was used.
The test material was applied under occlusive conditions to the abraded and intact skin. The sites were unwrapped and examinedand scored for erythema and oedema at 24 and 72 hours.
No further information on the study design was stated,
Irritation parameter:
other: Primary Irritation Index (PII)
Time point:
other: 24 and 72 hours
Score:
0
Remarks on result:
other: PII score of 0 translates into an overall irritation score of 0 according to OECD 404 (2002). Zinc stearate was not irritating
Irritant / corrosive response data:
Zinc stearate was not irritating
Other effects:
not stated
Interpretation of results:
not irritating
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Zinc stearate was not irritating.
According to the criteria specified by Directive 67/548/EEC and subsequent regulations, the test item is not classified as skin irritant.
According to the Regulation (EC) No 1272/2008 and subsequent regulations, the test item is not classified as skin irritant.

This conclusion is in accordance with EU RAR.
Conclusions of EU RAR “Zinc stearate (CAS# 91051-01-3, CAS# 557-05-1) Part II – Human Health. EUR 21168 EN. Institute for Health and Consumer Protection. ECB - Existing Substances. Final Report, 2004:
"Limited data on zinc distearate indicate no skin and eye irritating potential. Based on the accepted derogation and the fact that both zinc phosphate and zinc oxide is not skin irritating, it is consequently concluded that zinc distearate is not likely to have skin irritation potential and, therefore does not need to be classified/labelled. This is supported by the fact that the use of zinc distearate in pharmaceutical and cosmetic preparations is not associated with irritation in humans."

Endpoint:
skin irritation: in vivo
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
1992-10-20 to 1992-10-29
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: GLP guideline study
Qualifier:
according to
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Version / remarks:
adopted 1981-05-12
GLP compliance:
yes
Species:
rabbit
Strain:
other: Kleinrussen, CHbb:HM
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Thomae GmbH, Biberach/D.
- Age at study initiation: approx. 9 months
- Weight at study initiation: approx. 2590 g
- Housing: individual accommodation in cages
- Diet (ad libitum): Ssniff rabbit diet K4 (Ssniff GmbH, Soest/D, Batch: 770992/09)
- Water (ad libitum): tap water
- Acclimation period: at least 1 week

ENVIRONMENTAL CONDITIONS
- Temperature: approx. 20-25 °C
- Relative humidity: approx. 45-70 %
- Air changes: at least eight per hour
- Photoperiod (hrs dark / hrs light): 12/12
Type of coverage:
semiocclusive
Preparation of test site:
shaved
Vehicle:
unchanged (no vehicle)
Controls:
no
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): the undiluted test substance Stabiol VZN 1950 was applied at the dose level of 0.5 g per animal.
Duration of treatment / exposure:
4 hours
Observation period:
1, 24, 48 and 72 hours after exposure
Number of animals:
3 male rabbits
Details on study design:
TEST SITE
- Area of exposure: the flank of each experimental animal was sheared approx. 24 hours prior to the application with an electric clipper. Animals with intact and healthy skin were used in the test.
The semi-occlusive exposure was performed by means of a 6 cm^2 adhesive air- and vapour permeable gauze-patch which was fixed by a hypoallergic adhesive gauze-bandage.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): the exposure was terminated after four hours by removing the patch and cleaning the relevant skin from the residual test substance.

SCORING SYSTEM: according to Draize scale
Irritation parameter:
erythema score
Basis:
animal: #1, #2, #3
Time point:
other: mean 24, 48 and 72 hours
Score:
0
Max. score:
4
Irritation parameter:
edema score
Basis:
animal: #1, #2, #3
Time point:
other: mean 24, 48 and 72 hours
Score:
0
Max. score:
4
Irritant / corrosive response data:
No dermal effects were observed at all experimental animals up to 72 hours after exposure.
Interpretation of results:
not irritating
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Octanoic acid, zinc salt, basic is not irritating to the skin.
According to the EC-Commission directive 67/548/EEC and its subsequent amendments, the test substance is not classified as skin irritant.
According to the EC-Regulation 1272/2008 and subsequent regulations, the test item is not classified as skin irritant.

