Trisodium nitrilotriacetate

Endpoint summary

Description of key information

Skin irritation:

In an OECD 404 guideline study (non-GLP) with 3 albino rabbits and 3 test sites per animal, the test substance was found to be non-irritating / non-corrosive after 3 minutes, 1 hour, and 4 hours of occlusive exposure; no erythema or edema was observed at any time during the study or during the 24, 48, or 72 -hour observation period following the removal of the test substance (Ascend, 2016).

Na3NTA was reported as non-irritating when applied as finely ground powder to abraded skin of 3 rabbits (Monsanto, 1968). In the same study the compound was classified as a mild irritant when applied as 25 % aqueous solution. Various dilutions (10 %, 40 %, undiluted) of Na3NTA (unknown purity) appear to be minimally irritant to skin of rabbits in two studies conducted by Dow (1967 and 1968). In a dermal sensitization study with a 50 % solution of NA3NTA 20 female guinea pigs were tested negative (BASF 1997). In a study similar to OECD 404 38-40 % Na3NTA was applied to the skin of 3 New Zealand White rabbits for 4 hours without any irritation effect (Akzo Nobel 1984). An unpublished report on primary irritation study (Proctor & Gamble, 1973) found moisture Na3NTA to be slightly irritating.

Respiratory irritation:

Respiratory irritation was assessed in Alarie tests in mice (P&G, 1971) and rats (TNA 2007).

Eye irritation:

A primary eye irritation study tested the installation of 100 mg of finely ground Na3NTA to 3 albino rabbits for 24 h. Na3NTA was found to be a moderate eye irritant (Monsanto 1968). Several studies with limited information on test compound concentration and purity rated Na3NTA as slightly or highly irritant (Dow 1967, 1968, 1981). In a primary eye irritation study 0.1 ml of 38 % aqueous solution Na3NTA was found to be mildly irritating to the eye of Vienna White rabbits (BASF 1982). In a study performed similar to OECD 405 38-40 % Na3NTA was applied to the eye of the 3 New Zealand White rabbit for 4 h. The substance was reported not to be an irritant (Akzo Nobel 1984).

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:

18 Nov. 2016 - 13 Dec 2016

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

GLP compliance:

no

Remarks:

GLP was not required to satisfy the purpose of the study. The study laboratory was, nonetheless, a GLP practicing laboratory.

Specific details on test material used for the study:

FlexaTrac-NTA-100
White, crystalline powder
CAS Name: Nitrilotriacetic acid trisodium salt monohydrate
CAS No. 18662-53-8
Purity: >=99%
% Moisture: 7% max

Species:

rabbit

Strain:

other: Albino

Type of coverage:

occlusive

Preparation of test site:

clipped

Vehicle:

water

Controls:

yes, concurrent no treatment

Amount / concentration applied:

0.5 grams

Duration of treatment / exposure:

3 minutes, 1 hour, and 4 hours

Observation period:

72 hours

Number of animals:

3 (2 males, 1 female), with 3 test sites per animal.

Details on study design:

TEST SITE
- Area of exposure: Right Anterior, Right Posterior, and Left Anterior
- % coverage: 8 x 8 cm area.
- Type of wrap if used: Surgical gauze secured in place with clear plastic wrap.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): Yes, upon unwrapping.
- Time after start of exposure: 3 min, 1 hour, and 4 hours.

OBSERVATION TIME POINTS
- 3 min and 1 hour after exposure, and 24 hours, 48 hours, and 72 hours after unwrapping.

SCORING SYSTEM:
- 0 thru 4 for Erythema and Edema

Irritation parameter:

erythema score

Basis:

animal: 1, 2, and 3

Time point:

24/48/72 h

Score:

0

Max. score:

0

Reversibility:

other: Not Applicable

Remarks on result:

no indication of irritation

Irritation parameter:

edema score

Basis:

animal: 1, 2, and 3

Time point:

24/48/72 h

Score:

0

Max. score:

0

Reversibility:

other: Not Applicable

Remarks on result:

no indication of irritation

Irritant / corrosive response data:

No erythema or edema was observed at any time point in any animal. All scores at all time points were 0.

