Sodium (3-hydroxy-2-pentylcyclopentyl)acetate

Endpoint summary

Description of key information

- not irritating to the skin, rabbit, OECD 404

- irreversible effects on the eyes (Category 1), rabbit, OECD 405

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records

Reference

Endpoint:

skin irritation / corrosion, other

Remarks:

skin irritation : in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2008-11-25 to 2009-05-15

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

Version / remarks:

as at 2002

Qualifier:

according to guideline

Guideline:

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

Version / remarks:

as at 2004

GLP compliance:

yes

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

TEST ANIMALS- Source: Grimaud Frères Sélection S.A.S., La Corbière, Roussay, France- Age at study initiation: 2 to 4 months- Weight at study initiation: 2.5 ± 0.2 kg- Housing: individually in Pajon cages (50 cm x 57 cm x 75 cm)- Diet (e.g. ad libitum): ad libitum, Control Ref.: 110 pelleted diet (SAFE, Augy, France)- Water (e.g. ad libitum): ad libitum, drinking water filtered by a FG Millipore membrane (0.22 micron)- Acclimation period: at least 5 dENVIRONMENTAL CONDITIONS- Temperature (°C): 18 ± 3- Humidity (%): 30 to 70- Air changes (per hr): ca. 12- 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): 0.5 mL- Concentration (if solution): 100 % of the mixture defined under "Details on test material" VEHICLE- Amount(s) applied (volume or weight with unit):- Concentration (if solution):- Lot/batch no. (if required):- Purity:

Duration of treatment / exposure:

- anterior left flank: application for 3 min- anterior right flank: application for 1 h- posterior right flank: application for 4 h

Observation period:

3 min, 1 hour, 24, 48 and 72 hours, study ended on day 4 in the absence of persistent irritation reactions.

Number of animals:

3

Details on study design:

TEST SITE- Area of exposure: - anterior left flank: application for 3 min (sentinel animal) - anterior right flank: application for 1 h (sentinel animal) - posterior right flank: application for 4 h (sentinel animal + 2 animals for confirmatory testing)- % coverage: 6 cm²- Type of wrap if used: dry gauze pad, held in contact with the skin by means of an adhesive hypoallergenic aerated semi-occlusive dressing and a restraining bandageREMOVAL OF TEST SUBSTANCE- Washing (if done): wiped off by means of a dry cotton pad- Time after start of exposure: - anterior left flank: after the application for 3 min (sentinel animal) - anterior right flank: after the application for 1 h (sentinel animal) - posterior right flank: after the application for 4 h (sentinel animal + 2 animals for confirmatory testing)SCORING SYSTEM:Draize scoring systemErythema and eschar formation:. no erythema........................................................................................................... 0. very slight erythema (barely perceptible) ............................................................. 1. well-defined erythema........................................................................................... 2. moderate to severe erythema................................................................................. 3. severe erythema (beet redness) to slight eschar formation (injuries in depth)...... 4Edema formation. no edema ............................................................................................................... 0. very slight edema (barely perceptible).................................................................. 1. slight edema (edges of area well-defined by definite raising) .............................. 2. moderate edema (raised approximately 1 millimeter) .......................................... 3. severe edema (raised more than 1 millimeter and extending beyond areaof exposure)........................................................................................................... 4Any other lesions were noted.

Irritation parameter:

erythema score

Basis:

animal #1

Time point:

other: 3 min

Score:

1

Max. score:

4

Reversibility:

fully reversible within: 24 h

Remarks on result:

other: 3 min exposure

Irritation parameter:

erythema score

Basis:

animal #1

Time point:

other: 1 h

Score:

1

Max. score:

4

Reversibility:

fully reversible within: 24 h

Remarks on result:

other: 1 h exposure

Irritation parameter:

erythema score

Basis:

mean

Time point:

other: 1 h

Score:

1

Max. score:

4

Reversibility:

fully reversible within: 48 h

Remarks on result:

other: 4 h exposure

Irritation parameter:

erythema score

Basis:

mean

Time point:

other: 24 h

Score:

0.33

Max. score:

4

Reversibility:

fully reversible within: 48

Remarks on result:

other: 4 h exposure

Irritation parameter:

erythema score

Basis:

mean

Time point:

other: 48

Score:

0

Max. score:

4

Remarks on result:

other: 4 h exposure

Irritation parameter:

erythema score

Basis:

mean

Time point:

other: 72 h

Score:

0

Max. score:

4

Remarks on result:

other: 4 h exposure

Irritation parameter:

edema score

Basis:

mean

Time point:

other: 3 min, 1 h, 4h, 24 h, 48 h, 72 h

Score:

0

Max. score:

4

Remarks on result:

other: No edema seen in any animal at any time point.

Irritant / corrosive response data:

After a 3-minute or 1-hour exposure (one animal):- a very slight erythema on day 1After a 4-hour exposure (three animals):- a very slight erythema in all animals on day 1, persisting in one of them on day 2- mean scores over 24, 48 and 72 hours for each animal - erythema: 0.0, 0.0 and 0.3 - edema: 0.0, 0.0 and 0.0

Other effects:

No other effects noted.

- Table 1:  Individual cutaneous examinations and mean values of the scores recorded for each animal

Rabbit number	Dermal Irritation			Scores		Mean irritation	Interpretation (+) (-)
		1h D1	24h, D2	48h, D3	72h, D4	score (1)
3-minute exposure - Cutaneous examinations and mean values of the scores recorded for the first animal (24, 48 and 72 hours)
750	Erythema	1	0	0	0	0.0
	Edema	0	0	0	0	0.0
	Other	*	*	*	*
1-hour exposure - Cutaneous examinations and mean values of the scores recorded for the first animal (24, 48 and 72 hours)
750	Erythema	1	0	0	0	0.0
	Edema	0	0	0	0	0.0
	Other	*	*	*	*
4-hour exposure - Individual cutaneous examinations and mean values of the scores recorded for each animal (24, 48 and 72 hours)
750	Erythema	1	0	0	0	0.0	(-)
	Edema	0	0	0	0	0.0	(-)
	Other	*	*	*	*
711	Erythema	1	0	0	0	0.0	(-)
	Edema	0	0	0	0	0.0	(-)
	Other	*	*	*	*
712	Erythema	1	1	0	0	0.3	(-)
	Edema	0	0	0	0	0.0	(-)
	Other	*	*	*	*

(1) mean of scores on days 2, 3 and 4 h = hour

D = day

(+) = irritant according to E.E.C. criteria

(-) = non-irritant according to E.E.C. criteria

* = none

Interpretation of results:

not irritating

Remarks:

Migrated informationCriteria used for interpretation of results: EU

Conclusions:

The potential of the test item R0034833C (batch No. R0034833C 027 P 001) to induce skin irritation was evaluated in rabbits according to OECD (No. 404, 24th April 2002) and EC (2004/73/EC, B.4, 29th April 2004) guidelines and GLP.Under the experimental conditions of this study, the test item R0034833C (batch No. R0034833C 027 P 001) was well-tolerated when applied topically to rabbits.

Executive summary:

The potential of the test item Mexoryl SBO (termed R0034833C in the study report, batch No. R0034833C 027 P 001) to induce skin irritation was evaluated in rabbits according to OECD (No. 404, 24th April 2002) and EC (2004/73/EC, B.4, 29th April 2004) guidelines . The study was conducted in compliance with the principles of Good Laboratory Practice Regulations.

The test item was first applied for periods of 3 minutes, 1 hour and 4 hours to a single male New Zealand White rabbit. Since the test item was neither severely irritant nor corrosive on this first animal, it was then applied simultaneously for 4 hours to two other animals. A single dose of 0.5 mL of the undiluted test item was applied to the closely-clipped skin of one flank. The test item was held in contact with the skin by means of a semi-occlusive dressing. Cutaneous reactions were observed approximately 1 hour, 24, 48 and 72 hours after removal of the dressing.

