L-Aspartic acid, N,N'-1,2-ethanediylbis-, sodium salt (1:3)

Endpoint summary

Description of key information

In GLP studies conducted according to OECD Guideline 404 and EU Method B.4, no evidence of irritation was observed when trisodium EDDS was applied for 4 h (under semi-occlusive conditions) to the intact skin of three rabbits

Trisodium EDDS showed no irritating potential when three applications (given at least 24 h apart) of 0.4 mL each of 3, 15 and 30% aqueous solutions were applied for 24 h under an occluded patch to the skin of the upper arm of 12 healthy volunteers (Pitts, 1993). In addition, in the induction phase of a sensitisation study, no irritation was seen in humans following 24-h occluded application of trisodium EDDS at a concentration of 5% (in water) to the upper arm of 111 volunteers on alternate days over a 3-week period (9 applications) (Rybicki, 1993).

In a GLP study conducted accorrding to OECD Guideline 405 and EU Method B.5, instillation of 0.1 g trisodium EDDS to the eyes of three rabbits produced no iridial or corneal effects and only mild transient conjunctivial effects (Arcelin, 1993b). In a GLP study conducted according to a protocol similar to OECD Guideline 405, no evidence of corneal damage, iridial inflammation or conjunctival reactions were observed when 4 mg of trisodium EDDS was instilled into one eye of each of three rabbits (Liggett, 1989b). In a guideline study with the related material, EDDS acid, moderate irritation of the conjunctivae after 1 h was reported, which had completely reversed by 48 h. No effects on the cornea or iris were evident (Brunt, 2002).

There are no data in relation to respiratory irritation in humans or animals. However, the low skin and eye irritation potential of trisodium EDDS suggests that this substance would not cause such an effect.

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:

26 to 29 May 1993

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

Deviations:

no

Qualifier:

according to guideline

Guideline:

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

Deviations:

no

Qualifier:

according to guideline

Guideline:

EPA OTS 798.4470 (Acute Dermal Irritation)

Deviations:

not specified

GLP compliance:

yes (incl. QA statement)

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Dr Karl Thomae GmbH, Postfach 1755, D-7950 Biberach an der Riss, Germany
- Age at study initiation: 15 weeks
- Weight at study initiation: male, 2.8 kg; females 2.3-2.8 kg
- Housing: individually in stainless steel cages
- Diet (e.g. ad libitum): conventional, ad libitum
- Water (e.g. ad libitum): tap water, ad libitum
- Acclimation period: 4 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 +/- 3
- Humidity (%): 40-70
- Air changes (per hr): 10-15
- Photoperiod (hrs dark / hrs light): 12/12

Type of coverage:

semiocclusive

Preparation of test site:

other: clipped

Vehicle:

water

Controls:

no

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 500 mg


VEHICLE
- Amount(s) applied (volume or weight with unit): "the test article was slightly moistened with tap water"

Duration of treatment / exposure:

4 h

Observation period:

1, 24, 48 and 72 h

Number of animals:

3

Details on study design:

TEST SITE
- Area of exposure: back, 6 cm2
- % coverage: no data
- Type of wrap if used: surgical gauze covered with a semi-occlusive dressing wrapped around the abdomen and secured with an elastic bandage


REMOVAL OF TEST SUBSTANCE
- Washing (if done): with lukewarm tap water
- Time after start of exposure: 4 h then skin washed prior to the first reading with double-distilled water so any reactions would be clearly visible


SCORING SYSTEM: scored at 30 min after removal of the patches and at 24, 48 and 72 h for erythema and eschar formation and edema as follows:
No erythema 0
Very slight erythema 1
Well-defined erythema 2
Moderate to severe erythema 3
Severe erythema to slight eschar formation 4

No edema 0
Very slight edema 1
Slight edema 2
Moderate edema (raised about 1 mm) 3
Severe edema (raised more than 1 mm) 4

Irritation parameter:

primary dermal irritation index (PDII)

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

8

Remarks on result:

no indication of irritation

Irritation parameter:

erythema score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Remarks on result:

no indication of irritation

Irritation parameter:

edema score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Remarks on result:

no indication of irritation

Irritant / corrosive response data:

No irritation response was seen in any of the three animals during the observation period

Other effects:

No mortaility or systemic effects were noted, and the body weight gain was within normal ranges. No staining of the treated area or corrosion was reported in any animal at any time point.