Interpretation of results:

GHS criteria not met

Conclusions:

The test substance, as a wetted powder, was not irritating or corrosive to rabbit skin.

Executive summary:

In an OECD 404 guideline study (non-GLP) with 3 albino rabbits and 3 test sites per animal, the test substance was found to be non-irritating / non-corrosive after 3 minutes, 1 hour, and 4 hours of occlusive exposure. No erythema or edema was observed at any time during the study or during the 24, 48, or 72 -hour observation period following the removal of the test substance.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Eye irritation

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Additional information

Skin irritation:

Ambiguous data on the skin irritating properties of Na3NTA are available from studies using different dilutions and formulations. In an OECD 404 guideline study (non-GLP) with 3 albino rabbits and 3 test sites per animal, the test substance was found to be non-irritating / non-corrosive after 3 minutes, 1 hour, and 4 hours of occlusive exposure; no erythema or edema was observed at any time during the study or during the 24, 48, or 72 -hour observation period following the removal of the test substance (Ascend, 2016). Na3NTA was reported as non-irritating when applied as finely ground powder to intact skin of 3 rabbits. In the same study the compound was found to be a mild irritant when applied as 25 % aqueous solution (Monsanto 1968). In an unpublished concise report moisture Na3NTA was applied to the abraded and intact skin of 3 rabbits. A mean erythema score of 1.50 was concluded from the 24 h and 72 h observation showing mild degree of primary irritation. (Proctor and Gamble, 1973).

In two studies presenting very limited data Na3NTA is found to be slightly irritating in rabbits (Dow Company, 1967 and 1968). Due to the limited information provided it is not possible to judge the data against current standards for the assessment of irritants. Given the residual hydroxide that is normally present in solutions of Na3NTA the authors conclude it likely that the substance is irritating and may be corrosive if the level of hydroxide is high enough. Nixon (1971) tested up to 12 % Na3NTA as part of a detergent formulation. 1 % of this solution was applied to abraded or intact skin of 3 albino rabbits for 24 h. Moderate primary irritation was produced on rabbit skin. However, a control formulation without Na3NTA was also found to be moderate irritant.

In a dermal sensitization study 50 % solution of Na3NTA was applied to the abraded skin of 20 female guinea pigs for 6 h. No irritation was reported (BASF 1997). Due to the fact that a 50 % dilution was applied the result cannot be used for the risk assessment of pure undiluted Na3NTA.

A study performed similar to OECD 404 assessed the irritancy potential of 38-40 % NTA Na3 liquid, to the skin of 3 New Zealand White rabbit after a single 4 h application (Akzo Nobel, 1984). No dermal reactions occurred at any time point up to 72 h. The test material was classified as a non-irritant to rabbit skin according to OECD-GHS. Although one animal died before the 48 h reading, (its death was not considered to be treatment-related) and therefore full results were only available for 2 animals, the 2 animals of the preliminary test also showed no dermal reactions following a 4 h application.

Eye irritation:

Mild eye irritation (mean conjunctivae value of 4) was noted in a Draize test according to OECD TG 405, applying 0.1 ml of a 38 % solution to the conjunctival sac of 3 albino rabbits. After 24 hours, average values for redness and chemosis of the conjunctiva were 2.0 and 0.7, respectively. After 48 hours, the conjunctival reddening score was 1.0 and no chemosis was present. There were no findings for cornea and iris. Irritation of the conjunctivae fully recovered within 8 days (BASF, 1982). Moderate eye irritation was detected in a Draize test using Na3NTA monohydrate. 100 mg of finely ground powder were placed in the conjunctival sac of each of 3 albino rabbits for 24 h. Considerable discomfort was shown immediately upon application. Copious discharge, edema with partial eversion of the lids, moderate redness, and sufficient congestion to mildly obscure iris details was recorded after 1 hour. The eyes were rinsed with warm isotonic saline solution after 24 hours when discharge and edema had already reduced. Edema disappeared within 5 days leaving mild redness and slight corneal dullness (no information on scores) which were observed also after 7 days when the study was terminated (Monsanto, 1968).

