[nitrilotris(methylene)]trisphosphonic acid, sodium salt

Endpoint summary

Description of key information

In the key in vivo skin irritation study, conducted according to OECD Test Guideline 404 and in compliance with GLP, ATMP-xNa (CAS 20592-85-2, EC 243-900-0; aqueous solution containing 41% w/w active salt) was not irritating to the skin of rabbits following a 4-hour exposure (SafePharm Laboratories Ltd., 1982d, Reliability 1).

In the key in vivo eye irritation study, conducted according to OECD Test Guideline 405 and in compliance with GLP, ATMP-xNa (aqueous solution containing 41% w/w active salt) was not irritating to the eyes of rabbits (SafePharm Laboratories Ltd., 1982e, Reliability 1).

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records

Reference

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

27.07.1982 to 30.07.1982

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

GLP compliance:

yes

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Nottingham University, UK and Hylyne Rabbits Ltd, Cheshire, UK.
- Age at study initiation: 12-16 weeks
- Weight at study initiation: 2.75 to 2.96 kg
- Housing: Individually in suspended metal cages
- Diet (e.g. ad libitum): Ad libitum
- Water (e.g. ad libitum): Ad libitum
- Acclimation period: Five days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22± 3
- Humidity (%): Not controlled (76-80)
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12


IN-LIFE DATES: From: 27.07.1982 to 30.07.1982

Type of coverage:

occlusive

Preparation of test site:

shaved

Vehicle:

unchanged (no vehicle)

Controls:

not required

Amount / concentration applied:

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

Duration of treatment / exposure:

4 hours

Observation period:

Seven days

Number of animals:

Three

Details on study design:

TEST SITE
- Area of exposure: Back
- % coverage: No data
- Type of wrap if used: Elasticated corset


REMOVAL OF TEST SUBSTANCE
- Washing (if done): Yes
- Time after start of exposure: Four hours


SCORING SYSTEM: Draize

Irritation parameter:

erythema score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0

Max. score:

4

Remarks on result:

no indication of irritation

Irritation parameter:

erythema score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0

Max. score:

4

Remarks on result:

no indication of irritation

Irritation parameter:

erythema score

Basis:

animal #3

Time point:

24/48/72 h

Score:

0

Max. score:

4

Remarks on result:

no indication of irritation

Irritation parameter:

edema score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0

Max. score:

4

Remarks on result:

no indication of irritation

Irritation parameter:

edema score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0

Max. score:

4

Remarks on result:

no indication of irritation

Irritation parameter:

edema score

Basis:

animal #3

Time point:

24/48/72 h

Score:

0

Max. score:

4

Remarks on result:

no indication of irritation

Irritant / corrosive response data:

Slight erythema in one animal after one hour. No other signs of irritation.

Other effects:

None

Interpretation of results:

GHS criteria not met

Conclusions:

In an in vivo skin irritation study, conducted according to OECD Test Guideline 404 and in compliance with GLP (Reliability 1), ATMP-xNa (aqueous solution containing 41% w/w active salt) was not irritating to the skin of rabbits following a 4-hour exposure.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Eye irritation

Link to relevant study records

Reference

Endpoint:

eye irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

24.08.1982 to 27.08.1982

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

GLP compliance:

yes

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

TEST ANIMALS
- Source: Hylyne Rabbits Ltd., Cheshire, UK.
- Age at study initiation: 12-16 weeks
- Weight at study initiation: 2.12 to 2.33 kg
- Housing: Individually housed in suspended metal cages.
- Diet (e.g. ad libitum): Ad libitum
- Water (e.g. ad libitum): Ad libitum
- Acclimation period: Minimum five days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19.5 ±2.5
- Humidity (%): 68-70
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12


IN-LIFE DATES: From: 24.08.1982 to 27.08.1982

Vehicle:

unchanged (no vehicle)

Controls:

not required

Amount / concentration applied:

Amount applied: 0.1 ml

Duration of treatment / exposure:

Eyes not rinsed.

