Registration Dossier

Administrative data

Description of key information

The acute oral LD50 of K3EDTA is 2800 mg/kg bw as determined by read-across.

Dermal exposure is unlikely thus no study was performed.

The acute inhalative LD50 of K3EDTA is > 1000 mg/m³ as determined by read-across.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Referenceopen allclose all

Endpoint:
acute toxicity: oral
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Principles of method if other than guideline:
various methods as several studies are reported in this review paper.
GLP compliance:
not specified
Test type:
other: various. not specified
Sex:
male/female
Dose descriptor:
LD50
Effect level:
3 700 mg/kg bw
Based on:
test mat.
Remarks on result:
other: Wistar Rats, Disodium EDTA, Hasegawa et al 1989
Sex:
not specified
Dose descriptor:
LD50
Effect level:
12 000 mg/kg bw
Based on:
test mat.
Remarks on result:
other: Dogs, Sodium EDTA, FDA 1998
Sex:
not specified
Dose descriptor:
LD50
Effect level:
7 000 mg/kg bw
Based on:
test mat.
Remarks on result:
other: Rabbit, Sodium EDTA, FDA 1998
Sex:
not specified
Dose descriptor:
LD50
Effect level:
> 4 000 - < 8 000 mg/kg bw
Based on:
test mat.
Remarks on result:
other: Rats, Trisodium EDTA, Dow Chemical Co, 1987
Sex:
not specified
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Remarks on result:
other: Rats,Disodium EDTA, BASF, 1996
Conclusions:
The sodium salts of EDTA were essentially non-toxic based on observed effects in acute oral toxicity tests, with LC50> 2000 mg/L for all species tested.
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Comparable to OECD 401 guideline study with acceptable restrictions [Body weight was only determined at the beginning of the study (OECD: weekly); Observation period: 7 days (OECD:14 days)]
Principles of method if other than guideline:
BASF-TEST: In principle, the methods described in the OECD Guideline 401 were used. Young adult laboratory rats were purchased from breeder. Usually the source and strain of animals were not documented. Several groups of 5 rats per sex and dose were treated simultaneously by gavage with preparations of the test substance in suitable vehicle. The concentrations of these preparations were used to achieve comparable volumes per kg body weight. Group-wise documentation of clinical signs was performed over the 7 day study period. Body weight was determined before the start of the study only, as it was needed for determination of dose
GLP compliance:
no
Test type:
standard acute method
Species:
rat
Strain:
not specified
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Mean body weight at study initiation:
259 g males/ 211 g females
Route of administration:
oral: gavage
Vehicle:
CMC (carboxymethyl cellulose)
Details on oral exposure:
DOSAGE PREPARATION:
- Stock solutions prepared:
30%
- Dose volume applied:
2500 mg/kg bw dose group: 8.33 ml/kg bw
3200 mg/kg bw dose group: 10.66 ml/kg bw
4000 mg/kg bw dose group: 13.33 ml/kg bw
5000 mg/kg bw dose group: 16.66 ml/kg bw
6400 mg/kg bw dose group: 21.4 ml/kg bw
Doses:
2500; 3200; 4000; 5000; 6400 mg/kg bw
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
- Duration of observation period following administration: 7 days;
- The animals were observed for mortality and clinical signs of toxicity;
- Frequency of observations: Several times on the application day, thereafter once each working day;
- Body weights were only recorded at the beginning of the study;
- Necropsy of survivors and animals which died performed: yes
Sex:
male/female
Dose descriptor:
LD50
Effect level:
2 800 mg/kg bw
Mortality:
- One female died in the 2500 mg/kg bw dose group; 9/10 animals died in the 3200 mg/kg bw dose group and all animals of the higher dose groups (see table 1).
Clinical signs:
- 2500, 3200 and 4000 mg/kg bw: directly after application: accelerated respiration, squatting posture, twitching, ataxia, red eyes, some animals showed light secretion, reluctance to move; the next day: squatting posture, contaminated fur, intermittened respiration, reluctance to move; fully reversible within 6 days
- 5000 and 6400 mg/kg bw: directly after application: accelerated respiration, squatting posture, twitching, ataxia, red eyes, some animals showed light secretion, reluctance to move; later: prone position
Body weight:
Body weights were not recorded during and at the end of the observation period
Gross pathology:
Animals which died:
- heart: acute dilatation, venous hyperemia
- liver: congestion
- gut: diarrhea like content
- stomach: dilatation
- kidneys: degeneration
Animals which were sacrificed:
- nothing abnormal detected