The mean values of the scores for erythema and edema were calculated for each animal. The interpretation of results was carried out according to the classification criteria laid down in Council Directive 67/548/EEC (and subsequent adaptations).

After a 3-minute or 1-hour exposure (one animal) a very slight erythema was noted on day 1. After a 4-hour exposure (three animals) a very slight erythema was noted in all animals on day 1, persisting in one of them on day 2. Mean scores over 24, 48 and 72 hours for each animal were 0.0, 0.0 and 0.3 for erythema and 0.0,

0.0 and 0.0 for edema.

Under the experimental conditions of this study, the test item R0034833C (batch No. R0034833C 027 P 001) was well-tolerated when applied topically to rabbits.

According to the classification criteria laid down in Council Directive 67/548/EEC (and subsequent adaptations) and CLP as implementation of UN GHS in the EU (REGULATION (EC) No 1272/2008 OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL, the test item should not be classified as irritating to the skin.

 

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Eye irritation

Link to relevant study records

Reference

Endpoint:

eye irritation, other

Remarks:

eye irritation : in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2008-12-03 to 2009-11-03

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: OECD guideline compliantGLP compliant

Qualifier:

according to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

Version / remarks:

as at 2002

Qualifier:

according to guideline

Guideline:

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

Version / remarks:

as at 2004

GLP compliance:

yes

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

TEST ANIMALS- Source: Grimaud Frères Sélection S.A.S., La Corbière, Roussay, France- Age at study initiation: 2 to 4 months- Weight at study initiation: 2.9 ± 0.3 kg- Housing: individually in Pajon cages (50 cm x 57 cm x 75 cm)- Diet (e.g. ad libitum): ad libitum, Control Ref.: 110 pelleted diet (SAFE, Augy, France)- Water (e.g. ad libitum): ad libitum, drinking water filtered by a FG Millipore membrane (0.22 micron)- Acclimation period: at least 5 dENVIRONMENTAL CONDITIONS- Temperature (°C): 18 ± 3- Humidity (%): 30 to 70- Air changes (per hr): ca. 12- Photoperiod (hrs dark / hrs light): 12/12

Vehicle:

other: two paralled experiments: unchanged and with purified water (prepared at CIT by reverse osmosis) as vehicle

Controls:

no

Amount / concentration applied:

TEST MATERIAL- Amount(s) applied (volume or weight with unit): 0.1 mL in both experiments- Concentration (if solution): - experiment 1: undiluted test item as described under "Details on test materials" - experiment 2: 10 % (w/w) of the test item as described under "Details on test materials"VEHICLE- Amount(s) applied (volume or weight with unit): ca. 0.9 mL- Concentration (if solution): 10 % (w/w) of the test item in the vehicle- Purity: purified water (prepared at CIT by reverse osmosis)

Duration of treatment / exposure:

single treatment, instilled into the conjunctival sac of the left eye after gently pulling the lower lid away from the eyeball

Observation period (in vivo):

1 hour, 24, 48 and 72 hours after administration of the test item, study ended on day 4 in the absence of persistent ocular reactions

Number of animals or in vitro replicates:

- experiment 1: 1 animal- experiment 2: 3 animals

Details on study design:

REMOVAL OF TEST SUBSTANCE- Washing (if done): noSCORING SYSTEM:Draize Score SystemConjunctival lesions and dischargeChemosis (lids and/or nictitating membranes). no swelling ...............................................................................................................................0. any swelling above normal (includes nictitating membranes) .................................................1. obvious swelling with partial eversion of lids..........................................................................2. swelling with lids about half-closed.........................................................................................3. swelling with lids more than half-closed .................................................................................4. blood vessels normal ................................................................................................................0. a number of blood vessels definitely hyperemic (injected)......................................................1. diffuse, crimson colour, individual vessels not easily discernible ...........................................2. diffuse, beefy red......................................................................................................................3Discharge. absence of discharge ................................................................................................................0. slight discharge (does not include small amounts normally found in inner canthus) ...........1. discharge with moistening of lids and hairs adjacent to lids....................................................2. discharge with moistening of lids and hairs on wide area around the eye...............................3Iris lesions. normal .....................................................................................................................................0. markedly deepened rugae, congestion, swelling, moderate circum-cornealhyperemia, or injection, any of these or combination of any thereof, iris stillreacting to light (sluggish reaction is positive) ........................................................................1. no reaction to light, haemorrhage, gross destruction (any or all of these) ...............................2Corneal lesionsDegree of opacity (area most dense taken for reading). no ulceration or opacity............................................................................................................0. scattered or diffuse areas of opacity (other than slight dulling or normal lustre),details of iris clearly visible .....................................................................................................1. easily discernible translucent area, details of iris slightly obscured ........................................2. nacreous areas, no details of iris visible, size of pupil barely discernible ...............................3. opaque cornea, iris not discernible through the opacity...........................................................4Area of opacity. one quarter (or less) but not zero..............................................................................................1. greater than one quarter but less than a half.............................................................................2. greater than one half but less than three quarters.....................................................................3. greater than three quarters up to whole area. ...........................................................................4Any other lesions observed were noted.TOOL USED TO ASSESS SCORE: fluorescein

Irritation parameter:

cornea opacity score

Basis:

animal: 750

Time point:

other: mean of 24 and 48 h post treatment

Score:

3

Max. score:

4

Reversibility:

other: animal sacrificed for humane reasons on d 4

Irritation parameter:

chemosis score

Basis:

animal: 750

Time point:

other: mean of 24 and 48 h post treatment

Score:

2.5

Max. score:

4

Reversibility:

other: animal sacrificed for humane reasons on d 4

Irritation parameter:

conjunctivae score

Basis:

animal: 750

Time point:

other: mean of 24 and 48 h post treatment

Score:

2

Max. score:

3

Reversibility:

other: animal sacrificed for humane reasons on d 4

Irritation parameter:

iris score

Basis:

animal: 750

Time point:

other: mean of 24 and 48 h post treatment

Score:

1

Max. score:

2

Reversibility:

other: animal sacrificed for humane reasons on d 4

Irritation parameter:

cornea opacity score

Basis:

mean

Remarks:

of animals no. 711, 712 and 736

Time point:

other: mean score of 1h, 24, 48 h and 72 h

Score:

0

Max. score:

4

Irritation parameter:

chemosis score

Basis:

mean

Remarks:

of animals no. 711, 712 and 736

Time point:

other: mean score of 1h, 24, 48 h and 72 h

Score:

0

Max. score:

4

Irritation parameter:

conjunctivae score

Basis:

mean

Remarks:

of animals no. 711, 712 and 736

Time point:

other: mean score of 1h, 24, 48 h and 72 h

Score:

0

Max. score:

3

Irritation parameter:

iris score

Basis:

mean

Remarks:

of animals no. 711, 712 and 736

Time point:

other: mean score of 1h, 24, 48 h and 72 h

Score:

0

Max. score:

2

Irritant / corrosive response data:

Undiluted test item (one animal)- a marked then moderate chemosis (grade 3 then 2) and a moderate redness of the conjunctiva (grade 2)from day 1 until day 3- a clear discharge (grade 2 then grade 1) and an iritis (grade 1) on days 2 and 3- moderate then marked opacity of the cornea (grade 2 then 3), which covered the whole area of the cornea, from day 1 until day 3According to the severe reactions observed, this animal was sacrificed on day 3 for ethicalreasons.Test item at the concentration of 10%- a slight chemosis (grade 1) in all the animals on day 1- a slight redness of the conjunctiva (grade 1) in 2/3 animals on day 1, persiting in one of them on day 2. - a clear discharge in 1/3 animals on day 2Mean scores calculated for each animal over 24, 48 and 72 hours were 0.0, 0.0 and 0.0 forchemosis, 0.0, 0.3 and 0.0 for redness of the conjunctiva, 0.0, 0.0 and 0.0 for iris lesions and 0.0,0.0 and 0.0 for corneal opacity.For details see Table 1.