Two test samples (no details on composition) were tested on individual animals produced severe irritation in the eye that resulted in corneal opacity. The effects did not resolve within 21 days, suggesting that the substance should be considered as highly irritating or corrosive to the eyes (Dow 1981). The test materials appear to be slightly irritating to the eyes in two studies based on limited data (Dow 1968, 1967).

Two granular detergent formulations containing up to 35 % Na3NTA caused transient diffuse areas of corneal translucency and slight to moderate conjunctivitis when left unrinsed (Nixon 1971). The addition of Na3NTA did not materially affect the eye irritation potential of the respective materials which were irritant as such. This result is of limited use for the risk assessment of pure undiluted NTA.

The irritancy potential of 38-40 % Na3NTA to the eye of 3 the New Zealand White rabbit were tested in a study similar to OECD 405 (Akzo Nobel, 1984). A single application of the test material to the eye of three rabbits produced slight to moderate conjunctival irritation (redness and chemosis). All treated eyes appeared normal within 4 days. Based on the absence of corneal and iridial inflammation, only slight conjuntivae after 24 h and a mean score of 1.22 for redness and 0.58 for chemosis, and the absence of reactions 4 days after application, the test material, although slightly irritating to the eye, does not need classification according to OECD-GHS.

Respiratory irritation:

In an Alarie test 4 rats/dose were exposed to Na3NTA for 30 min at dose levels of 0.91, 2.86, and 4.25 mg/L (TNO 2007). Sensory irritation was present at levels of 2.86 and 4.25 mg/L. The RD50 value was estimated to be close to 4.25 mg/L. Although there was high inter-individual variability in responses amongst the rats, these results suggest that sensory irritation is confined to high exposure levels, close to the technically highest attainable concentration. 

In an acute inhalation toxicity study in mice (P&G, 1971) 5 minutes exposure to 0.22, 1.09, 1.41, or 7.60 mg/l were assessed [IUCLID 7.2.2]. NTA has irritant properties with respect to the inhaled concentration (slight sensory irritant at 0.220 mg/l, moderate irritant at 1.09 and 1.41 mg/l, Severe irritant at 7.6 mg/l). Only limited information on test compound and method are available. Thus the study is of limited use for risk assessment of Na3NTA.

Effects on skin irritation/corrosion: slightly irritating

Effects on eye irritation: irritating

Justification for classification or non-classification

Skin irritation:

Ambiguous results were reported for the skin irritating properties of Na3NTA ranging from none to moderate irritating. Na3NTA is currently not classified as irritating to the skin. In an OECD 404 guideline study (non-GLP) with 3 albino rabbits and 3 test sites per animal, the test substance was found to be non-irritating / non-corrosive after 3 minutes, 1 hour, and 4 hours of occlusive exposure; no erythema or edema was observed at any time during the study or during the 24, 48, or 72 -hour observation period following the removal of the test substance (Ascend, 2016). This is supported by a primary skin irritation study using moisture Na3NTA (Proctor and Gamble, 1973). A mean erythema score of 1.50 was concluded according to Draize 1944 from the 24h and 72h observation showing mild degree of primary irritation. This score is below the classification threshold of 2.3 according to GHS.

Eye Irritation:

Ambiguous results were reported for the eye irritating properties of Na3NTA. A lack of irritation up to severe effects was reported. Studies conducted with diluted Na3NTA are of limited use for the risk assessment of pure, undiluted compound. One study applies undiluted Na3NTA concluding moderate eye irritation after application of 100 mg finely ground powder (Monsanto, 1968). This is in accordance with current classification as irritating to eyes (R36).

Respiratory Irritation:

Following acute and repeated inhalation of dust, Na 3 NTA may exert some irritation of the respiratory tract as evidenced in mice and rats. Since significant reactions only occurred at highest concentrations in the range of the maximal technically achievable level, no respiratory irritation was reported after repeated dose inhalation studies [IUCLID 7.5.3] and there is no evidence for respiratory tract irritation in humans, these findings do not warrant classification as “Irritating to respiratory system“.