Interpretation of results:

GHS criteria not met

Conclusions:

In a GLP study conducted according to OECD Guideline 404 and EU Method B.4, no evidence of irritation was observed when 0.5 g of trisodium EDDS was applied for 4 h (under a semi-occlusive dressing) to the intact skin of three rabbits.

Executive summary:

In a GLP study conducted according to OECD Guideline 404 and EU Method B.4, the ability of trisodium EDDS to induce skin irritation was assessed in a study in New Zealand White rabbits. The test substance, moistened slightly with water, was applied to the intact skin of the dorsal trunk region of three young rabbits (one male and two females) under a semi-occlusive dressing. The patch was removed after 4 h and the skin washed with lukewarm water and examined for erythema, eschar and edema after 1, 24, 48 and 72 h.

No signs of irritation (or corrosion or staining) were evident in any animal throughout the observation period.

In conclusion, no evidence of irritation was observed when 0.5 g of trisodium EDDS was applied for 4 h (under a semi-occlusive dressing) to the intact skin of three rabbits. According to EU CLP regulation, trisodium EDDS would not be classiffied as a skin irritant under the conditions of this test.

Reference 2

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

18 to 21 April 1989

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study with acceptable restrictions

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

Deviations:

yes

Remarks:

examined at 30 min not the recommended 60 min

GLP compliance:

yes

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: A Smith, Warlingham, Surrey, UK
- Age at study initiation: 11-14 weeks
- Weight at study initiation: 2.6-3.3 kg
- Housing: individually in metal cages wirh perforated floors
- Diet (e.g. ad libitum): conventional, ad libitum
- Water (e.g. ad libitum): tap water, ad libitum
- Acclimation period: 7 days minimum


ENVIRONMENTAL CONDITIONS
- Temperature (°C): about 19
- Humidity (%): 30-70
- Air changes (per hr): 19
- Photoperiod (hrs dark / hrs light): 12/12

Type of coverage:

semiocclusive

Preparation of test site:

other: clipped

Vehicle:

water

Controls:

no

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.66 g


VEHICLE
- Amount(s) applied (volume or weight with unit): 0.66 mL distilled water

Duration of treatment / exposure:

4 h

Observation period:

1, 24, 48 and 72 h

Number of animals:

3

Details on study design:

TEST SITE
- Area of exposure: dorso-lumbar region, 5 cm2
- % coverage: no data
- Type of wrap if used: gauze pad covered with elastic adhesive dressing


REMOVAL OF TEST SUBSTANCE
- Washing (if done): site wiped with wet tissue paper
- Time after start of exposure: 4 h


SCORING SYSTEM: scored at 30 min after removal of the patches and at 24, 48 and 72 h for erythema and eschar formation and edema as follows:
No erythema 0
Very slight erythema 1
Well-defined erythema 2
Moderate to severe erythema 3
Severe erythema to slight eschar formation 4

No edema 0
Very slight edema 1
Slight edema 2
Moderate edema (raised about 1 mm) 3
Severe edema (raised more than 1 mm) 4

Irritation parameter:

primary dermal irritation index (PDII)

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

8

Remarks on result:

no indication of irritation

Irritation parameter:

erythema score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Remarks on result:

no indication of irritation

Irritation parameter:

edema score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Remarks on result:

no indication of irritation

Irritant / corrosive response data:

No animal showed any irritant response to the test substance

Other effects:

None reported

Interpretation of results:

GHS criteria not met

Conclusions:

In a GLP study conducted according to OECD Guideline 404 and EU Method B.4, no evidence of irritation was observed when 0.66 g of trisodium EDDS was applied for 4 h (under a semi-occlusive dressing) to the intact skin of three rabbits.