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

Eye irritation

Link to relevant study records

Referenceopen allclose all

Endpoint:
eye irritation: in vivo
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Well performed, reliable, GLP compliant study, used in EU risk assessment for zinc oxide 2004
Qualifier:
according to
Guideline:
EU Method B.5 (Acute Toxicity: Eye Irritation / Corrosion)
Qualifier:
according to
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Principles of method if other than guideline:
none
GLP compliance:
yes
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
see reference
Vehicle:
unchanged (no vehicle)
Controls:
yes, concurrent no treatment
Amount / concentration applied:
64 mg ZnO (volume of 0.1 mL)
Duration of treatment / exposure:
24 hours
Observation period (in vivo):
1, 24, 48 and 72 hours after exposure
Number of animals or in vitro replicates:
3 males
Details on study design:
see reference
Irritation parameter:
conjunctivae score
Basis:
mean
Time point:
other: 24-72 h
Score:
>= 0.7 - <= 1
Reversibility:
fully reversible within: 72 h
Irritant / corrosive response data:
No symptoms of systemic toxicity were observed and no mortality occurred. Slight iridial irritation (grade 1) was observed in one animal, at 1 hour only. Slight irritation of the conjuctivae (grade 1-2) was seen as redness (mean scores over 24-72 hours 0.7, 1 and 1), which had completely resolved at 72 hours in all animals. Chemosis (grade 2) and discharge (grade 1) were also observed in all animals, but at 1 hour only. No corneal opacity or epithelial damage was observed in any of the animals
Other effects:
none
Interpretation of results:
not irritating
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
ZnO not irritating in an vivo rabbit study.
Executive summary:

In an eye irritation/corrosion well-performed study according to Directive 92/69/EEC B.5 and OECD guideline 405, three male New Zealand White rabbits were treated by instillation of approximately 64 mg of zinc oxide (a volume of about 0.1 ml) into the conjuctival sac of one eye. The other eye remained untreated and served as control. After 24 hours, both eyes of two animals were rinsed with water. The eyes were examined at 1, 24, 48 and 72 hours after instillation. No symptoms of systemic toxicity were observed and no mortality occurred. Slight iridial irritation (grade 1) was observed in one animal, at 1 hour only. Slight irritation of the conjuctivae (grade 1-2) was seen as redness (mean scores over 24-72 hours 0.7, 1 and 1), which had completely resolved at 72 hours in all animals. Chemosis (grade 2) and discharge (grade 1) were also observed in all animals, but at 1 hour only. No corneal opacity or epithelial damage was observed in any of the animals.

Endpoint:
eye irritation: in vivo
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
2011-12-08 to 2011-12-18
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Read-across of a GLP guideline study RL1
Qualifier:
according to
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Version / remarks:
adopted April 24, 2002
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.5 (Acute Toxicity: Eye Irritation / Corrosion)
Version / remarks:
2008
Deviations:
no
GLP compliance:
yes (incl. certificate)
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: approx. 4.5- 5.5 months
- Weight at study initiation: 2.5 - 2.8 kg
- Housing: animals were kept singly in cages of 380 mm x 425mm x 600 mm (manufacturer: Dipl. Ing. W. EHRET GmbH, 16352 Schönwalde, Germany) during the acclimatisation period and after the 8 hours period in restrainers (for 8 hours following test item application the animals were kept singly in restrainers).
- Diet (ad libitum): commercial diet, ssniff K-H V2333 (Ssniff Spezialdiäten GmbH, 59494 Soest, Germany)
- Water (ad libitum before and after the exposure period): tap water
- Acclimation period: at least 20 adaptation days

ENVIRONMENTAL CONDITIONS:
- Temperature: 20°C ± 3°C (maximum range)
- Relative humidity: 30% to 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
Duration of treatment / exposure:
1 hours
Observation period (in vivo):
72 hours
Number of animals or in vitro replicates:
3 male rabbits
Details on study design:
INITIAL AND CONFORMATORY 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.

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.

APPLICATION
- 100 mg of the test item were administered into one eye each of three animals. The volume of particulates was measured after gently compacting them, e.g. by tapping the measuring container. 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.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): the eyes were rinsed with portions of 20 mL 0.9% aqueous NaCl solution, each.
- Time after start of exposure: 1 hour after administration

