Neodecanoic acid, zinc salt, basic

Endpoint summary

Description of key information

Skin irritation for analogue substance: not irritating (OECD 404, GLP)

Eye irritation for analogue substance: not irritating (OECD 405; GLP)

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records

Reference

Reference 1

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2013-03-21 to 2013-04-05

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 6 - 7 months
- 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): 0.5 mL of the test item was applied to the test site undiluted.

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 was applied to the test site (area: approx. 6 cm2) 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 irritancy, all 3 animals were applied at one time, i.e. no initial test was carried out.

SCORING SYSTEM: according to the Draize scale

Irritation parameter:

erythema score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0

Max. score:

4

Irritation parameter:

edema score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0

Max. score:

4

Irritation parameter:

erythema score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0

Max. score:

4

Irritation parameter:

edema score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0

Max. score:

4

Irritation parameter:

erythema score

Basis:

animal #3

Time point:

24/48/72 h

Score:

0

Max. score:

4

Irritation parameter:

edema score

Basis:

animal #3

Time point:

24/48/72 h

Score:

0

Max. score:

4

Irritant / corrosive response data:

None of the three rabbits exposed for 4 hours to 0.5 mL zinc neodecanoate/animal showed any skin reactions.

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 substance is not irritating to the skin.
According to the EC-Commission directive 67/548/EEC and its subsequent amendments, the test substance is not irritating to the skin.
According to the EC-Regulation 1272/2008 and subsequent regulations, the test item is not classified as skin irritant.

Reference 2

Endpoint:

skin irritation: in vivo

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Justification for type of information:

REPORTING FORMAT FOR THE ANALOGUE APPROACH
This read-across is based on the hypothesis that source and target substances have similar toxicological properties because they hydrolyse to common products.

This prediction is supported by toxicological data on the substances themselves and on the dissolution products of the substances.
Target and source substances are UVCB substances, the UVCB character is derived from the educt of the production process of that substances, namely neodecanoic acid. Both substances differ only in the production process, resulting in (i) an neutral product and (ii) a basic product.

The target substance is the overbased product containing a slightly higher zinc content. The dissolution product, namely the zinc cation, is not the driver for toxic effects.
Consequently, the target substance is identical to the source substance and share a structural similarity with common functional groups, carboxylic acid, alkyl side chains.

Therefore, read-across from the existing skin and eye irritation studies on the source substance is considered as an appropriate adaption to the standard information requirements of Annex VII and VIII, 8.1 and 8.2 of the REACH Regulation for the target substance, in accordance with the provisions of Annex XI, 1.5 of the REACH Regulation.

The justification of the proposed read-across approach is elaborated in the next chapters. Please find this information in the attachements as well.


1. HYPOTHESIS FOR THE ANALOGUE APPROACH
This read-across is based on the hypothesis that source and target substances have similar toxicological properties because they hydrolyse to common products.
This prediction is supported by toxicological data on the substances themselves and on the dissolution products of the substances.
Target and source substances are UVCB substances, the UVCB character is derived from the educt of the production process of that substances, namely neodecanoic acid. Both substances differ only in the production process, resulting in (i) an neutral product and (ii) a basic product.
The target substance is the overbased product containing a slightly higher zinc content. The dissolution product, namely the zinc cation, is not the driver for toxic effects.
Consequently, the target substance is identical to the source substance and share a structural similarity with common functional groups, carboxylic acid, alkyl side chains.
Therefore, read-across from the existing skin and eye irritation studies on the source substance is considered as an appropriate adaption to the standard information requirements of Annex VII and VIII, 8.1 and 8.2 of the REACH Regulation for the target substance, in accordance with the provisions of Annex XI, 1.5 of the REACH Regulation.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
a) Target substance
The target substance zinc neodecanoate, basic is a UVCB substance (EC: 282-780-4, CAS: 84418-68-8).
b) Source substance
The source substance zinc neodecanoat is a UVCB substance (EC: 248-370-4, CAS: 27253-29-8).
c) Purity and impurities
Both substances are UVCB substances, thus specification of impurity profiles is not applicable. Additionally, the source substance is derived from the same educts in the production process. Consequently, the hazard profile of the target substance is intrinsically covered.