Executive summary:

In a GLP study conducted according to a protocol equivalent to OECD Guideline 404, the ability of trisodium EDDS to cause skin irritation was assessed in a study in New Zealand White rabbits.

About 24 h after removal of the hair from the dorso-lumbar region, three rabbits were exposed to 0.66 g of the test substance moistened with water under a semi-occlusive dressing for 4 h. Any remaining test substance was then wiped off with wet tissues and the treated area examined 30 min after removal of the patch and 24, 48 and 72 h later for erythema, eschar formation and edema.

None of the animals showed any signs of skin irritation during the observation period.

In conclusion, no evidence of irritation was observed when 0.66 g of trisodium EDDS was applied for 4 h (under a semi-occlusive dressing) to the intact skin of three rabbits. According to EU CLP regulation, trisodium EDDS would not be classiffied as a skin irritant under the conditions of this test.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Eye irritation

Link to relevant study records

Reference

Reference 1

Endpoint:

eye irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

24 April to 11 May 1989

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study with acceptable restrictions

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

Deviations:

yes

Remarks:

eyes were not examined at 1 h and eye irritation was scored in accordance with Draize

Principles of method if other than guideline:

The study was designed to assess eye irritation potential using a procedure based on Proctor and Gamble Protocol No. C2B-E (Dated 16 March 1987). This protocol is essentially equivalent to OECD Guideline 405. Occular lesions were scored using the Draize numerical scoring system (Draize JH, 1959).

GLP compliance:

yes

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

TEST ANIMALS
- Source: Smith A, Warlingham, Surrey and Froxfield Farms UK Ltd, Petersfield, Hampshire, England
- Age at study initiation: 10 to 13 weeks
- Weight at study initiation: 2.3-3.0 kg
- Housing: individually in metal cages with perforated floors
- Diet (e.g. ad libitum): SDS standard rabbit diet, ad libitum
- Water (e.g. ad libitum): tap water ad libitum
- Acclimation period: "were acclimated" no further details given

ENVIRONMENTAL CONDITIONS
- Temperature (°C): approximately 19
- Humidity (%): 30-70
- Air changes (per hr): 19
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: To: 24 April 1989 to 11 May 1989

Vehicle:

unchanged (no vehicle)

Controls:

yes, concurrent no treatment

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 4 mg [this is quite a low amount]

Duration of treatment / exposure:

The treated eyes were not rinsed after instillation

Observation period (in vivo):

7 d

Number of animals or in vitro replicates:

3

Details on study design:

REMOVAL OF TEST SUBSTANCE
- Washing (if done): no rinse

SCORING SYSTEM: based on the numerical scoring system of Draize (Draize JH, 1959. Appraisal of the safety of chemicals in foods, drugs and cosmetics. Assn. of Food and Drug Officials of the United States, 51). The Maximum Average Score (MAS) was defined as "the highest Primary Irritation Score recorded for any observation period". The Primary Irritation Score at each observation period for each group of animals was calculated by totalling all of the cornea, iris, and conjunctivae scores and dividing by the number of animals in the group.

TOOL USED TO ASSESS SCORE: handheld torch

Irritation parameter:

maximum mean total score (MMTS)

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

110

Reversibility:

other: not applicable

Remarks on result:

other: No occular reactions were recorded at any of the observation time points.

Irritation parameter:

cornea opacity score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Remarks on result:

no indication of irritation

Irritation parameter:

iris score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Remarks on result:

no indication of irritation

Irritation parameter:

conjunctivae score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Remarks on result:

no indication of irritation

Irritation parameter:

chemosis score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Remarks on result:

no indication of irritation

Irritant / corrosive response data:

No corneal damage, iridial inflammation or conjunctival reactions were seen in any of the three animals during the observation period

Other effects:

none reported

Interpretation of results:

GHS criteria not met

Conclusions:

In a GLP study conducted according to a protocol similar to OECD Guideline 405, no evidence of corneal damage, iridial inflammation or conjunctival reactions were observed when 4 mg of trisodium EDDS was instilled into one eye of each of three rabbits.

