Trisodium hydrogen ethylenediaminetetraacetate

Endpoint summary

Description of key information

subchronic toxicity:

oral, 90 day, rat (no guideline followed): NOAEL: 500 mg/kg bw/day

inhalation, 90 days (65 exposures), rat (OECD 413): NOAEC: 3 mg/m³ (local effects), NOAEC >= 15 mg/m³ (systemic effects)

Read across from disodium dihydrogen EDTA (CAS 139-33-3)

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

sub-chronic toxicity: oral

Type of information:

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

Adequacy of study:

key study

Justification for type of information:

Refer to analogue justification provided in IUCLID section 13.

Reason / purpose for cross-reference:

read-across source

Key result

Dose descriptor:

NOAEL

Effect level:

500 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male

Basis for effect level:

body weight and weight gain

clinical signs

food consumption and compound intake

mortality

Remarks on result:

other:

Remarks:

source: CAS 139-33-3, Wynn, 1970, rat

Critical effects observed:

not specified

Conclusions:

The read across approach is justified in the analogue justification (see IUCLID section 13). The target and source substance are considered unlikely to differ in their repeated dose toxicity potential. The oral repeated dose toxicity of the target substance is estimated based on an adequate and reliable 13-weeks repeated dose toxicity study with the source substance disodium hydrogen EDTA (CAS 139-33-3), conducted in rats. The NOAEL for repeated dose toxicity was 500 mg/kg bw/day. Therefore, a NOAEL for systemic repeated dose toxicity of 500 mg/kg bw/day is expected for the target substance trisodium hydrogen EDTA.

Accordingly, based on read-across, the data on the repeated dose toxicity of trisodium hydrogen EDTA are conclusive but not sufficient for classification according to Regulation (EC) No. 1272/2008.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

500 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

The available information comprises an adequate and reliable study (Klimisch score 2) from a source substance with similar structure and intrinsic properties. Read-across is justified based on (bio)transformation to common compound(s) (refer to endpoint discussion for further details). The selected study is thus sufficient to fulfil the standard information requirements set out in Annex VIII, 8.6, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006.

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records

Reference

Endpoint:

sub-chronic toxicity: inhalation

Type of information:

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

Adequacy of study:

key study

Justification for type of information:

Refer to analogue justification provided in IUCLID section 13.

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Key result

Dose descriptor:

LOAEC

Remarks:

local effects

Effect level:

15 mg/m³ air

Based on:

test mat.

Sex:

female

Basis for effect level:

histopathology: non-neoplastic

Remarks on result:

other:

Remarks:

source: CAS 139-33-3, BASF SE, 2010, 90 days, rat

Key result

Dose descriptor:

NOAEC

Remarks:

local effects

Effect level:

15 mg/m³ air

Based on:

test mat.

Sex:

male

Basis for effect level:

other: No signs of adverse local effects noted up to the highest concentration tested

Key result

Dose descriptor:

NOAEC

Remarks:

local effects

Effect level:

3 mg/m³ air

Based on:

test mat.

Sex:

male/female

Basis for effect level:

histopathology: non-neoplastic

Remarks on result:

other:

Remarks:

source: CAS 139-33-3, BASF SE, 2010, 90 days, rat

Key result

Dose descriptor:

NOAEC

Remarks:

systemic effects

Effect level:

15 mg/m³ air

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No signs of systemic toxicity noted up to the highest concentration tested

Remarks on result:

other:

Remarks:

source: CAS 139-33-3, BASF SE, 2010, 90 days, rat

Critical effects observed:

not specified

A supporting 5 day inhalation toxicity conducted with the source substance disodium dihydrogen EDTA (CAS 139-33-3) was conducted in rats (BASF SE, 2010). In this study a NOAEC for local effects could not be established due to histopathological findings in the lungs noted at the lowest exposure concentration. A single inhalation exposure to 1000 mg/m³ disodium dihydrogen EDTA for 6 hours caused lethality in 6 out of 20 male rats. Histological examination of the lung of the dead rats revealed congestion, edema, multifocal hemorraghes and inflammatory cell infiltrates. Inhalation exposure of rats to disodium dihydrogen EDTA for 6 hours per day on 5 consecutive days caused concentration dependent lesions in the larynx and lungs that were fully reversible within 14 days. Due to histopahological changes in the low dose group a no observed effect level for local effects could not be determined and the LOAEC for local effects was considered to be 30 mg/m³. The NOAEC for systemic effects was considered to be 30 mg/m³air based on reduced body weight, food consumption and clinical signs noted at 300 mg/m³.