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 and 72 hours after the administration. The eye reactions were observed and registered.
24 hours and 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
Body weight of all animals was measured at the beginning of the study. Behaviour and food consumption were monitored.
Irritation parameter:
iris score
Basis:
animal: #1, #2, #3
Time point:
other: mean 24, 48, 72 hours
Score:
0
Max. score:
2
Irritation parameter:
cornea opacity score
Basis:
animal: #1, #2, #3
Time point:
other: mean 24, 48, 72 hours
Score:
0
Max. score:
4
Irritation parameter:
conjunctivae score
Remarks:
Redness
Basis:
animal: #1, #2
Time point:
other: mean 24, 48, 72 hours
Score:
0
Max. score:
3
Irritation parameter:
conjunctivae score
Remarks:
Redness
Basis:
animal #3
Time point:
other: mean 24, 48, 72 hours
Score:
0.33
Max. score:
3
Reversibility:
fully reversible within: 48 h
Irritation parameter:
chemosis score
Basis:
animal: #1, #2, #3
Time point:
other: mean 24, 48, 72 hours
Score:
0
Max. score:
4
Irritant / corrosive response data:
Conjunctival redness (grade 1) was observed in all animals for 60 minutes, and in one animal for 24 hours after the instillation.
The corneae and irises were not affected by instillation of the test item.
The fluorescein test performed 24 hours after instillation did not reveal any changes.
Other effects:
There were no systemic intolerance reactions.
Interpretation of results:
not irritating
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The test material is non-irritating to the eyes.
According to 67/548/EC and subsequent regulations, the substance is not classified as an eye irritant.
According to the EC Regulation No. 1272/2008 and subsequent regulations, the substance is not classified as an eye irritant.
Endpoint:
eye irritation: in vivo
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
The study was peer-reviewed and rated reliable within the framework of the EU RAR “Zinc stearate (CAS# 91051-01-3, CAS# 557-05-1) Part II – Human Health. EUR 21168 EN. Institute for Health and Consumer Protection. ECB - Existing Substances. Final Report, 2004". In accordance with Section 1 (0.5), Annex I of Regulation (EC) No 1907/2006 (REACH), this study was considered reliable with restrictions.
Qualifier:
according to
Guideline:
other: Draize et al. (1944) Methods for the study of irritation and toxicity of substances, applied topically to the skin and mucous membranes. J. Pharmacol. Exp. Ther. 82, 377.
Principles of method if other than guideline:
100 % zinc stearate was applied to the eyes of rabbits. Observations were made on days 1 and 2.
GLP compliance:
not specified
Species:
rabbit
Strain:
not specified
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
Rabbits were used.
No further information on the test animals was stated.
Vehicle:
not specified
Controls:
not specified
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 100 % concentration of zinc stearate was applied to the eyes of the rabbits.
No further information on the amount/concentration applied was stated.
Observation period (in vivo):
Days 1 and 2
Number of animals or in vitro replicates:
6 rabbits
Details on study design:
REMOVAL OF TEST SUBSTANCE
Eyes were not unrinsed.
The method of Draize was used in this study.
No further information on the study design was stated.
Irritation parameter:
other: Primary irritation index (PII)
Basis:
mean
Time point:
other: day 1
Score:
2
Max. score:
2
Remarks on result:
other: PII score of 2 translates into "Practically Non-Irritating". 100 % zinc stearate is "practically non-irritating".
Irritation parameter:
other: Primary irritation index (PII)
Basis:
mean
Time point:
other: day 2
Score:
0
Max. score:
0
Remarks on result:
other: PII score of 0 translates into a score of 0 according to OECD 405 (2002). 100 % zinc stearate caused no eye irritation.

A 100 % concentration of zinc stearate caused minimal irritation and is considered "practically non-irritating".