3. ANALOGUE APPROACH JUSTIFICATION
a) Structural similarity and functional groups
The structure of the target and source substances are the same, namely a neodecanoic acid, zinc salt. The target substance is the overbased product containing a slightly higher zinc content. The dissolution product, namely the zinc cation, is not the driver for toxic effects with regard to Human Health and especially to local effects.
b) Common breakdown products
The common characteristic of the target substance and the source substance is that both liberate the same moiety upon dissolution in aqueous media. Zinc cations and neodecanoate is formed upon dissolution under toxicological relevant conditions such as body fluids and in the environment.


4. DATA MATRIX
A comparison of the experimental toxicological data between the source and target substance is not applicable in the applied approach, since the overall ecotoxicity/systemic toxicity of the target substance is assessed by taking the (eco-)toxicological profile of the zinc cation and the acid anion (neodecanoate) into account. An endpoint-specific description is provided in the respective endpoint summaries of both assessment entities.

The structural similarities between the source and the target substances and the similarities in their breakdown products presented above support the read-across hypothesis. Adequate, reliable and available scientific information indicates that the source and target substances and their subsequent degradation product have similar toxicity profiles.
Based on the considerations above, it can be concluded that the results of the skin and eye irritation studies conducted with the source substance is likely to predict the properties of the target substance and are considered as adequate to fulfil the information requirements of Annex VII and VIII, 8.1 and 8.2.
No classification and labelling criteria with regard to the information requirements of Annex VII and VIII, 8.1 and 8.2. are fulfilled by the source or target substance.

Reason / purpose for cross-reference:

read-across source

Qualifier:

according to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

Version / remarks:

adopted 2002-04-24

Deviations:

no

Irritation parameter:

erythema score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0

Max. score:

4

Irritation parameter:

edema score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0

Max. score:

4

Irritation parameter:

erythema score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0

Max. score:

4

Irritation parameter:

edema score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0

Max. score:

4

Irritation parameter:

erythema score

Basis:

animal #3

Time point:

24/48/72 h

Score:

0

Max. score:

4

Irritation parameter:

edema score

Basis:

animal #3

Time point:

24/48/72 h

Score:

0

Max. score:

4

Irritant / corrosive response data:

None of the three rabbits exposed for 4 hours to 0.5 mL zinc neodecanoate/animal showed any skin reactions.

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 substance is not irritating to the skin.
According to the EC-Commission directive 67/548/EEC and its subsequent amendments, the test substance is not irritating to the skin.
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

Reference

Reference 1

Endpoint:

eye irritation: in vitro / ex vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2012-10-19

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 437 (Bovine Corneal Opacity and Permeability Test Method for Identifying Ocular Corrosives and Severe Irritants)

Version / remarks:

adopted 2009-09-07

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU method B.47 (Bovine corneal opacity and permeability test method for identifying ocular corrosives and severe irritants)

Version / remarks:

, 2010

Deviations:

no

Qualifier:

according to guideline

Guideline:

other: Bovine Corneal Opacity and Permeability (BCOP) Assay, SOP of Microbiological Associates Ltd., UK, Procedure Details, April 1997

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Remarks:

signed 2009-03-30

Details on test animals or tissues and environmental conditions:

Not applicable - Since this is an in vitro study there is no information on test animals.

Vehicle:

unchanged (no vehicle)

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.75 mL

Duration of treatment / exposure:

10 minutes

Observation period (in vivo):

not applicable

Number of animals or in vitro replicates:

not applicable

Details on study design:

COLLECTION OF BOVINE EYES
Freshly isolated bovine eyes from at least 9 month old donor cattle were collected from the abattoir. Excess tissue was removed from the excised eyes. The isolated eyes were transported to the laboratory in Hank’s BSS supplemented with streptomycin / penicillin at ambient temperature. The corneae were isolated on the same day after delivery of the eyes, inserted in pre-cooled preservation medium composed of Medium 199 supplemented with Lglutamine, Na-bicarbonate and Taurine. Shortly before use, Dextran was added to the medium.

PREPARATION OF CORNEAE
All eyes were carefully examined macroscopically for defects. Those presenting defects such as vascularization, pigmentation, opacity and scratches were discarded. The cornea was carefully removed from the eye using scalpel and rounded scissors.
Each isolated cornea was mounted in a specially designed cornea holder according to the description given in OECD guideline 437, annex III, that consists of anterior and posterior compartments, which interface with the epithelial and endothelial sides of the cornea, respectively. The endothelial side of the cornea was positioned against the sealing ring (Oring) of the posterior part of the holder. The cornea was gently flattened over the O-ring but stretching was avoided. After the anterior part of the holder was positioned on top of the cornea and fixed in place with screws, both compartments of the holder were filled with complete medium. The posterior compartment was filled first to return the cornea to its natural convex position. Care was taken to assure no air bubbles were present within the compartments.
For equilibration, the corneae in the holder were incubated in a vertical position for one hour at 32 ± 1 °C in a water-bath.
At the end of the incubation period, the basal opacity was determined (t0).