Table 1: Mortalities of rats after oral application

2500 mg/kg bw 3200 mg/kg bw 4000 mg/kg bw 5000 mg/kg bw 6400 mg/kg bw
1 h male  0/5 0/5 0/5 0/5 0/5
female 0/5 0/5 0/5 0/5 0/5
24 h male  0/5 3/5 5/5 5/5 5/5
female 1/5 5/5 5/5 5/5 5/5
48 h male  0/5 3/5 5/5 5/5 5/5
female 1/5 5/5 5/5 5/5 5/5
7 d male  0/5 4/5 5/5 5/5 5/5
female 1/5 5/5 5/5 5/5 5/5
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 800 mg/kg bw

Acute toxicity: via inhalation route

Link to relevant study records

Referenceopen allclose all

Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2009-2010
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
other: OECD Guideline 412, dose range finding study
GLP compliance:
yes (incl. QA statement)
Test type:
acute toxic class method
Limit test:
yes
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Batch No.: of test material: 06088797V0
Species:
rat
Strain:
Wistar
Sex:
male
Details on test animals or test system and environmental conditions:
Age: 7 weeks (approx)
Identification: Tattooing of ears
All animals free of disease and clinical signs
Rats housed together (5 animals per cage) in Polysulfon cages
Bedding: Type Lignocel fibres, dust free bedding
Woodne gnawing blocks for enrichment
Rooms: Fully ariconditioned, temperature range 20 to 24 degrees celcius, 30 to 70% humidity
Light/dark cycle of 12 hours (6 am to 6pm light, 6pm to 6 am dark)
Food, drinking water and bedding/enrichment materials were analysed for chemical and microbiological contaminants.
Route of administration:
inhalation: aerosol
Type of inhalation exposure:
nose/head only
Vehicle:
air
Remark on MMAD/GSD:
MMAD / GSD: MMAD : 2.0 - 2.7 µm
GSD: 2.0 - 2.22
Details on inhalation exposure:
A dust aerosol was generated using a dust generator and compressed air inside a mixing stage mixed with conditioned dilution air and passed into the inhalation system. The test substance was mixed with Aerosil R972 prior to facilitate aerosol generation.

The inhalation atmosphere was maintained inside aerodynamic exposure systems consisting of cylindrical inhalation chamber made of stainless steel sheeting and cone shaped outlets and inlets. The rats were restrained in glass exposure tubes with their snouts projecting into the inhalation chamber.
The animals did not ave access to feed or water during the exposure period.
Analytical verification of test atmosphere concentrations:
yes
Remarks on duration:
Exposures: 6 hours per day High dose group (1000 mg/m³) was exposued for 1 day only All other groups were exposed for 5 consecutive days
Concentrations:
Concentrations of the inhalation atmospheres were analyzed using gravimetry. Daily means were calculated based on 2 measured samples per concentration and exposure. From the Daily mean values of each concentration, mean concentrations and standard deviations were derived.
Consistency of concentrations in each inhalation system was continuously monitored using scattered light photometry.
Particle size analysis was conducted using a cascade impactor.
The concentrations were [mg/m³]:
- dose group one: 30 (nominal), 33.3 +- 2.3 (actual)
- dose group one: 300 (nominal), 320 +- 27 (actual)
- dose group one: 1000 (nominal), 1103 +- 52 (actual)
No. of animals per sex per dose:
10 animals per dose group
An additional 10 animals for the high dose group and control
Control animals:
yes
Details on study design:
The animals were exposed to a respirable dust aerosol for 6 hours per day for 5 consecutive days. The exception was the high dose group (1000mg/m³) where exposure was for one day only due to mortality observed.
In the control, low and mid dose groups, 5 animals were sacrificed on the day after the last exposure period and 5 were sacrificed 17 days after the last exposure.
10 additional control animals and the 14 surviving high dose group animals were sacrificed on day 14 of the study (14 days after first exposure).
Key result
Sex:
male
Dose descriptor:
LC50
Effect level:
>= 1 103 mg/m³ air (analytical)
95% CL:
>= 1 051 - <= 1 155
Exp. duration:
6 h
Mortality:
6 deaths in the high dose group on days 0 and 1. Accelerated respiration, respiration sounds, piloer
ection, red encrusted nose, hunched position; Mid dose group - accelerated respiration, respiration
sounds, piloerection, reduced fur care

Detials on Results

Histopathology results:

High dose: Multifocal hemorraghes in the lungs; Inflammatory cell infiltrates

Mid dose:

Larynx: laryngeal, epithelial necrosis, multifocal, in various levels of the larynx

Inflammatory cell infiltrates in various levels of the larynx

laryngeal squamous metaplasia, multifocal, in various levels of the larynx

Regenerative hyperplasia of the laryngeal epithelium, multifocal, in various levels of the larynx

Lungs: Regenerative hyperplasia of bronchiolar epithelium (predominantly: medium bronchi, terminal bronchioles)

Mucous cell hyperplasia in large bronchi

interstitial infiltration of eosinophylic granulocytic cells

Low dose:

Larynx: Laryngeal, epithelial necrosis, multifocal, at the base of the epiglittis (level 1)

Inflammatory cell infiltrates at the base of the epiglottis (level 1)

Lungs: Regenerative hyperplasia of the bronchiolar epithelium (predominantly medium bronchi and terminal bronchioles)

Mucous cell hyperplasia in large bronchi

interstitial infiltration of eosinophylic granulocytic cells.