Conclusions:

The read across approach is justified in the analogue justification (see IUCLID section 13). The target and source substances are considered unlikely to differ in their repeated dose toxicity potential. The inhalation repeated dose toxicity of the target substance is estimated based on an adequate and reliable sub-chronic repeated dose toxicity study with the source substance disodium dihydrogen EDTA (CAS 139-33-3), conducted in rats. In this study, inhalation exposure of rats to the test item for 90 days (65 exposures) did not lead to any substance-related clinical signs of toxicity. Nor were there any effects in clinical chemistry, hematology. Histological examination revealed some effects in larynx at the highest tested concentration of 15 mg/m³ in female animals. No signs of systemic toxicity were observed up to a concentration of 15 mg/m³. Signs of local toxicity were observed only at the high concentration of 15 mg/m³ in female animals.
Under the current test conditions, the No Observed Adverse Effect Concentration (NOAEC) for local effects in larynx was 3 mg/m3, the NOAEC for systemic effects was 15 mg/m³.

A supporting 5 day inhalation toxicity conducted with the source substance disodium dihydrogen EDTA (CAS 139-33-3) was conducted in rats. In this study a NOAEC for local effects could not be established due to histopathological findings in the lungs noted at the lowest exposure concentration. A single inhalation exposure to 1000 mg/m³ disodium dihydrogen EDTA for 6 hours caused lethality in 6 out of 20 male rats. Histological examination of the lung of the dead rats revealed congestion, edema, multifocal hemorraghes and inflammatory cell infiltrates. Inhalation exposure of rats to disodium dihydrogen EDTA for 6 hours per day on 5 consecutive days caused concentration dependent lesions in the larynx and lungs that were fully reversible within 14 days. Due to histopahological changes in the low dose group a no observed effect level for local effects could not be determined and the LOAEC for local effects was considered to be 30 mg/m3. The NOAEC for systemic effects was considered to be 30 mg/m3 air based on reduced body weight, food consumption and clinical signs noted at 300 mg/m3.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEC

15 mg/m³

Study duration:

subchronic

Species:

rat

Quality of whole database:

The available information comprises an adequate and reliable study (Klimisch score 1) from a source substance with similar structure and intrinsic properties. Read-across is justified based on (bio)transformation to common compound(s) (refer to endpoint discussion for further details). The selected study is thus sufficient to fulfil the standard information requirements set out in Annex VIII, 8.6, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006.

Repeated dose toxicity: inhalation - local effects

Link to relevant study records

Reference

Endpoint:

sub-chronic toxicity: inhalation

Type of information:

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

Adequacy of study:

key study

Justification for type of information:

Refer to analogue justification provided in IUCLID section 13.

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Key result

Dose descriptor:

LOAEC

Remarks:

local effects

Effect level:

15 mg/m³ air

Based on:

test mat.

Sex:

female

Basis for effect level:

histopathology: non-neoplastic

Remarks on result:

other:

Remarks:

source: CAS 139-33-3, BASF SE, 2010, 90 days, rat

Key result

Dose descriptor:

NOAEC

Remarks:

local effects

Effect level:

15 mg/m³ air

Based on:

test mat.

Sex:

male

Basis for effect level:

other: No signs of adverse local effects noted up to the highest concentration tested

Key result

Dose descriptor:

NOAEC

Remarks:

local effects

Effect level:

3 mg/m³ air

Based on:

test mat.

Sex:

male/female

Basis for effect level:

histopathology: non-neoplastic

Remarks on result:

other:

Remarks:

source: CAS 139-33-3, BASF SE, 2010, 90 days, rat

Key result

Dose descriptor:

NOAEC

Remarks:

systemic effects

Effect level:

15 mg/m³ air

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No signs of systemic toxicity noted up to the highest concentration tested

Remarks on result:

other:

Remarks:

source: CAS 139-33-3, BASF SE, 2010, 90 days, rat

Critical effects observed:

not specified

A supporting 5 day inhalation toxicity conducted with the source substance disodium dihydrogen EDTA (CAS 139-33-3) was conducted in rats (BASF SE, 2010). In this study a NOAEC for local effects could not be established due to histopathological findings in the lungs noted at the lowest exposure concentration. A single inhalation exposure to 1000 mg/m³ disodium dihydrogen EDTA for 6 hours caused lethality in 6 out of 20 male rats. Histological examination of the lung of the dead rats revealed congestion, edema, multifocal hemorraghes and inflammatory cell infiltrates. Inhalation exposure of rats to disodium dihydrogen EDTA for 6 hours per day on 5 consecutive days caused concentration dependent lesions in the larynx and lungs that were fully reversible within 14 days. Due to histopahological changes in the low dose group a no observed effect level for local effects could not be determined and the LOAEC for local effects was considered to be 30 mg/m³. The NOAEC for systemic effects was considered to be 30 mg/m³air based on reduced body weight, food consumption and clinical signs noted at 300 mg/m³.