OUTLINE OF STUDY
The anterior compartment received the test item or negative control (0.9% (w/v) NaCl in deionised water (produced in-house, lot. no. 240912)) or positive control (2-Ethoxyethanol (Sigma, 82024 Taufkirchen, Germany, lot no. BCBD1053V)) at a volume of 0.75 mL on the surface of the corneae and was incubated at 32 ± 1 °C in the water-bath, while the corneae were in a horizontal position. The test item, positive control and negatice control were tested in triplicate.
The incubation time lasted ten minutes.
After the test item or control items, respectively, were rinsed off from the application side with 0.9% (w/v) NaCl in deionised water, fresh cMEM was added into the anterior compartment. The corneae were then incubated at 32 ± 1 °C for further two hours in a vertical position, followed by a 2nd opacity reading (t130).
In the second step of the assay, permeability of the cornea was determined. 1 mL of a Na-fluorescein solution, 0.5 % (w/v) dissolved in HBSS (Hank’s buffered salt solution), was placed in the anterior compartment. Corneae were incubated again in a horizontal position for an additional 90 minutes at 32 ± 1 °C in the water-bath. The optical density of an aliquot of the mixed complete medium from the posterior chamber was measured spectrophotometrically at 490 nm (OD490).

OPACITY MEASUREMENT
The basal opacity of all corneae was recorded (t0). Each corneae with a value of the basal opacity > 7 was discarded. Sets of three corneae were used for treatment with the test items and the negative and positive controls. The opacity was measured again after treatment with the test item, positive control and negative control followed by two hours incubation (t130).

PERMEABILITY DETERMINATION
After the final opacity measurement was performed, the complete medium was removed from the anterior compartment and replaced by 1 mL of a 0.5% (w/v) sodium fluorescein solution in HBSS. Corneae were incubated again in a horizontal position for 90 minutes in a water-bath at 32 ± 1 °C. Complete medium from the posterior compartment was removed, well mixed and the optical density at 490 nm (OD490) was determined with a spectrophotometer.

CRITERIA FOR DETERMINATION OF A VALID TEST
The test was acceptable if the in vitro irritation score of the positive control was ≥ 30 and the in vitro irritation score of the negative control was ≤ 3.

EVALUATION OF RESULTS
- Opacity: the change of opacity value of each treated cornea or positive and negative control corneae was calculated by subtracting the initial basal opacity from the post treatment opacity reading (t130 – t0), for each individual cornea. The average change in opacity of the negative control corneae was calculated and this value was subtracted from the change in opacity of each treated cornea or positive control to obtain a corrected opacity.
- Permeability: the corrected OD490 value of each cornea treated with positive control and test item was calculated by subtracting the average negative control cornea value from the original permeability value for each cornea.

IN VITRO IRRITATION SCORE CALCULATION
The following formula was used to determine the in vitro irritation score of the negative control:
In vitro Irritation Score = opacity value + (15 x OD490 value)
The following formula was used to determine the in vitro irritation score of the positive control and the test item:
In vitro Irritation Score = (opacity value – opacity value mean negative control) + (15 x corrected OD490 value)
The in vitro irritation score was calculated for each individual treatment and positive control cornea. The mean in vitro irritation score value of each treated group was calculated from the individual in vitro irritation score values.
Depending on the score obtained, the test item was classified into the following category according to OECD guideline 437 (table 1 in the field "Any other information on materials and methods incl. tables" below).

Irritation parameter:

in vitro irritation score

Run / experiment:

mean: 10 minutes

Value:

5.25

Irritant / corrosive response data:

Relative to the negative control, the test item zinc neodecanoate caused a slight increase of the corneal opacity. Permeability effects were not observed. The calculated mean in vitro irritation score was 5.25 (threshold for corrosivity / severe irritancy: ≥ 55.1). According to OECD 437 the test item is classified as not corrosive / not severe irritant to the eye.