Executive summary:

In a GLP study conducted according to a protocol similar to OECD Guideline 405, the ability of trisodium EDDS to cause eye irritation and corrosion was investigated by instilling 4 mg of the undiluted material into the conjunctival sac of one eye of each of three New Zealand White rabbits. Treated eyes were not rinsed after substance application. The contralateral eye remained untreated and served as a control. Scoring of occular effects was performed at 1, 2, 3, 4 and 7 days after test substance administration.

No corneal damage, iridial inflammation or conjunctival reactions were seen in any of the three animals throughout the 7-d observation period. Under the conditions of this study, trisodium EDDS would not be classified as capable of producing serious eye damage/eye irritation according to EU CLP regulation.

Reference 2

Endpoint:

eye irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

25 May to 1 June 1993

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study with acceptable restrictions

Qualifier:

according to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

Deviations:

yes

Remarks:

The study does not mention any preparation of the test substance prior to use, however, the Guideline states that solid test material should be ground to a fine dust before instillation.

Qualifier:

equivalent or similar to guideline

Guideline:

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

Deviations:

not specified

Qualifier:

equivalent or similar to guideline

Guideline:

EPA OTS 798.4500 (Acute Eye Irritation)

Deviations:

not specified

GLP compliance:

yes (incl. QA statement)

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

TEST ANIMALS
- Source: Dr Karl Thomae GmbH, Postfach 1755, D-7950 Biberach a.d. Riss
- Age at study initiation: 15 wks
- Weight at study initiation: 2.5 kg (males), 2.6-2.9 kg (females)
- Housing: individual stainless steel cages
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20+/-3
- Humidity (%): 40-70
- Air changes (per hr): 10-15
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 20 May 1993 To: 1 June 1993

Vehicle:

unchanged (no vehicle)

Controls:

yes, concurrent no treatment

Amount / concentration applied:

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

Duration of treatment / exposure:

The treated eyes were not rinsed after substance instillation

Observation period (in vivo):

7 days

Number of animals or in vitro replicates:

3

Details on study design:

REMOVAL OF TEST SUBSTANCE
- Washing (if done): treated eyes were not rinsed after substance instillation
- Time after start of exposure: not applicable

SCORING SYSTEM: Scored according to the numerical system described in EEC Commission Directive 91/325/EEC. Maximum attainable score of 13.

TOOL USED TO ASSESS SCORE: slit-lamp 30 SL/M and a Varta Cliptrix diagnostic lamp

Irritation parameter:

cornea opacity score

Basis:

animal #1

Remarks:

male

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

other: not applicable

Remarks on result:

other: no ulceration or opacity

Irritation parameter:

cornea opacity score

Basis:

animal #2

Remarks:

female

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

other: not applicable

Remarks on result:

other: no ulceration or opacity

Irritation parameter:

cornea opacity score

Basis:

animal #3

Remarks:

female

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

other: not applicable

Remarks on result:

other: no ulceration or opacity

Irritation parameter:

iris score

Basis:

animal #1

Remarks:

male

Time point:

24/48/72 h

Score:

0

Max. score:

2

Reversibility:

other: not applicable

Remarks on result:

other: normal

Irritation parameter:

iris score

Basis:

animal #2

Remarks:

female

Time point:

24/48/72 h

Score:

0

Max. score:

2

Reversibility:

other: not applicable

Remarks on result:

other: normal

Irritation parameter:

iris score

Basis:

animal #3

Remarks:

female

Time point:

24/48/72 h

Score:

0

Max. score:

2

Reversibility:

other: not applicable

Remarks on result:

other: normal

Irritation parameter:

conjunctivae score

Basis:

animal #1

Remarks:

male

Time point:

24 h

Score:

1

Max. score:

3

Reversibility:

fully reversible within: 48 h

Irritation parameter:

conjunctivae score

Basis:

animal #2

Remarks:

female

Time point:

24 h

Score:

1

Max. score:

3

Reversibility:

fully reversible within: 48 h

Irritation parameter:

conjunctivae score

Basis:

animal #3

Remarks:

female

Time point:

24/48/72 h

Score:

1

Max. score:

3

Reversibility:

fully reversible within: 7 days

Irritation parameter:

chemosis score

Basis:

animal #1

Remarks:

male

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

other: not applicable

Remarks on result:

other: no swelling

Irritation parameter:

chemosis score

Basis:

animal #2

Remarks:

female

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

other: not applicable

Remarks on result:

other: no swelling

Irritation parameter:

chemosis score

Basis:

animal #3

Remarks:

female

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

other: not applicable

Remarks on result:

other: no swelling

Irritation parameter:

overall irritation score

Remarks:

primary

Basis:

mean

Remarks:

cumulative

Time point:

24/48/72 h

Score:

0.56

Max. score:

13

Reversibility:

fully reversible

Irritant / corrosive response data:

The scores of each animal at 24, 48 and 72 h were used in calculating the respective mean values for each type of lesion. Mild effects on the conjuctivae were reported in all animals, which have fully reversed within 48 h in two rabbits and by day 7 in the remaining female.

Other effects:

No corrosion was observed at any of the measuring intervals. No staining of the cornea and conjunctivae of the treated eyes by the test article was observed. Slight redness of the nictitating membrane was seen in the treated eyes of all three rabbits at up to 48-72 h post-treatment. A slight discharge was also noted at the 1-h observation period in the treated eyes of two of the three rabbits.

Interpretation of results:

GHS criteria not met

Conclusions:

In a GLP study conducted accorrding to OECD Guideline 405 and EU Method B.5, instillation of 0.1 g trisodium EDDS to the eyes of three rabbits produced no iridial or corneal effects and only mild transient conjunctivial effects.

Executive summary:

In a GLP study conducted accorrding to OECD Guideline 405 and EU Method B.5, the ability of trisodium EDDS to cause eye irritation and corrosion was investigated by instilling the undiluted material into the conjuctival sac of one eye of each of three New Zealand white rabbits (one male and 2 female) at a dose of 0.1 g. Treated eyes were not rinsed after substance application. The untreated eye of each rabbit served as the respective reference control. Scoring of irritation effects was performed at 1, 24, 48, 72 h and 7 days after test substance administration.

No iridial or corneal effects were observed over the 7-day observation period. Only mild conjunctival redness (score 1 out of 3) and slight redness of the nictitating membrane was seen in the treated eye of all animals at 1 and 24 h. All of these effects were observed to be fully reversible within 48 h in two animals, and 7 days in the remaining female. A slight discharge was also noted in the treated eyes of two of the three rabbits at 1 h post-treatment. No corrosion or staining of the treated eyes or clinical signs of systemic toxicity or adverse effects on body weight gain were observed.

Under the conditions of this study, the test material is judged to have low irritation potential and would not be classified as capable of producing serious eye damage/eye irritation under the EU CLP regulation.

Reference 3

Endpoint:

eye irritation: in vivo

Type of information:

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

Adequacy of study:

supporting study

Study period:

20 to 27 December 2001

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study with acceptable restrictions

Qualifier:

according to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

Deviations:

no

Qualifier:

according to guideline

Guideline:

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

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

TEST ANIMALS
- Source: David Percival Ltd, Moston, Sandbach, Cheshire, UK
- Age at study initiation: 12-16 weeks
- Weight at study initiation: 2-3.5 kg
- Housing:individually in suspended metal cages
- Diet (e.g. ad libitum): conventional, ad libitum
- Water (e.g. ad libitum): mains drinking water, ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 17-23
- Humidity (%): 30-70
- Air changes (per hr): at least 15
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 20 December 2001 To: 27 December 2001