Conclusions:

The read across approach is justified in the analogue justification (see IUCLID section 13). The target and source substances are considered unlikely to differ in their repeated dose toxicity potential. The inhalation repeated dose toxicity of the target substance is estimated based on an adequate and reliable sub-chronic repeated dose toxicity study with the source substance disodium dihydrogen EDTA (CAS 139-33-3), conducted in rats. In this study, inhalation exposure of rats to the test item for 90 days (65 exposures) did not lead to any substance-related clinical signs of toxicity. Nor were there any effects in clinical chemistry, hematology. Histological examination revealed some effects in larynx at the highest tested concentration of 15 mg/m³ in female animals. No signs of systemic toxicity were observed up to a concentration of 15 mg/m³. Signs of local toxicity were observed only at the high concentration of 15 mg/m³ in female animals.
Under the current test conditions, the No Observed Adverse Effect Concentration (NOAEC) for local effects in larynx was 3 mg/m3, the NOAEC for systemic effects was 15 mg/m³.

A supporting 5 day inhalation toxicity conducted with the source substance disodium dihydrogen EDTA (CAS 139-33-3) was conducted in rats. In this study a NOAEC for local effects could not be established due to histopathological findings in the lungs noted at the lowest exposure concentration. A single inhalation exposure to 1000 mg/m³ disodium dihydrogen EDTA for 6 hours caused lethality in 6 out of 20 male rats. Histological examination of the lung of the dead rats revealed congestion, edema, multifocal hemorraghes and inflammatory cell infiltrates. Inhalation exposure of rats to disodium dihydrogen EDTA for 6 hours per day on 5 consecutive days caused concentration dependent lesions in the larynx and lungs that were fully reversible within 14 days. Due to histopahological changes in the low dose group a no observed effect level for local effects could not be determined and the LOAEC for local effects was considered to be 30 mg/m3. The NOAEC for systemic effects was considered to be 30 mg/m3 air based on reduced body weight, food consumption and clinical signs noted at 300 mg/m3.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEC

3 mg/m³

Study duration:

subchronic

Species:

rat

Quality of whole database:

The available information comprises an adequate and reliable study (Klimisch score 1) from a source substance with similar structure and intrinsic properties. Read-across is justified based on (bio)transformation to common compound(s) (refer to endpoint discussion for further details). The selected study is thus sufficient to fulfil the standard information requirements set out in Annex IX, 8.5, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006.

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Justification for read-across

There are no reliable experimental data available regarding the short-term or subchronic repeated dose toxicity of trisodium hydrogen EDTA (CAS 150-38-9). However, long-term toxicity studies with the target substance trisodium hydrogen EDTA are available. Thus, read-across from an appropriate source substance, disodium dihydrogen EDTA (CAS 139-33-3), is conducted in accordance with Regulation (EC) No 1907/2006, Annex XI, 1.5 in order to fulfil the standard information requirements defined in Regulation (EC) No 1907/2006, Annex VIII, 8.6. (Bio)transformation to common compounds are the basis of read-across. A detailed justification for the analogue read-across approach is provided in the technical dossier (see IUCLID Section 13).

Oral route

A 90 days feeding study of disodium dihydrogen EDTA (CAS 139-33-3) in rats revealed a NOAEL of 500 mg/kg bw (Wynn, 1970). Groups of 10 male Holzman rats received 1, 5 and 10 % (corresponding to 500, 2500 and 5000 mg/kg bw/day) test item in the diet for 90 days. The mid and high dose animals expressed a significant decrease of body weights and food consumption. Dose dependent mortality was evident by 20 % in the 5 % and 60 % in the 10 % group. In these groups animals exhibited diarrhea and were emaciated. Water consumption was increased. In the high dose there was an intermittent decrease of hematocrite and hemoglobin levels, livers appeared to be pale. Histological investigation failed to reveal any pathological alteration. From this investigation, a NOAEL of 500 mg/kg bw/day can be deduced for male rats. It should be noted that in this study no complete clinical biochemistry has been performed as required by the OECD 408 guideline.