Table 1: Results after 10 minutes incubation time

Test group	Opacity value = Difference (t130 – t0) of opacity		Permeability at 490 nm (OD490)		In vitro irritation score	Mean in vitro irritation score	Proposed in vitro irritation scale
		Mean		Mean
Negative control	1	1.00	0.092	0.101	2.38	2.51	Non corrosive / non severe irritant
	1		0.107		2.61
	1		0.103		2.55
Positive control	70.00*		0.339*		75.09	75.37	Corrosive / severe irritant
	66.00*		0.386*		71.80
	68.00*		0.747*		79.21
Zinc neodecanoate	7.00*		0.005*		7.08	5.25	Non corrosive / non severe irritant
	6.00*		-0.017*		5.75
	3.00*		-0.006*		2.92

* corrected values

- With the negative control neither an increase of opacity nor permeability of the corneae could be observed (mean in vitro irritation score 2.51).

- The positive control (2-Ethoxyethanol) showed clear opacity and distinctive permeability of the corneae (mean in vitro irritation score 75.37) corresponding to a classification as corrosive / severe irritant to the eye (CLP/EPA/GHS (Cat 1)).

Table 2: Historical data

	Positive control	Negative control
Mean in vitro Irritation Score	72.88	1.08
Standard Deviation	20.11	0.81
Range of in vitro irritation scores	46.48 - 116.40	0.00 - 2.80

Values of 168 studies with liquid test items performed until November 2012

Interpretation of results:

other: not corrosive/not severe irritant to the eye

Remarks:

Criteria used for interpretation of results: EU

Conclusions:

In conclusion, according to the current study and under the experimental conditions reported, the test item zinc neodecanoate is not corrosive to the eye (CLP/EPA/GHS (Cat 1)).

Reference 2

Endpoint:

eye irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2012-11-26 to 2012-12-11

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 2002-04-24

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Remarks:

date of inspection: 2012-07-10

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

TEST ANIMALS - New Zealand White (Hsdlf:NZW) strain rabbits
- Source: Harlan Laboratories UK Ltd., Leicestershire, UK
- Age at study initiation: twelve to twenty weeks old
- Weight at study initiation: 2.17 or 2.40 kg
- Housing: the animals were individually housed in suspended cages.
- Diet (ad libitum): 2930C Teklad Global Certified Rabbit diet supplied by Harlan Laboratories UK Ltd., Oxon, UK)
- Water (ad libitum): mains drinking water
- Acclimation period: at least five days

The animals were provided with environmental enrichment items which were considered not to contain any contaminant of a level that might have affected the purpose or integrity of the study.

ENVIRONMENTAL CONDITIONS
- Temperature: 17 to 23°C
- Relative humidity: 30 to 70%
- Air exchange: at least fifteen changes per hour
- 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): a volume of 0.1 ml of the test item was placed into the conjunctival sac of the right eye, formed by gently pulling the lower lid away from the eyeball. The upper and lower eyelids were held together for about one second immediately after treatment, to prevent loss of the test item, and then released. The left eye remained untreated and was used for control purposes.

Duration of treatment / exposure:

not applicable

Observation period (in vivo):

Approximately 1 hour and 24, 48 and 72 hours following treatment as well as on Day 7

Number of animals or in vitro replicates:

2 male rabbits

Details on study design:

Immediately before the start of the test, both eyes of the provisionally selected test rabbits were examined for evidence of ocular irritation or defect with the aid of a light source from a standard ophthalmoscope. Only animals free of ocular damage were used.

INITIAL AND CONFIRMATORY TEST
Initially, a single rabbit was treated. Immediately after administration of the test item, an assessment of the initial pain reaction was made according to the six point scale (please refer to table 2 in the field "Any other information on materials and methods incl. tables" below).
After consideration of the ocular responses produced in the first treated animal, a second animal was treated.

SCORING SYSTEM: according to the Draize scale
Any other ocular effects were also noted.
Any clinical signs of toxicity, if present, were also recorded.
Individual bodyweights were recorded on Day 0 (the day of dosing) and at the end of the observation period.
If evidence of irreversible ocular damage is noted, the test item will be classified as corrosive to the eye.

TOOL USED TO ASSESS SCORE: examination of the eye was facilitated by the use of the light source from a standard ophthalmoscope.

Irritation parameter:

cornea opacity score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0

Max. score:

4

Remarks on result:

other: Initial pain reaction: slight initial pain was observed; Moderate discharge was observed at the 1 hour observation and slight discharge was observed at the 24 hour observation.

Irritation parameter:

iris score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0

Max. score:

2

Irritation parameter:

conjunctivae score

Basis:

animal #1

Time point:

24/48/72 h

Score:

1.67

Max. score:

3

Reversibility:

fully reversible within: 7 days

Remarks on result:

other: Moderate conjunctival redness was observed at the 1 hour observation.