Vehicle:

unchanged (no vehicle)

Controls:

yes, concurrent no treatment

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.1 mL (about 55 mg)

Duration of treatment / exposure:

the test substance was not washed out of the eye during the 72-h observation period

Observation period (in vivo):

1, 24, 48 and 72 h

Number of animals or in vitro replicates:

Initially 1, then 2 more tested

Details on study design:

REMOVAL OF TEST SUBSTANCE
- Washing (if done): none

SCORING SYSTEM: using the Draize scale (Draize, 1977):
Score for conjunctiva = (redness + chemosis + discharge) X 2
Score for iris = degree of effects X 5
Score for cornea = (degree of opacity X area involved) X 5

Ocular irritancy potential was classified according to a modified version of the method of Kay and Calandra (1962). The scores for cornea, iris and conjunctiva for each time point were added together for each rabbit and the group mean calculated. The highest of these group means, together with the persistence of the reactions was used to classify the irritancy potential.

TOOL USED TO ASSESS SCORE: ophthalmoscope

Irritation parameter:

overall irritation score

Basis:

mean

Time point:

24/48/72 h

Score:

ca. 4.2

Max. score:

110

Reversibility:

fully reversible within: 48 h

Remarks on result:

probability of weak irritation

Irritation parameter:

cornea opacity score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

80

Remarks on result:

no indication of irritation

Irritation parameter:

iris score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

10

Remarks on result:

no indication of irritation

Irritation parameter:

conjunctivae score

Basis:

mean

Time point:

24/48/72 h

Score:

ca. 4.2

Max. score:

20

Reversibility:

fully reversible within: 48 h

Remarks on result:

probability of weak irritation

Irritant / corrosive response data:

No effects were seen on the cornea or iris in any of the three rabbits. Moderate conjunctival irritation was noted in all of the rabbits after 1 h, which was minimal at 24 h and had fully reversed by 48 h.

Other effects:

There was an initial pain reaction of 2 (slight pain; rabbit blinks and tries to open eye, but reflex closes it)

Interpretation of results:

GHS criteria not met

Conclusions:

In a GLP study conducted according to OECD Guideline 405, EDDS acid (when applied to the right eye of three rabbits) produced moderate irritation of the conjunctivae after 1 h, which had completely reversed by 48 h. No effects on the cornea or iris were evident.

Executive summary:

In a GLP study conducted according to OECD Guideline 405, EDDS acid was tested for its ability to cause eye irritation in rabbits.

The test substance (0.1 mL) was placed in the conjunctival sac of the right eye of three New Zealand White rabbits and the eyelids held together for about one second (no washing). The left eye was left untreated and acted as the control. Assessment of ocular irritation was made at 1, 24, 48 and 72 h using the scoring method of Kay and Calandra (1962) and an ophthalmoscope.

No effects on the cornea or iris were evident. Moderate irritation of the conjunctivae was seen with scores of 2 each for redness, chemosis and discharge at 1 h, which had receded to a score of 1 (at the most) for each parameter by 24 h. The eyes of all three rabbits appeared normal at 48 and 72 h.

In conclusion, under the conditions of this test, EDDS was considered to be non-irritating when applied to the rabbit eye (mean scores at 24, 48 and 72 h) according to the EU CLP regulation.

[Due to its structural similarity to EDDS acid, trisodium EDDS is also considered unlikely to be an eye irritant.]

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Additional information

In a GLP study conducted according to OECD Guideline 404 and EU Method B.4, the ability of trisodium EDDS to induce skin irritation was assessed in a study in New Zealand White rabbits. The test substance, moistened slightly with water, was applied to the intact skin of the dorsal trunk region of three young rabbits (one male and two females) under a semi-occlusive dressing. The patch was removed after 4 h and the skin washed with lukewarm water and examined for erythema, eschar and edema after 1, 24, 48 and 72 h. No signs of irritation (or corrosion or staining) were evident in any animal throughout the observation period (Arcelin, 1993a).