Observation period (in vivo):

72 hours

Number of animals or in vitro replicates:

Three

Details on study design:

REMOVAL OF TEST SUBSTANCE
- Washing (if done): No


SCORING SYSTEM: Draize


TOOL USED TO ASSESS SCORE: fluorescein

Irritation parameter:

cornea opacity score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0

Max. score:

4

Remarks on result:

no indication of irritation

Irritation parameter:

cornea opacity score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0

Max. score:

4

Remarks on result:

no indication of irritation

Irritation parameter:

cornea opacity score

Basis:

animal #3

Time point:

24/48/72 h

Score:

0

Max. score:

4

Remarks on result:

no indication of irritation

Irritation parameter:

iris score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0

Max. score:

2

Remarks on result:

no indication of irritation

Irritation parameter:

iris score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0

Max. score:

2

Remarks on result:

no indication of irritation

Irritation parameter:

iris score

Basis:

animal #3

Time point:

24/48/72 h

Score:

0

Max. score:

2

Remarks on result:

no indication of irritation

Irritation parameter:

conjunctivae score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0.66

Max. score:

3

Reversibility:

fully reversible

Remarks on result:

no indication of irritation

Irritation parameter:

conjunctivae score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0

Max. score:

3

Remarks on result:

no indication of irritation

Irritation parameter:

chemosis score

Basis:

animal #3

Time point:

24/48/72 h

Score:

0

Max. score:

3

Remarks on result:

no indication of irritation

Irritation parameter:

chemosis score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0

Max. score:

4

Remarks on result:

no indication of irritation

Irritation parameter:

chemosis score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0

Max. score:

4

Remarks on result:

no indication of irritation

Irritation parameter:

chemosis score

Basis:

animal #3

Time point:

24/48/72 h

Score:

0

Max. score:

4

Remarks on result:

no indication of irritation

Irritant / corrosive response data:

Mild conjunctival inflammation, with or without slight swelling was observed in all three animals after one hour. A dulling of the normal lustre of the cornea was observed in two rabbits at the one hour reading. In one animal this was accompanied by iritis. The reactions had ameliorated in two rabbits by 24 hours when mild conjunctival inflammation only was seen in the remaining animal. This reaction persisted until the 72 hour observation point.

Other effects:

None

Interpretation of results:

GHS criteria not met

Conclusions:

In an in vivo eye irritation study, conducted according to OECD Test Guideline 405 and in compliance with GLP (Reliability 1), ATMP-xNa (aqueous solution containing 41% w/w active salt) was not irritating to the eyes of rabbits.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

In the key in vivo skin irritation study, conducted according to OECD Test Guideline 404 and in compliance with GLP, 0.5 ml ATMP-xNa (aqueous solution containing 41% w/w active salt) was applied to the skin of 3 rabbits for 4 hours under occlusive dressing. The skin reactions were assessed for 7 days. Slight erythema was observed in one animal at 1 hour after test substance removal. No other signs of skin irritation were observed for the other treated animals throughout the 7-day observation period. ATMP-xNa (aqueous solution containing 41% w/w active salt) was concluded to be not irritating to the skin of rabbits following a 4-hour exposure (SafePharm Laboratories Ltd., 1982d, Reliability 1).

In a supporting in vivo skin irritation study, conducted prior to OECD Test Guideline 404 and GLP, ATMP-xNa (without information on active acid content) was concluded to be not irritating to skin following a 24-hour semi-occlusive exposure (Younger Laboratories, 1971, Reliability 2).

In another supporting in vivo skin irritation study, conducted prior to the adoption of OECD test guidelines and GLP, undiluted aqueous solution of ATMP-xNa (40 % w/w active salt) was applied to the clipped, intact skin of albino rabbits under an occlusive dressing, for 24 hours. After 24 hours the skin was washed with soap and warm water. Observations for irritation were made over a period of several days, at 1, 4, 24, 48, 72, 120 and 168 hours, and scored according to the method of Draize. After one and four hours the skin showed no change. Overnight, 2/3 animals developed barely perceptible redness with no oedema, with an average score of 0.6/8. Removal of the test substance resulted in one of three animals being free of redness by 48 hours, and all animals had a score of zero by 72 hours. It was concluded that the test substance was slightly irritating to the skin of rabbits, but the effects were not sufficient for classification (Younger Laboratories, 1962, Reliability 2).

