2-Butenedioic acid (2Z)-, reaction products with ammonium di-.mu.3-hydroxyhexacosa-.mu.-oxododecaoxododecatungstate(6-) (6:1), ammonium octa-.mu.-oxodi-.mu.3-oxodi-.mu.4-oxododecaoxoheptamolybdate(6-) (6:1), nickel(2+) nitrate (1:2) and nickel(2+) sulfate (1:1)

Endpoint summary

Description of key information

Skin irritation (OECD 404): not irritating
Eye irritation (OECD 405): irritating

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:

key study

Study period:

26 Jun - 06 Jul 2012

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)

Deviations:

yes

Remarks:

no information on systemic effects are given in the test report

Qualifier:

according to guideline

Guideline:

EU Method B.4 (Acute Toxicity: Dermal Irritation / Corrosion)

Deviations:

yes

Remarks:

no information on systemic effects are given in the test report

GLP compliance:

yes (incl. QA statement)

Remarks:

GROUPE INTERMINISTERIEL DES PRODUITS CHIMIQUES

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Elevage de Gérome, Quartier Labaste, Linxe, France
- Age at study initiation: 11 - 13 weeks
- Weight at study initiation: 2.39 - 2.70 kg
- Housing: individual
- Diet: SDS - C15, ad libitum
- Water: tap-water from public distribution system, ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 ± 3
- Humidity (%): 30 - 70
- Air changes (per hr): approx. 15
- Photoperiod (hrs dark / hrs light): 12 / 12

Type of coverage:

semiocclusive

Preparation of test site:

clipped

Vehicle:

unchanged (no vehicle)

Remarks:

(the test item was moistened with distilled water prior to treatment to ensure good contact with the skin)

Controls:

other: not required, untreated sites of the same animal served as control

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.5 g

Duration of treatment / exposure:

4 h

Observation period:

72 h
Reading time points: 1, 24, 48 and 72 h

Number of animals:

1 female (initial test)
2 females (confirmatory test)

Details on study design:

TEST SITE
- Area of exposure: 6 cm² on the flank
- Type of wrap if used: The patch containing the test substance was secured in position with a strip of surgical adhesive tape.

SCORING SYSTEM: Draize scoring system

Irritation parameter:

erythema score

Basis:

animal #1

Time point:

other: mean over 24, 48 and 72 h

Score:

0.7

Max. score:

4

Reversibility:

fully reversible within: 72 h

Irritation parameter:

erythema score

Basis:

animal #2

Time point:

other: mean over 24, 48 and 72 h

Score:

0.3

Max. score:

4

Reversibility:

fully reversible within: 48 h

Irritation parameter:

erythema score

Basis:

animal #3

Time point:

other: mean over 24, 48 and 72 h

Score:

0

Max. score:

4

Reversibility:

other: not applicable

Irritation parameter:

edema score

Basis:

other: mean out of all 3 animals

Time point:

other: mean over 24, 48 and 72 h

Score:

0

Max. score:

4

Reversibility:

other: not applicable

Irritant / corrosive response data:

Slight erythema were noted on the treated area in 2/3 animals starting 1 h after patch removal which lasted for up to 72 h.

Other effects:

Yellow coloration was noted on the treatment site of animal#2 which did not interfere with erythema assessment.

Interpretation of results:

not irritating

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

CLP: not classified
DSD: not classified

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:

2 Jul - 24 Jul 2012

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP-Guideline study (according to OECD Guideline 405 adopted 24th April 2002 (no anesthetics or analgesics were used)

Qualifier:

according to guideline

Guideline:

other: OECD Guideline 405 (Acute Eye Irritation / Corrosion) (adopted 24 April 2002)

Deviations:

yes

Remarks:

no information on clinical signs or pain/distress are given in the test report

Qualifier:

according to guideline

Guideline:

EU Method B.5 (Acute Toxicity: Eye Irritation / Corrosion)

Deviations:

yes

Remarks:

no information on clinical signs or pain/distress are given in the test report

GLP compliance:

yes (incl. QA statement)

Remarks:

GROUPE INTERMINISTERIEL DES PRODUITS CHIMIQUES

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

TEST ANIMALS
- Source: Elevage de Gérome, Quartier Labaste, Linxe, France
- Age at study initiation: 12 - 13 weeks
- Weight during study period: 2.66 - 3.78 kg
- Housing: individual
- Diet: SDS - C15, ad libitum
- Water: tap-water from public distribution system, ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 ± 3
- Humidity (%): 30 - 70
- Air changes (per hr): 10 - 15
- Photoperiod (hrs dark / hrs light): 12 / 12

Vehicle:

unchanged (no vehicle)

Controls:

other: The untreated eye served as control.

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.1 g

Duration of treatment / exposure:

1 h (remaining test item was rinsed with physiological saline 1 h after instillation in all animals)

Observation period (in vivo):

14 days
Reading time points: 1, 24, 48, 72 h and on Day 7 and 14

Number of animals or in vitro replicates:

1 female (initial test)
2 females (confirmatory test)

Details on study design:

SCORING SYSTEM: similar to Draize scoring system, supplemented with scoring for discharge and extent of opacity

Discharge:
No discharge - 0
Slight discharge (normal slight secretions in the inner corner to be taken into account) -2
Discharge with moistening of the eyelids and neighbouring hairs - 2
Discharge with moistening of the eyelids and large areas around the eye -3

Cornea: Extent of opacity:
Opaque area present but covering 1/4 or less - 1
Between 1/4 or 1/2 - 2
Between 1/2 and 3/4 - 3
Between 3/4 and the entire surface - 4

Irritation parameter:

cornea opacity score

Basis:

animal #1

Time point:

other: mean over 24, 48 and 72 h

Score:

0.3

Max. score:

4

Reversibility:

fully reversible within: 2 days

Irritation parameter:

cornea opacity score

Basis:

animal #2

Time point:

other: mean over 24, 48 and 72 h

Score:

0.7

Max. score:

4

Reversibility:

fully reversible within: 2 days

Irritation parameter:

cornea opacity score

Basis:

animal #3

Time point:

other: mean over 24, 48 and 72 h

Score:

0.3

Max. score:

4

Reversibility:

fully reversible within: 2 days

Irritation parameter:

iris score

Basis:

animal #1

Time point:

other: mean over 24, 48 and 72 h

Score:

0

Max. score:

2

Reversibility:

other: not applicable

Irritation parameter:

iris score

Basis:

animal #2

Time point:

other: mean over 24, 48 and 72 h

Score:

0.3

Max. score:

2

Reversibility:

fully reversible within: 2 days

Irritation parameter:

iris score

Basis:

animal #3

Time point:

other: mean over 24, 48 and 72 h

Score:

0

Max. score:

2

Reversibility:

other: not applicable

Irritation parameter:

conjunctivae score

Basis:

animal #1

Time point:

other: mean over 24, 48 and 72 h

Score:

2

Max. score:

3

Reversibility:

fully reversible within: 14 days

Irritation parameter:

conjunctivae score

Basis:

animal #2

Time point:

other: mean over 24, 48 and 72 h

Score:

3

Max. score:

3

Reversibility:

fully reversible within: 14 days

Irritation parameter:

conjunctivae score

Basis:

animal #3

Time point:

other: mean over 24, 48 and 72 h

Score:

1.3

Max. score:

3

Reversibility:

fully reversible within: 7 days

Irritation parameter:

chemosis score

Basis:

animal #1

Time point:

other: mean over 24, 48 and 72 h

Score:

1.7

Max. score:

4

Reversibility:

fully reversible within: 7 days

Irritation parameter:

chemosis score

Basis:

animal #2

Time point:

other: mean over 24, 48 and 72 h

Score:

3

Max. score:

4

Reversibility:

fully reversible within: 14 days

Irritation parameter:

chemosis score

Basis:

animal #3

Time point:

other: mean over 24, 48 and 72 h

Score:

0.3

Max. score:

4

Reversibility:

fully reversible within: 2 days

Irritant / corrosive response data:

The test item induced slight to severe eye reactions:
- slight to moderate corneal opacity in 3/3 animals noted 24 h after instillation which was fully reversible within 2 days.
- congestion of the iris in 1/3 animals noted 24 h after instillation which was fully reversible within 2 days.
- moderate to severe redness of the conjunctivae in 3/3 animals noted after 24 h instillation which was fully reversible latest within 14 days.
- slight to severe chemosis in 3/3 animals noted 24 h after instillation which was fully reversible latest within 14 days.
Further, white coloration of the inferior conjunctiva was noted in animal#1 between Day 2 and Day 7.