A two year feeding study with trisodium hydrogen EDTA (CAS 139-33-3) to rats revealed a NOAEL of 495 mg/kg/day (corresponding to 7500 ppm in the diet) (NTIS, 1977). In this feeding study with two dose levels, 3750 ppm and 7500 ppm (corresponding to 248 and 495 mg/kg bw/day), no substance related toxic effects were observed. The same study at the same dose levels (3750 ppm and 7500 ppm; corresponding to approximately 469 and 938 mg/kg bw/day) conducted with mice showed a NOAEL of 938 mg/kg bw/day. There were also no treatment related changes.

Inhalation route

In a subchronic repeated dose toxicity study (BASF SE, 2014) according to OECD guideline No. 413, Wistar rats were exposed to a respirable dust aerosol of disodium dihydrogen EDTA for 6h/d on 5 consecutive d/w for 13 weeks (65 exposures in total) at concentrations of 0.5, 3, 15 mg/m³ air. Inhalation exposure of rats did not lead to any test item-related clinical signs of toxicity. Nor were there any effect on clinical chemistry, hematology. Histological examination revealed some effects in larynx at the highest tested concentration of 15 mg/m³ in females. No signs of systemic toxicity were observed up to a concentration of 15 mg/m³.

Signs of local toxicity were observed only at the high concentration of 15 mg/m³. Under the current test conditions, the No Observed Adverse Effect Concentration (NOAEC) for local effects in the larynx was 3 mg/m³, the NOAEC for systemic effects was 15 mg/m³.

The local key effect of respirable disodium dihydrogen EDTA in the respiratory tract (larynx) is assumed to be mainly concentration-related; hence, the impact of exposure time should be low at subcritical concentrations, which was confirmed by the 90 day study: although the number of exposures was factor 13 higher than in the 5-day dose-range-finder study, the local effects at 15 mg/m³ in the subchronic inhalation study were comparably mild compared to the 5-day dose-range-finder study (BASF SE, 2010) that showed a more severe effect at 30 mg/m³.

In a supporting subacute repeated dose toxicity study (BASF SE, 2010), 10 male Wistar rats per concentration were exposed to a respirable dust aerosol of disodium hydrogen EDTA for 6 hours per day for 5 consecutive days at concentrations of 30, 300, 1000 mg/m³ air. The study was planned as range finder study and conducted according to OECD Guideline 412.

Exposure in the high dose group (1000 mg/m³) was for one day only due to mortality observed. Inhalation exposure to 1000 mg/m³ disodium EDTA for 6 hours caused lethality in 6 out of 20 male rats. Histological examination of the lung of the dead rats revealed congestion, edema, multifocal hemorrhages and inflammatory cell infiltrates. Inhalation exposure of rats to disodium hydrogen EDTA for 6 hours per day, 5 consecutive days caused concentration-dependent lesions in the larynx and lungs that were fully reversible within 14 days. Due to histopathological changes in the respiratory tract of the low dose group, a NOAEC for local effects could not be determined. The LOAEC for local effects was considered to be 30 mg/m³ air. The NOAEC for systemic effects was considered to be 30 mg/m³ air based on reduced body weight, food consumption and clinical signs noted at 300 mg/m³.

Justification for classification or non-classification

The available data on oral subchronic repeated dose toxicity from a 90-day rat study conducted with the source substance disodium dihydrogen EDTA (CAS 139-33-3) revealed a NOAEL of 500 mg/kg bw/day. Therefore, no adverse effects are expected for the target substance at doses up to and including 500 mg/kg bw/day. Therefore and based on read across, data of trisodium hydrogen EDTA with respect to oral repeated dose exposure do not meet the classification criteria according to Regulation (EC) No. 1272/2008, and are therefore conclusive but not sufficient for classification.

The available data on inhalation repeated dose toxicity as available from a 90 day study in rats conducted with the source substance disodium hydrogen EDTA (CAS 139-33-3) revealed a local LOAEC of 15 mg/m³. Therefore, and based on read across the target substance is classified according to Regulation (EC) No. 1272/2008 as STOT Rep. Exp. 2, H373.

It is justified to classify trisodium hydrogen EDTA for repeated dose effects due to the low concentrations of the source substance, disodium hydrogen EDTA (CAS 139-33-3) that induces the local effects with a potential human relevance of the effects. However, due to the low severity and incidence of the effects at 15 mg/m³ in the subchronic toxicity study and the reversibility of the local effects, a STOT RE Cat.2 (H373: May cause damage to organs through prolonged or repeated exposure) is considered sufficiently conservative.