Interpretation of results:
not irritating
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Within the EU RAR “Zinc stearate (CAS# 91051-01-3, CAS# 557-05-1) Part II – Human Health. EUR 21168 EN. Institute for Health and Consumer Protection. ECB - Existing Substances. Final Report, 2004, this study was used for classification and labelling with the following conclusion: "Limited data on zinc distearate indicate no skin and eye irritating potential. Based on the accepted derogation, and the fact that both zinc phosphate and zinc oxide are not eye irritating and zinc oxide is not skin irritating, it is consequently concluded that zinc distearate is not likely to have eye and skin irritation potential and, therefore does not need to be classified/labelled. This is supported by the fact that the use of zinc distearate in pharmaceutical and cosmetic preparations is not associated with irritation in humans."
Endpoint:
eye irritation: in vivo
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
The study was peer-reviewed and rated reliable within the framework of the EU RAR “Zinc stearate (CAS# 91051-01-3, CAS# 557-05-1) Part II – Human Health. EUR 21168 EN. Institute for Health and Consumer Protection. ECB - Existing Substances. Final Report, 2004". In accordance with Section 1 (0.5), Annex I of Regulation (EC) No 1907/2006 (REACH), this study was considered reliable with restrictions.
Reason / purpose:
reference to same study
Qualifier:
according to
Guideline:
other: Draize, J.H. (1959). Dermal toxicity. Appraisal of the safety of chemicals in foods, drugs, and cosmetics. Assoc. of Food and Drug Officials of the U.S., compiled by the Div. of Pharm., Food and Drug Admin., Dept. of Health, Education and Welfare, Austin,
Principles of method if other than guideline:
100 % zinc stearate was applied to the eyes of albino rabbits. Observations were made on days 1,2, and 3.
GLP compliance:
not specified
Species:
rabbit
Strain:
not specified
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
Albino rabbits were used.
No further information on the test animals was stated.
Vehicle:
not specified
Controls:
not specified
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.1 g (100 % concentration) of zinc stearate was applied.
No further information on the amount/concentration applied was stated.
Observation period (in vivo):
Days 1, 2, and 3
Number of animals or in vitro replicates:
6 rabbits
Details on study design:
REMOVAL OF TEST SUBSTANCE
Eyes were not rinsed.
The ocular irritation was scored according to the system of Draize on days 1, 2, and 3.
No further information on the study design was stated.
Irritation parameter:
other: Primary irritation index (PII)
Time point:
other: days 1, 2 and 3
Score:
0
Remarks on result:
other: PII score of 0 translates into a score of 0 according to OECD 405 (2002). 0.1 g (100 % concentration) of zinc stearate caused no eye irritation.
Irritant / corrosive response data:
0.1 g (100 % concentration) of zinc stearate caused no eye irritation.
Interpretation of results:
not irritating
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
0.1 g (100 % concentration) of zinc stearate caused no eye irritation.
According to the criteria specified by Directive 67/548/EEC and subsequent regulations, the test item is not classified as eye irritant.
According to the Regulation (EC) No 1272/2008 and subsequent regulations, the test item is not classified as eye irritant.

This conclusion is in accordance with EU RAR.
Conclusions of EU RAR “Zinc stearate (CAS# 91051-01-3, CAS# 557-05-1) Part II – Human Health. EUR 21168 EN. Institute for Health and Consumer Protection. ECB - Existing Substances. Final Report, 2004:"Limited data on zinc distearate indicate no skin and eye irritating potential. Based on the
accepted derogation, and the fact that both zinc phosphate and zinc oxide are not eye irritating and zinc oxide is not skin irritating, it is consequently concluded that zinc distearate is not likely to have eye and skin irritation potential and, therefore does not need to be classified/labelled.
This is supported by the fact that the use of zinc distearate in pharmaceutical and cosmetic preparations is not associated with irritation in humans."
Endpoint:
eye irritation: in vivo
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
other: Documentation insufficient for assessment The purity of the test item, detailed methodological information (duration of observation, number of animals, method of scoring ocular lesions) and individual data are missing
Reason / purpose:
reference to same study
Principles of method if other than guideline:
The effect of zinc caprylates on mucous membranes was studied via insufflating 50 mg of powder into the conjunctival sac of the rabbits.
GLP compliance:
not specified
Species:
rabbit
Strain:
not specified
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
As test animal the rabbit was used.
No further information on the test animals was stated.
Vehicle:
unchanged (no vehicle)
Controls:
not specified
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): The effect of zinc caprylates on mucous membranes was studied via insufflating 50 mg of powder into the conjunctival sac of the rabbits.
No further information on the amount/concentration applied was stated.
Duration of treatment / exposure:
not stated
Observation period (in vivo):
not stated
Number of animals or in vitro replicates:
not stated
Details on study design:
No further information on the study design was stated.
Remarks on result:
other: Study of the local effect of zinc caprylate showed that it produces a more pronounced effect on the mucouse membranes of the eye. Due to insufficient documentation the study cannot be used for hazard assessment.