Irritation parameter:

chemosis score

Basis:

animal #1

Time point:

24/48/72 h

Score:

1.67

Max. score:

4

Reversibility:

fully reversible within: 7 days

Remarks on result:

other: Moderate chemosis was observed at the 1 hour observation.

Irritation parameter:

cornea opacity score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0

Max. score:

4

Remarks on result:

other: Initial pain reaction: slight initial pain was observed; Moderate discharge was observed at the 1 hour observation and slight discharge was observed at the 24, 48 and 72 hour observations.

Irritation parameter:

iris score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0.67

Max. score:

2

Reversibility:

fully reversible within: 72 hours

Remarks on result:

other: Iridial inflammation was observed at the 1 hour observation.

Irritation parameter:

conjunctivae score

Basis:

animal #2

Time point:

24/48/72 h

Score:

1.33

Max. score:

3

Reversibility:

fully reversible within: 7 days

Remarks on result:

other: Moderate conjunctival redness was observed at the 1 hour observation.

Irritation parameter:

chemosis score

Basis:

animal #2

Time point:

24/48/72 h

Score:

1.33

Max. score:

4

Reversibility:

fully reversible within: 7 days

Remarks on result:

other: Moderate chemosis was observed at the 1 hour observation.

Irritant / corrosive response data:

No corneal effects were noted during the study.
Iridial inflammation was noted in one treated eye one hour after treatment and at the 24 and 48-hour observations.
Moderate conjunctival irritation was noted in all treated eyes one and 24 hours after treatment. Moderate conjunctival irritation persisted in one treated eye with minimal conjunctival irritation noted in the other treated eye at the 48-hour observation. Minimal conjunctival irritation was noted in both treated eyes at the 72-hour observation.
Both treated eyes appeared normal at the 7-Day observation.

Other effects:

- Bodyweight: both animals showed expected gain in bodyweight during the study.

Interpretation of results:

not irritating

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

The test material is not 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.

Reference 3

Endpoint:

eye irritation: in vitro / ex vivo

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Justification for type of information:

REPORTING FORMAT FOR THE ANALOGUE APPROACH
This read-across is based on the hypothesis that source and target substances have similar toxicological properties because they hydrolyse to common products.

This prediction is supported by toxicological data on the substances themselves and on the dissolution products of the substances.
Target and source substances are UVCB substances, the UVCB character is derived from the educt of the production process of that substances, namely neodecanoic acid. Both substances differ only in the production process, resulting in (i) an neutral product and (ii) a basic product.

The target substance is the overbased product containing a slightly higher zinc content. The dissolution product, namely the zinc cation, is not the driver for toxic effects.
Consequently, the target substance is identical to the source substance and share a structural similarity with common functional groups, carboxylic acid, alkyl side chains.

Therefore, read-across from the existing skin and eye irritation studies on the source substance is considered as an appropriate adaption to the standard information requirements of Annex VII and VIII, 8.1 and 8.2 of the REACH Regulation for the target substance, in accordance with the provisions of Annex XI, 1.5 of the REACH Regulation.

The justification of the proposed read-across approach is elaborated in the next chapters. Please find this information in the attachements as well.


1. HYPOTHESIS FOR THE ANALOGUE APPROACH
This read-across is based on the hypothesis that source and target substances have similar toxicological properties because they hydrolyse to common products.
This prediction is supported by toxicological data on the substances themselves and on the dissolution products of the substances.
Target and source substances are UVCB substances, the UVCB character is derived from the educt of the production process of that substances, namely neodecanoic acid. Both substances differ only in the production process, resulting in (i) an neutral product and (ii) a basic product.
The target substance is the overbased product containing a slightly higher zinc content. The dissolution product, namely the zinc cation, is not the driver for toxic effects.
Consequently, the target substance is identical to the source substance and share a structural similarity with common functional groups, carboxylic acid, alkyl side chains.
Therefore, read-across from the existing skin and eye irritation studies on the source substance is considered as an appropriate adaption to the standard information requirements of Annex VII and VIII, 8.1 and 8.2 of the REACH Regulation for the target substance, in accordance with the provisions of Annex XI, 1.5 of the REACH Regulation.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
a) Target substance
The target substance zinc neodecanoate, basic is a UVCB substance (EC: 282-780-4, CAS: 84418-68-8).
b) Source substance
The source substance zinc neodecanoat is a UVCB substance (EC: 248-370-4, CAS: 27253-29-8).
c) Purity and impurities
Both substances are UVCB substances, thus specification of impurity profiles is not applicable. Additionally, the source substance is derived from the same educts in the production process. Consequently, the hazard profile of the target substance is intrinsically covered.