There were no histopathological findings in any of the recovery group animals. Thus all pathology was reversible within the recovery period.

Interpretation of results:
Category 4 based on GHS criteria
Conclusions:
In a repeated dose range finding study rats were exposed to aerosol of the test substance.
6 death occured in the high dose group. No deaths occured in the middle dose group (300 mg/m³).
Taking into account that the exposure duration was significantly extended compared to an acute toxicity study it is reasonable that less than 50% of the animals of the highest dose group would die when exposed to the substance once for 4 hours.
Thus the LC50 can be stated as:
LC50 > 1000 mg/m³ (nominal)
LC50 > 1103 mg/m³ (actual)
Executive summary:

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 hemorraghes and inflammatory cell infiltrates. Inhalation exposure of rats to disodium EDTA for 6 hours per day, 5 consecutive days cause concentration dependant lesions inthe larynx and lungs that were fully reversible within 14 days. Due to histopahological changes in the low dosegroup a no observed effect level could not be determined.


In a subacute repeated dose toxicity study (BASF, 2009) 10 male Wistar rats per dose were exposed to a respirable dust aerosol of Na2H2EDTA for 6 hours per day for 5 consecutive days at concentrations of 0, 30, 300, 1000 mg/m³ air (also see capter 7.5).

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 hemorraghes and inflammatory cell infiltrates.

Inhalation exposure of rats to disodium EDTA for 6 hours per day, 5 consecutive days cause concentration dependant 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 could not be determined.

The LOAEC was considered to be 30 mg/m³ air.

Endpoint:
acute toxicity: inhalation
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
2009-2010
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Justification for type of information:
Tripotassium hydrogen ethylenediaminetetraacetate dissociates into potassium cations and anions of edetic acid.
The first are known to be non-toxic as potassium is an essential element for all species.
The toxicity by the latter is evaluated by a read-across approach to disodium edetate (CAS 139-33-3).
This substance dissociates in non-toxic as well and exactly the same species of edetic acid. Thus read-across is justified.
Reason / purpose for cross-reference:
read-across source
Qualifier:
according to guideline
Guideline:
other: OECD Guideline 412, dose range finding study
GLP compliance:
yes (incl. QA statement)
Test type:
acute toxic class method
Limit test:
yes
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Batch No.: of test material: 06088797V0
Species:
rat
Strain:
Wistar
Sex:
male
Details on test animals or test system and environmental conditions:
Age: 7 weeks (approx)
Identification: Tattooing of ears
All animals free of disease and clinical signs
Rats housed together (5 animals per cage) in Polysulfon cages
Bedding: Type Lignocel fibres, dust free bedding
Woodne gnawing blocks for enrichment
Rooms: Fully ariconditioned, temperature range 20 to 24 degrees celcius, 30 to 70% humidity
Light/dark cycle of 12 hours (6 am to 6pm light, 6pm to 6 am dark)
Food, drinking water and bedding/enrichment materials were analysed for chemical and microbiological contaminants.
Route of administration:
inhalation: aerosol
Type of inhalation exposure:
nose/head only
Vehicle:
air
Remark on MMAD/GSD:
MMAD / GSD: MMAD : 2.0 - 2.7 µm
GSD: 2.0 - 2.22
Details on inhalation exposure:
A dust aerosol was generated using a dust generator and compressed air inside a mixing stage mixed with conditioned dilution air and passed into the inhalation system. The test substance was mixed with Aerosil R972 prior to facilitate aerosol generation.