Other effects:

No information on clinical signs or pain/distress are reported.

Table 1. Eye reactions after instillation.

 

Rabbit #   1           2           3	Time [h]	conjunctivae		iris	cornea		conjunctivae		iris	cornea
		redness	swelling				redness	swelling
	24	2	3	0	1
	48	2	1	0	0
	72	2	1	0	0
	average	2	1.7	0.0	0.3	Time to reversion	14 days	7 days	0	2 days
	24	3	4	1	2
	48	3	3	0	0
	72	3	2	0	0
	average	3	3	0.3	0.7	Time to reversion	14 days	14 days	2 days	2 days
	24	2	1	0	1
	48	1	0	0	0
	72	1	0	0	0
	average	1.3	0.3	0.0	0.3	Time to reversion	2 days	7 days	0	2 days

Interpretation of results:

irritating

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

CLP: Eye irrit 2, H319
DSD: not classified

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (irritating)

Additional information

Skin irritation/corrosion

A GLP-guideline study according to OECD guideline 404 did not determine skin irritating properties of 2-Butenedioic acid (2Z)-, reaction products with ammonium di-µ3-hydroxyhexacosa-µ-oxododecaoxododecatungstate(6-) (6:1), ammonium octa-µoxodi-µ3-oxo-µ4-oxododecaoxoheptamolybdate(6-) (6:1), nickel(2+) nitrate (1:2) and nickel(2+) sulfate (1:1) (Colas, 2012). Thus, the test item is considered to be non-irritating to skin.

Eye irritation

In a GLP-guideline study performed according to OECD guideline 405 (adopted 24^thApril 2002), 3 female New Zealand White rabbits were treated with 0.1 g test material (Colas, 2013). 2-Butenedioic acid (2Z)-, reaction products with ammonium di-µ3-hydroxyhexacosa-µ-oxododecaoxododecatungstate(6-) (6:1), ammonium octa-µ-oxodi-µ3-oxo-µ4-oxododecaoxoheptamolybdate(6-) (6:1), nickel(2+) nitrate (1:2) and nickel(2+) sulfate (1:1) induced slight to severe eye reactions visible as slight to moderate corneal opacity in 3/3 animals with overall cornea scores of 0.3 or 0.7, congestion of the iris in 1/3 animals (mean score 0.3), moderate to severe redness of the conjunctivae in 3/3 animals (overall score 1.3, 2 or 3) and slight to severe chemosis in 3/3 animals (overall score 0.3, 1.7 or 3). All effects were fully reversible latest within 14 days. Based on the effects observed, 2-Butenedioic acid (2Z)-, reaction products with ammonium di-µ3-hydroxyhexacosa-µ-oxododecaoxododecatungstate(6-) (6:1), ammonium octa-µoxodi-µ3-oxo-µ4-oxododecaoxoheptamolybdate(6-) (6:1), nickel(2+) nitrate (1:2) and nickel(2+) sulfate (1:1) is considered as eye irritant.

Justification for selection of skin irritation / corrosion endpoint:
There is only one study available.

Justification for selection of eye irritation endpoint:
There is only one study available.

Effects on eye irritation: irritating

Justification for classification or non-classification

The available data on skin irritation do not meet the classification criteria according to Regulation (EC) 1272/2008 or Directive 67/548/EEC, and are therefore conclusive but not sufficient for classification.

The available data on eye irritation do not meet the classification criteria according to Directive 67/548/EEC but meet the classification criteria as serious eye irritant according to Regulation (EC) 1272/2008.