In a GLP study conducted according to a protocol equivalent to OECD Guideline 404, the ability of trisodium EDDS to cause skin irritation was assessed in a study in New Zealand White rabbits. About 24 h after removal of the hair from the dorso-lumbar region, three rabbits were exposed to 0.66 g of the test substance moistened with water under a semi-occlusive dressing for 4 h. Any remaining test substance was then wiped off with wet tissues and the treated area examined 30 min after removal of the patch and 24, 48 and 72 h later for erythema, eschar formation and edema. None of the animals showed any signs of skin irritation during the observation period (Liggett, 1989a).

Trisodium EDDS was assessed for its ability to induce skin irritation in a 24-h repeat application patch test in twelve healthy volunteers. After swabbing the skin of the upper arm with alcohol to remove any surface oils, 0.4 mL each of 2.94, 14.7 and 29.41% aqueous solutions of test substance were applied in Hill Top chambers to separate sites on the skin of the upper arm. After 24 h the patches were removed and the test sites were washed with water to remove any residue substance. Patches were applied on Friday, Monday and Wednesday, leaving at least 24 h after removal of the previous patch. The test sites were graded, both visually and colorimetrically before each application and 24 h after removal of the third patch. No signs of irritation were evident in any of the volunteers at any time point (Pitts, 1993). In addition, in the induction phase of a sensitisation study, no irritation was seen in humans following 24-h occluded application of trisodium EDDS at a concentration of 5% (in water) to the upper arm of 111 volunteers on alternate days over a 3-week period (9 applications) (Rybicki, 1993).

In a GLP study conducted accorrding to OECD Guideline 405 and EU Method B.5, the ability of trisodium EDDS to cause eye irritation and corrosion was investigated by instilling the undiluted material into the conjuctival sac of one eye of each of three New Zealand white rabbits (one male and 2 female) at a dose of 0.1 g. Treated eyes were not rinsed after substance application. The untreated eye of each rabbit served as the respective reference control. Scoring of irritation effects was performed at 1, 24, 48, 72 h and 7 days after test substance administration. No iridial or corneal effects were observed over the 7-day observation period. Only mild conjunctival redness (score 1 out of 3) and slight redness of the nictitating membrane was seen in the treated eye of all animals at 1 and 24 h. All of these effects were observed to be fully reversible within 48 h in two animals, and 7 days in the remaining female. A slight discharge was also noted in the treated eyes of two of the three rabbits at 1 h post-treatment. No corrosion or staining of the treated eyes or clinical signs of systemic toxicity or adverse effects on body weight gain were observed (Arcelin, 1993b).

In a GLP study conducted according to a protocol similar to OECD Guideline 405, the ability of trisodium EDDS to cause eye irritation and corrosion was investigated by instilling 4 mg of the undiluted material into the conjunctival sac of one eye of each of three New Zealand White rabbits. Treated eyes were not rinsed after substance application. The contralateral eye remained untreated and served as a control. Scoring of occular effects was performed at 1, 2, 3, 4 and 7 days after test substance administration. No corneal damage, iridial inflammation or conjunctival reactions were seen in any of the three animals throughout the 7-day observation period (Liggett, 1989b).

In a GLP study conducted according to OECD Guideline 405, the related material EDDS acid (when applied to the right eye of three rabbits) produced moderate irritation of the conjunctivae after 1 h, which had completely reversed by 48 h. No effects on the cornea or iris were evident (Brunt, 2002). [Although it must be viewed with caution for this endpoint, data on EDDS free acid is considered relevant to use for understanding the eye irritation potential of trisodium EDDS, and is acceptable for using as read-across information].

Justification for classification or non-classification

According to EU CLP regulation, trisodium EDDS would not be classified as a skin, eye or respiratory tract irritant based on the information described.