The lacrimal canal at the internal angle of the eye contracted for 1 min after the administration of the substance. The observation after applying zinc caprylate were as follows: after 1 h, profuse epiphora and photophobia; after 3 h, hyperaemia of conjunctiva of the eyelid and eyeball, oedema of conjunctiva and the conjunctival fold and a purulent dischange from the eye. By 24th hour, the above-described phenomena of irritation had considerably abated after zinc caprylate administration. Fourty-eight hours after the administration of zinc caprylate, there still continued hyperaemia of the conjunctiva and a purulent discharge; by day 4 essentially all the irritation phenomena had disappeared: the eye was clear, there was no discharge, only weak hyperaemia remaining.

Interpretation of results:
other: Due to insufficient documentation the study cannot be used for hazard assessment.
Conclusions:
The study of local effect of zinc caprylate showed that it produces a more pronounced effect on the mucouse membranes of the eye.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Respiratory irritation

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

Additional information

ZINC DITETRADECANOATE:

Zinc ditetradecanoate (synonym: zinc myristate, CAS 16260-27-8) is a zinc salt of a fatty acid containing 14 C-atoms. Thus, read-across of data available for zinc salts of shorter-chained (C8, C12) and longer-chained (C16-18) fatty acids (bridging principle) based on structural similarity, water solubility and zinc content in a conservative, worst-case approach is assumed to adequately describe the skin and eye irritation potential of zinc ditetradecanoate.

The irritation and corrosion potential is described with information read-across from relevant zinc soaps (zinc salts of shorter-chained (C8, C12) and longer-chained (C16-18) fatty acids) as well as supporting information from slightly soluble/insoluble zinc compounds. A 1:1 read-across of toxicological data of (i) Octanoic acid, zinc salt, basic (C8); (ii) zinc dilaurate (C12); (iii) Fatty acids, C16 -18, zinc salts; and (iv) zinc oxide is applied to zinc ditetradecanoate as it is assumed that zinc ditetradecanoate liberates ionic zinc and its fatty acid tetradecanoate moiety upon contact with (mucous) biological membranes. Consequently, following the worst-case approach, the studies on the fatty acid zinc salt with highest zinc amount and lowest pH of the non-saponified free fatty acid were selected. Octanoic acid, zinc salt, basic (C8) is not irritating to the skin and zinc dilaurate (C12) is not irritating to the eye. In addition, the results of the histopathological examination of lung tissue following acute exposure to zinc dilaurate (C12) via inhalation (OECD 436 test) do not indicate an irritative potential. Furthermore, zinc ditetradecanoate is not expected to be irritating to the skin or the eye based on the lack of respective irritation potential of zinc salts of longer-chained (C16-18) fatty acids as well as supporting information from slightly soluble/insoluble zinc compounds. Thus, a lack of skin, eye and respiratory irritancy is considered for zinc ditetradecanoate and classification according to Regulation (EC) 1272/2008 is not required.

These conclusions are in line with conclusions for the structural analogue (i.e. Fatty acids, C16-18, zinc salts) from EU Risk assessment report “Zinc stearate (CAS# 91051-01-3, CAS# 557-05-1) Part II – Human Health.EUR 21168 EN (http://echa.europa.eu/documents/10162/08799aec-42c5-44e0-9969-baa022c66db1):

"It is consequently concluded that zinc distearate is not likely to have eye and skin irritation potential and, therefore does not need to be classified/labelled... Zinc distearate is not corrosive to skin or eyes."

A similar lack of skin and eye irritancy is considered for zinc ditetradecanoate. For a comprehensive overview of the (non) irritancy of zinc, see the hazard assessment of "Zinc" within the framework of Regulation (EC) No 1907/2006 cited below.

 

ZINC:

Based on the available information it appears that he slightly soluble zinc oxide and insoluble zinc sulphide are not skin irritants and therefore slightly soluble zinc hydroxide, zinc phosphate, zinc carbonate and zinc metal are also expected to be not irritating to skin. Zinc oxide, zinc phosphate, zinc metal and zinc sulphide are not eye irritants and therefore zinc carbonate and zinc hydroxide are also expected to be not irritating to eyes. None of the slightly soluble or insoluble zinc compounds appear to cause respiratory tract irritation.

The slightly soluble and insoluble zinc compounds (zinc oxide, zinc hydroxide, zinc phosphate, zinc carbonate, zinc metal and zinc sulphide) are not corrosive based on the available irritation data.

Justification for classification or non-classification

Zinc ditetradecanoate as slightly soluble zinc compound is not irritating or corrosive based on the available information from analogous zinc carboxylates. Therefore, classification is not required for irritation or corrosion according to the criteria laid down in Regulation (EC) No 1272/2008.