The inhalation atmosphere was maintained inside aerodynamic exposure systems consisting of cylindrical inhalation chamber made of stainless steel sheeting and cone shaped outlets and inlets. The rats were restrained in glass exposure tubes with their snouts projecting into the inhalation chamber.
The animals did not ave access to feed or water during the exposure period.
Analytical verification of test atmosphere concentrations:
yes
Remarks on duration:
Exposures: 6 hours per day High dose group (1000 mg/m³) was exposued for 1 day only All other groups were exposed for 5 consecutive days
Concentrations:
Concentrations of the inhalation atmospheres were analyzed using gravimetry. Daily means were calculated based on 2 measured samples per concentration and exposure. From the Daily mean values of each concentration, mean concentrations and standard deviations were derived.
Consistency of concentrations in each inhalation system was continuously monitored using scattered light photometry.
Particle size analysis was conducted using a cascade impactor.
The concentrations were [mg/m³]:
- dose group one: 30 (nominal), 33.3 +- 2.3 (actual)
- dose group one: 300 (nominal), 320 +- 27 (actual)
- dose group one: 1000 (nominal), 1103 +- 52 (actual)
No. of animals per sex per dose:
10 animals per dose group
An additional 10 animals for the high dose group and control
Control animals:
yes
Details on study design:
The animals were exposed to a respirable dust aerosol for 6 hours per day for 5 consecutive days. The exception was the high dose group (1000mg/m³) where exposure was for one day only due to mortality observed.
In the control, low and mid dose groups, 5 animals were sacrificed on the day after the last exposure period and 5 were sacrificed 17 days after the last exposure.
10 additional control animals and the 14 surviving high dose group animals were sacrificed on day 14 of the study (14 days after first exposure).
Key result
Sex:
male
Dose descriptor:
LC50
Effect level:
>= 1 103 mg/m³ air (analytical)
95% CL:
>= 1 051 - <= 1 155
Exp. duration:
6 h
Mortality:
6 deaths in the high dose group on days 0 and 1. Accelerated respiration, respiration sounds, piloer
ection, red encrusted nose, hunched position; Mid dose group - accelerated respiration, respiration
sounds, piloerection, reduced fur care

Detials on Results

Histopathology results:

High dose: Multifocal hemorraghes in the lungs; Inflammatory cell infiltrates

Mid dose:

Larynx: laryngeal, epithelial necrosis, multifocal, in various levels of the larynx

Inflammatory cell infiltrates in various levels of the larynx

laryngeal squamous metaplasia, multifocal, in various levels of the larynx

Regenerative hyperplasia of the laryngeal epithelium, multifocal, in various levels of the larynx

Lungs: Regenerative hyperplasia of bronchiolar epithelium (predominantly: medium bronchi, terminal bronchioles)

Mucous cell hyperplasia in large bronchi

interstitial infiltration of eosinophylic granulocytic cells

Low dose:

Larynx: Laryngeal, epithelial necrosis, multifocal, at the base of the epiglittis (level 1)

Inflammatory cell infiltrates at the base of the epiglottis (level 1)

Lungs: Regenerative hyperplasia of the bronchiolar epithelium (predominantly medium bronchi and terminal bronchioles)

Mucous cell hyperplasia in large bronchi

interstitial infiltration of eosinophylic granulocytic cells.

There were no histopathological findings in any of the recovery group animals. Thus all pathology was reversible within the recovery period.

Interpretation of results:
Category 4 based on GHS criteria
Conclusions:
In a repeated dose range finding study rats were exposed to aerosol of the test substance.
6 death occured in the high dose group. No deaths occured in the middle dose group (300 mg/m³).
Taking into account that the exposure duration was significantly extended compared to an acute toxicity study it is reasonable that less than 50% of the animals of the highest dose group would die when exposed to the substance once for 4 hours.
Thus the LC50 can be stated as:
LC50 > 1000 mg/m³ (nominal)
LC50 > 1103 mg/m³ (actual)
Executive summary:

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 hemorraghes and inflammatory cell infiltrates. Inhalation exposure of rats to disodium EDTA for 6 hours per day, 5 consecutive days cause concentration dependant lesions inthe larynx and lungs that were fully reversible within 14 days. Due to histopahological changes in the low dosegroup a no observed effect level could not be determined.


In a subacute repeated dose toxicity study (BASF, 2009) 10 male Wistar rats per dose were exposed to a respirable dust aerosol of Na2H2EDTA for 6 hours per day for 5 consecutive days at concentrations of 0, 30, 300, 1000 mg/m³ air (also see capter 7.5).

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 hemorraghes and inflammatory cell infiltrates.

Inhalation exposure of rats to disodium EDTA for 6 hours per day, 5 consecutive days cause concentration dependant 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 could not be determined.

The LOAEC was considered to be 30 mg/m³ air.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LC50
Value:
1 103 mg/m³

Acute toxicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Based on read-across from the related substances including disodium dihydrogen ethylenediaminetetraacetate, an acute oral LC50> 2000 mg/L was determined for tripotassium hydrogen EDTA.

Both sodium and potassium ions have low toxicity levels. E.g. the recommended daily intake for humans is 1 – 3g sodium and 2 – 3.4g potassium with symptoms reported for insufficient (hypokaliaemy) as well as overdoses (hyperkaliaemy) of potassium only. The potassium ion therefore does not contribute to the toxicity or ecotoxicity of the tripotassium salt of EDTA.

In the naturally-buffered conditions in the plasma in the human body and in animals, the anions will dissociate from the EDTA, leaving the EDTA anion available to chelate with other cations (as is its function).  This is also true in in vitro experiments that are buffered.  So, it does not matter what the cationic component of the salt is.  Therefore, using the available study data for the disodium salt of EDTA is valid for registration purposes for the tripotassium salt of EDTA.

Justification for classification or non-classification