Table 1: Individual ocular examinations and mean values of the scores recorded for each animal (24, 48 and 72 hours)

Rabbit number	Region of eye	Description of ocular		Scores			Mean irritation
		reactions	1h, D1	24h, D2	48h, D3	72h, D4	score (1)
Undiluted test item
750	Conjunctivae	Chemosis	3	3	2	-	(2)
		Redness	2	2	2	-	(2)
		Discharge	E	2	1	-	(2)
	Iris		0	1	1	-	(2)
	Corneal opacity	Intensity	2	3	3	-	(2)
		Area	2	4	4	-	(2)
	Other		*	*	*	-
	Fluorescein		/	U	U	-
Test item at the concentration of 10%
711	Conjunctivae	Chemosis	1	0	0	0	0.0
		Redness	1	0	0	0	0.0
		Discharge	E	1	0	0	0.3
	Iris		0	0	0	0	0.0
	Corneal opacity	Intensity	0	0	0	0	0.0
		Area	0	0	0	0	0.0
	Other		*	*	*	*
	Fluorescein		/	U	/	/
712	Conjunctivae	Chemosis	1	0	0	0	0.0
		Redness	1	1	0	0	0.3
		Discharge	E	0	0	0	0.0
	Iris		0	0	0	0	0.0
	Corneal opacity	Intensity	0	0	0	0	0.0
		Area	0	0	0	0	0.0
	Other		*	*	*	*
	Fluorescein		/	U	/	/
736	Conjunctivae	Chemosis	1	0	0	0	0.0
		Redness	0	0	0	0	0.0
		Discharge	E	0	0	0	0.0
	Iris		0	0	0	0	0.0
	Corneal opacity	Intensity	0	0	0	0	0.0
		Area	0	0	0	0	0.0
	Other		*	*	*	*
	Fluorescein		/	U	/	/

(1) mean of scores on days 2, 3 and 4

(2) = not calculable

h = hour

D = day

* = none

U = fluorescein batch No. P756

/ = fluorescein not used

E = scoring masked by residual test item

Interpretation of results:

Category 1 (irreversible effects on the eye)

Remarks:

Migrated informationCriteria used for interpretation of results: EU

Conclusions:

the potential of the test item R0034833C (batch No. R0034833C 027 P 001) at the concentration of 10% in purified water to induce ocular irritation was evaluated in rabbits according to OECD (No. 405, 24th April 2002) and EC (2004/73/EC, part B.5, 29th April 2004) and GLP.Under the experimental conditions of the study, the undiluted test item R0034833C (batch No. R0034833C 027 P 001) caused severe effects in the rabbit eye. The animal had to be killed for humane reasons based on the inflicted effects.Under the experimental conditions of the study, the test item at the concentration of 10% in purified water was well-tolerated when administered by ocular route to rabbits.

Executive summary:

The potential of the test item Mexoryl SBO (termed R0034833C in the study report, batch No. R0034833C 027 P 001) undiluted and at the concentration of 10% in purified water to induce ocular irritation was evaluated in rabbits.

The study was conducted in compliance with the principles of Good Laboratory Practice

Regulations.

The undiluted test item was first administered to a single male New Zealand White rabbit. Since the test item showed severe irritant properties on this first animal, the undiluted test item was not evaluated on other animals.

At the request of the Sponsor, a second assay was performed with the test item at the concentration of 10%. The dosage form was first administered to a single animal. Since the dosage form was not severely irritant on this animal, it was then evaluated simultaneously in two other animals.

A single dose of 0.1 mL of the undiluted test item or test item at the concentration of 10% (w/w) was instilled into the left conjunctival sac. The right eye was not treated and served as control. The eyes were not rinsed after administration of the test item.

Ocular reactions were observed approximately 1 hour, 24, 48 and 72 hours after the administration. The mean values of the scores for chemosis, redness of the conjunctiva, iris lesions and corneal opacity were calculated for each animal.