3. ANALOGUE APPROACH JUSTIFICATION
a) Structural similarity and functional groups
The structure of the target and source substances are the same, namely a neodecanoic acid, zinc salt. The target substance is the overbased product containing a slightly higher zinc content. The dissolution product, namely the zinc cation, is not the driver for toxic effects with regard to Human Health and especially to local effects.
b) Common breakdown products
The common characteristic of the target substance and the source substance is that both liberate the same moiety upon dissolution in aqueous media. Zinc cations and neodecanoate is formed upon dissolution under toxicological relevant conditions such as body fluids and in the environment.


4. DATA MATRIX
A comparison of the experimental toxicological data between the source and target substance is not applicable in the applied approach, since the overall ecotoxicity/systemic toxicity of the target substance is assessed by taking the (eco-)toxicological profile of the zinc cation and the acid anion (neodecanoate) into account. An endpoint-specific description is provided in the respective endpoint summaries of both assessment entities.

The structural similarities between the source and the target substances and the similarities in their breakdown products presented above support the read-across hypothesis. Adequate, reliable and available scientific information indicates that the source and target substances and their subsequent degradation product have similar toxicity profiles.
Based on the considerations above, it can be concluded that the results of the skin and eye irritation studies conducted with the source substance is likely to predict the properties of the target substance and are considered as adequate to fulfil the information requirements of Annex VII and VIII, 8.1 and 8.2.
No classification and labelling criteria with regard to the information requirements of Annex VII and VIII, 8.1 and 8.2. are fulfilled by the source or target substance.

Reason / purpose for cross-reference:

read-across source

Qualifier:

according to guideline

Guideline:

OECD Guideline 437 (Bovine Corneal Opacity and Permeability Test Method for Identifying Ocular Corrosives and Severe Irritants)

Version / remarks:

adopted 2009-09-07

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU method B.47 (Bovine corneal opacity and permeability test method for identifying ocular corrosives and severe irritants)

Version / remarks:

, 2010

Deviations:

no

Qualifier:

according to guideline

Guideline:

other: Bovine Corneal Opacity and Permeability (BCOP) Assay, SOP of Microbiological Associates Ltd., UK, Procedure Details, April 1997

Deviations:

no

Irritation parameter:

in vitro irritation score

Run / experiment:

mean: 10 minutes

Value:

5.25

Irritant / corrosive response data:

Relative to the negative control, the test item zinc neodecanoate caused a slight increase of the corneal opacity. Permeability effects were not observed. The calculated mean in vitro irritation score was 5.25 (threshold for corrosivity / severe irritancy: ≥ 55.1). According to OECD 437 the test item is classified as not corrosive / not severe irritant to the eye.

Table 1: Results after 10 minutes incubation time

Test group	Opacity value = Difference (t130 – t0) of opacity		Permeability at 490 nm (OD490)		In vitro irritation score	Mean in vitro irritation score	Proposed in vitro irritation scale
		Mean		Mean
Negative control	1	1.00	0.092	0.101	2.38	2.51	Non corrosive / non severe irritant
	1		0.107		2.61
	1		0.103		2.55
Positive control	70.00*		0.339*		75.09	75.37	Corrosive / severe irritant
	66.00*		0.386*		71.80
	68.00*		0.747*		79.21
Zinc neodecanoate	7.00*		0.005*		7.08	5.25	Non corrosive / non severe irritant
	6.00*		-0.017*		5.75
	3.00*		-0.006*		2.92

* corrected values

- With the negative control neither an increase of opacity nor permeability of the corneae could be observed (mean in vitro irritation score 2.51).

- The positive control (2-Ethoxyethanol) showed clear opacity and distinctive permeability of the corneae (mean in vitro irritation score 75.37) corresponding to a classification as corrosive / severe irritant to the eye (CLP/EPA/GHS (Cat 1)).

Table 2: Historical data

	Positive control	Negative control
Mean in vitro Irritation Score	72.88	1.08
Standard Deviation	20.11	0.81
Range of in vitro irritation scores	46.48 - 116.40	0.00 - 2.80

Values of 168 studies with liquid test items performed until November 2012

Interpretation of results:

other: not corrosive/not severe irritant to the eye

Remarks:

Criteria used for interpretation of results: EU

Conclusions:

In conclusion, according to the current study and under the experimental conditions reported, the test item zinc neodecanoate is not corrosive to the eye (CLP/EPA/GHS (Cat 1)).