In the key in vivo eye irritation study, conducted according to OECD Test Guideline 405 and in compliance with GLP, 0.1 ml ATMP-xNa (aqueous solution containing 41% w/w active salt) was instilled into the eyes of 3 rabbits. The eyes were not rinsed following instillation. The eyes were observed for 72 hours post-exposure. Mild conjunctival inflammation, with or without slight swelling was observed in all the animals at 1-hour post-exposure. A dulling of the normal lustre of the cornea was observed in two rabbits at 1 hour reading. In one animal this was accompanied by iritis. The reactions had ameliorated in 2 rabbits by 24 hours when mild conjunctival inflammation was seen in the remaining animal. This reaction persisted until the 72-hour observation point. Overall, ATMP-xNa was concluded to be not irritating to the eyes of rabbits (SafePharm Laboratories Ltd., 1982e, Reliability 1).

In a supporting in vivo eye irritation study, conducted prior to OECD Test Guidelines and GLP, ATMP-xNa caused slight eye irritation but not sufficient for classification (Younger Laboratories, 1971, Reliability 2).

In another supporting eye irritation study, conducted prior to the adoption of OECD test guidelines and GLP, 0.1 ml aqueous solution of ATMP-xNa (40 % w/w active salt) was instilled into the conjunctival sac of the right eye of each of three albino rabbits. After 24 hours the eyes were rinsed with warm isotonic saline solution. The eyes were then observed and irritation reactions scored, according to the method of Draize, for seven days. Mild to moderate discomfort was observed upon application. Slight discharge and redness, very slight oedema and a trace of corneal dullness was recorded after one hour with an average score of 11.6/110. Some improvement was noted after 24 hours, and within 72 hours two animals were given a score of zero. A trace of conjunctival redness remained in the third animal, but had disappeared by 120 hours. It was concluded that ATMP-xNa was slightly irritating to the eyes of rabbits, but not sufficient to trigger classification (Younger Laboratories, 1962, Reliability 2).

Discussion on classification conclusion for eye irritation

The skin and eye irritation classification decision for ATMP-xNa is based on data for the substance itself. However, since the composition of the substance includes a known impurity, ammonium chloride, present at >1 % which has a classification for eye irritation listed in Annex VI of Regulation (EC) No 1272/2008, this has been considered separately for completeness.

The registered substance is typically manufactured as aqueous solutions containing about 50 % w/w solids hence about 50 % w/w water. However, in accordance with the definition in REACH of a substance, water (as a solvent that may be separated) is not considered to be a constituent. The concentration ranges specified in the boundary composition (see Section 1.2) are based on the substance as registered (without water); therefore, concentration ranges in the product as sold are approximately half of the values quoted here.

Ammonium chloride (CAS 12125-02-9, EC 235-186-4) is present at the concentration range of 0-3 % w/w (equivalent to 0-1.5 % of a 50 % aqueous solution; no solid products are on the market). It is the only impurity classified for eye irritation Category 2 according to Annex VI of CLP Regulation (EC) No 1272/2008. According to the generic concentration limits given in table 3.3.3 of CLP Regulation (EC) No 1272/2008, if ammonium chloride is present at concentration ≥10 % w/w it triggers classification for eye irritation Category 2. Since the concentration of ammonium chloride is below the cut-off concentration limit it does not to contribute to the classification for ATMP-xNa.

Justification for classification or non-classification

According to Sections 3.2.2.2.5 and 3.3.2.2.4. of Regulation (EC) No 1272/2008 substances at pH ≥11.5 are expected to produce significant effects on the skin and eyes and in the absence of any other information such as measured data for the substance, skin corrosion Category 1 and eye damage Category 1 classifications would apply based on high pH. The aqueous solutions of ATMP-xNa have pH ranges of pH 4-7 (ATMP-3Na), pH 7-9 (ATMP-4Na) and pH 10-11 (ATMP-5Na). Therefore, these solutions do not require classification based on pH.

In addition, the data from reliable studies with ATMP-xNa do not support any classification for skin irritation/corrosion or eye irritation.

Therefore, based on the available data it is concluded that ATMP-xNa in the pH range of 4-11, does not require classification for skin or eye irritation according to Regulation (EC) No 1272/2008.