Undiluted test item (one animal):

A marked then moderate chemosis and a moderate redness of the conjunctiva were observed from day 1. A clear discharge and an iritis was noted on days 2 and 3. Moderate then marked opacity of the cornea, which covered the whole area of the cornea, was noted from day 1. According to the severe reactions observed, this animal was sacrificed on day 3 for ethicalreasons.

Test item at the concentration of 10%:

A slight chemosis was noted in all the animals on day 1. A slight redness of the conjunctiva was noted in 2/3 animals on day 1; it persisted in one of them on day 2. A clear discharge was noted in 1/3 animals on day 2. Mean scores calculated for each animal over 24, 48 and 72 hours were 0.0, 0.0 and 0.0 for chemosis, 0.0, 0.3 and 0.0 for redness of the conjunctiva, 0.0, 0.0 and 0.0 for iris lesions and 0.0, 0.0 and 0.0 for corneal opacity.

Under the experimental conditions of the study, the undiluted test item R0034833C (batch No. R0034833C 027 P 001) caused severe effects in the rabbit eye.

Under the experimental conditions of the study, the test item R0034833C (batch No. R0034833C 027 P 001) at the concentration of 10% in purified water was well-tolerated when administered by ocular route to rabbits.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (irritating)

Additional information

Skin irritation

The potential of the test item Mexoryl SBO to induce skin irritation was evaluated in rabbits according to OECD TG 404.

A single dose of 0.5 mL of the undiluted test item was applied to the closely-clipped skin of 3 rabbits. The test item was held in contact with the skin by means of a semi-occlusive dressing. Cutaneous reactions were observed approximately 1 hour, 24, 48 and 72 hours after removal of the dressing. After a 4 -hour exposure (three animals) a very slight erythema was noted in all animals on day 1, persisting in one of them on day 2.

Under the experimental conditions of this study, the test item was well-tolerated when applied topically to rabbits and the test item should not be classified as irritating to the skin.

Eye irritation

The potential of the test item Mexoryl SBO undiluted and at the concentration of 10% in purified water to induce ocular irritation was evaluated in rabbits according to OECD TG 405. The undiluted test item was first administered to a single male New Zealand White rabbit. A single dose of 0.1 mL of the undiluted test item was instilled into the left conjunctival sac. The right eye was not treated and served as control. The eyes were not rinsed after administration of the test item. A marked then moderate chemosis and a moderate redness of the conjunctiva were observed from day 1. A clear discharge and an iritis was noted on days 2 and 3. Moderate then marked opacity of the cornea, which covered the whole area of the cornea, was noted from day 1. According to the severe reactions observed, this animal was sacrificed on day 3 for ethical reasons. Since the test item showed severe irritant properties on this first animal, the undiluted test item was not evaluated on other animals.

A second assay was performed with 3 rabbits with the test item at the concentration of 10%. A slight chemosis was noted in all the animals on day 1. A slight redness of the conjunctiva was noted in 2/3 animals on day 1; it persisted in one of them on day 2. A clear discharge was noted in 1/3 animals on day 2.

Under the experimental conditions of the study, the undiluted test item caused severe effects in the rabbit eye. At the concentration of 10% in purified water, it was well-tolerated when administered by ocular route to rabbits.

 

Respiratory irritation

No information on respiratory irritation is available.

Effects on eye irritation: corrosive

Justification for classification or non-classification

Skin irritation

In the skin irritation study, the observed mean scores for erythema/eschar and oedema that were obtained from ratings at 24, 48 and 72 hours after treatment were not exceeding 0.33 in all animals and thus were well below 2.3. All effects were fully reversible within 48 hours. The substance has therefore not to be classified as irritating to the skin according to Regulation (EC) No 1272/2008 (CLP).

Eye irritation

In the eye irritation study, the substance showed severe irritant properties in the treated animal. The animal had to be sacrificed on day 3 of the test for ethical reasons and the reversibility of the effects could not be observed. The substance has therefore to be classified as causing irreversible effects on the eye (Category 1) according to Regulation (EC) No 1272/2008 (CLP).