Reference 4

Endpoint:

eye irritation: in vivo

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Justification for type of information:

REPORTING FORMAT FOR THE ANALOGUE APPROACH
This read-across is based on the hypothesis that source and target substances have similar toxicological properties because they hydrolyse to common products.

This prediction is supported by toxicological data on the substances themselves and on the dissolution products of the substances.
Target and source substances are UVCB substances, the UVCB character is derived from the educt of the production process of that substances, namely neodecanoic acid. Both substances differ only in the production process, resulting in (i) an neutral product and (ii) a basic product.

The target substance is the overbased product containing a slightly higher zinc content. The dissolution product, namely the zinc cation, is not the driver for toxic effects.
Consequently, the target substance is identical to the source substance and share a structural similarity with common functional groups, carboxylic acid, alkyl side chains.

Therefore, read-across from the existing skin and eye irritation studies on the source substance is considered as an appropriate adaption to the standard information requirements of Annex VII and VIII, 8.1 and 8.2 of the REACH Regulation for the target substance, in accordance with the provisions of Annex XI, 1.5 of the REACH Regulation.

The justification of the proposed read-across approach is elaborated in the next chapters. Please find this information in the attachements as well.


1. HYPOTHESIS FOR THE ANALOGUE APPROACH
This read-across is based on the hypothesis that source and target substances have similar toxicological properties because they hydrolyse to common products.
This prediction is supported by toxicological data on the substances themselves and on the dissolution products of the substances.
Target and source substances are UVCB substances, the UVCB character is derived from the educt of the production process of that substances, namely neodecanoic acid. Both substances differ only in the production process, resulting in (i) an neutral product and (ii) a basic product.
The target substance is the overbased product containing a slightly higher zinc content. The dissolution product, namely the zinc cation, is not the driver for toxic effects.
Consequently, the target substance is identical to the source substance and share a structural similarity with common functional groups, carboxylic acid, alkyl side chains.
Therefore, read-across from the existing skin and eye irritation studies on the source substance is considered as an appropriate adaption to the standard information requirements of Annex VII and VIII, 8.1 and 8.2 of the REACH Regulation for the target substance, in accordance with the provisions of Annex XI, 1.5 of the REACH Regulation.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
a) Target substance
The target substance zinc neodecanoate, basic is a UVCB substance (EC: 282-780-4, CAS: 84418-68-8).
b) Source substance
The source substance zinc neodecanoat is a UVCB substance (EC: 248-370-4, CAS: 27253-29-8).
c) Purity and impurities
Both substances are UVCB substances, thus specification of impurity profiles is not applicable. Additionally, the source substance is derived from the same educts in the production process. Consequently, the hazard profile of the target substance is intrinsically covered.


3. ANALOGUE APPROACH JUSTIFICATION
a) Structural similarity and functional groups
The structure of the target and source substances are the same, namely a neodecanoic acid, zinc salt. The target substance is the overbased product containing a slightly higher zinc content. The dissolution product, namely the zinc cation, is not the driver for toxic effects with regard to Human Health and especially to local effects.
b) Common breakdown products
The common characteristic of the target substance and the source substance is that both liberate the same moiety upon dissolution in aqueous media. Zinc cations and neodecanoate is formed upon dissolution under toxicological relevant conditions such as body fluids and in the environment.


4. DATA MATRIX
A comparison of the experimental toxicological data between the source and target substance is not applicable in the applied approach, since the overall ecotoxicity/systemic toxicity of the target substance is assessed by taking the (eco-)toxicological profile of the zinc cation and the acid anion (neodecanoate) into account. An endpoint-specific description is provided in the respective endpoint summaries of both assessment entities.

The structural similarities between the source and the target substances and the similarities in their breakdown products presented above support the read-across hypothesis. Adequate, reliable and available scientific information indicates that the source and target substances and their subsequent degradation product have similar toxicity profiles.
Based on the considerations above, it can be concluded that the results of the skin and eye irritation studies conducted with the source substance is likely to predict the properties of the target substance and are considered as adequate to fulfil the information requirements of Annex VII and VIII, 8.1 and 8.2.
No classification and labelling criteria with regard to the information requirements of Annex VII and VIII, 8.1 and 8.2. are fulfilled by the source or target substance.

Reason / purpose for cross-reference:

read-across source

Qualifier:

according to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

Version / remarks:

adopted 2002-04-24

Deviations:

no

Irritation parameter:

cornea opacity score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0

Max. score:

4

Remarks on result:

other: Initial pain reaction: slight initial pain was observed; Moderate discharge was observed at the 1 hour observation and slight discharge was observed at the 24 hour observation.

Irritation parameter:

iris score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0

Max. score:

2

Irritation parameter:

conjunctivae score

Basis:

animal #1

Time point:

24/48/72 h

Score:

1.67

Max. score:

3

Reversibility:

fully reversible within: 7 days

Remarks on result:

other: Moderate conjunctival redness was observed at the 1 hour observation.

Irritation parameter:

chemosis score

Basis:

animal #1

Time point:

24/48/72 h

Score:

1.67

Max. score:

4

Reversibility:

fully reversible within: 7 days

Remarks on result:

other: Moderate chemosis was observed at the 1 hour observation.

Irritation parameter:

cornea opacity score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0

Max. score:

4

Remarks on result:

other: Initial pain reaction: slight initial pain was observed; Moderate discharge was observed at the 1 hour observation and slight discharge was observed at the 24, 48 and 72 hour observations.

Irritation parameter:

iris score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0.67

Max. score:

2

Reversibility:

fully reversible within: 72 hours

Remarks on result:

other: Iridial inflammation was observed at the 1 hour observation.

Irritation parameter:

conjunctivae score

Basis:

animal #2

Time point:

24/48/72 h

Score:

1.33

Max. score:

3

Reversibility:

fully reversible within: 7 days

Remarks on result:

other: Moderate conjunctival redness was observed at the 1 hour observation.

Irritation parameter:

chemosis score

Basis:

animal #2

Time point:

24/48/72 h

Score:

1.33

Max. score:

4

Reversibility:

fully reversible within: 7 days

Remarks on result:

other: Moderate chemosis was observed at the 1 hour observation.

Irritant / corrosive response data:

No corneal effects were noted during the study.
Iridial inflammation was noted in one treated eye one hour after treatment and at the 24 and 48-hour observations.
Moderate conjunctival irritation was noted in all treated eyes one and 24 hours after treatment. Moderate conjunctival irritation persisted in one treated eye with minimal conjunctival irritation noted in the other treated eye at the 48-hour observation. Minimal conjunctival irritation was noted in both treated eyes at the 72-hour observation.
Both treated eyes appeared normal at the 7-Day observation.

Other effects:

- Bodyweight: both animals showed expected gain in bodyweight during the study.

Interpretation of results:

not irritating

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

The test material is not 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 conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Additional information

Skin irritation

One reliable in vivo study described by Hansen (2013)(OECD 404; GLP compliant) is considered to be reliable without restrictions.The substance was determined not to be irritating to the skin.

Eye irritation

One reliable in vivo study described by Sanders (2013) (OECD 405; GLP compliant) is considered to be reliable without restrictions. The substance was determined to be not irritating to the eye.

Furthermore, a reliable in vitro study described by Heppenheimer (2012)(OECD 437; GLP compiant) is considered to be reliable without restrictions. The substance was determined not to be corrosive nor severely irritating to the eyes.

Justification for classification or non-classification

Skin irritation

Reference Hansen (2013) is considered as the key study for in vivo skin irritation and will be used for classification. The skin irritation was scored according to the Draize scale. The mean score (24, 48, 72 h) for erythema and oedema for all three animals were as follows:

Erythema: 0 for all animals

Oedema: 0 for all animals

Thus, according to Regulation (EC) 1272/2008 and subsequent amendments the substance will not be classified as irritating to the skin.Furthermore, the substance has not to be classified as skin irritant according toDirective 67/548 EC.

Eye irritation

Reference Sanders (2013) is considered as the key study for in vivo eye irritation and will be used for classification. During the study the test item was applied to one eye of two animals each and the eye irritation was scored according to the Draize scale. The following mean scores (24, 48 and 72 hours) were obtained for the two animals:

cornea: 0 for both animals

iris: 0 and 0.67

conjunctival redness: 1.67 and 1.33

chemosis: 1.67 and 1.33

The ocular effects were fully reversible within 7 days. Thus, according to Regulation (EC) 1272/2008 and subsequent amendments the substance will not be classified as irritating to the eyes. Furthermore, the substance has not to be classified as eye irritant according to Directive 67/548 EC.