Disodium dihydrogen ethylenediaminetetraacetate

Endpoint summary

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

basic toxicokinetics in vivo

Type of information:

read-across based on grouping of substances (category approach)

Adequacy of study:

weight of evidence

Justification for type of information:

READ-ACROSS CATEGORY APPROACH
The complete Read-across justification text incl. data matrix is attached in chapter 13 "Read-across Justification_2019_Tox" (two documents attached).

Read-across justification EDTA-DTPA-HEDTA aminocarboxylic acid-based metal chelants (2019). Category approach according to RAAF and the REACH Practical guide 6: How to report read-across and categories; REACH TGD, Chapter R.6: QSARs and grouping of chemicals.

Part 1: Physical Chemistry & Toxicology/Human Health
Part 2: Environmental Fate & Ecotoxicology

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across: supporting information

Reference 2

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

3 (not reliable)

Rationale for reliability incl. deficiencies:

other: Significant methodological deficiencies (Number of animals unclear, exact dose unclear, no individual data given)

Objective of study:

excretion

Principles of method if other than guideline:

Rats got ip applications of 14[C] labelled EDTA for 10 consecutive days. Additionally one control group was treated with 0.9 % saline and another group with diethylenetriaminepentaacetate (DTPA). Urine and feces were collected daily and the radioactivity was determined. At the end of the experiment the kidneys were analysed for histolgogic changes.

GLP compliance:

no

Specific details on test material used for the study:

RADIOLABELLING INFORMATION
- Specific activity: 1-2 mCi/mmol

Radiolabelling:

yes

Remarks:

14C

Species:

rat

Strain:

other: Long-Evans and Sprangue-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Individual metabolism cages: yes
- Diet: ad libitum
- Water: ad libitum

Route of administration:

intraperitoneal

Vehicle:

not specified

Details on exposure:

DOSAGE PREPARATION
The radioactive material was diluted and mixed with “cold” salt. The total activity injected per day ranged from 1.1 to 8.8E6 dpm.

Duration and frequency of treatment / exposure:

once daily for 10 consecutive days

Dose / conc.:

300 mg/kg bw/day

Dose / conc.:

436 mg/kg bw/day

No. of animals per sex per dose / concentration:

no data

Control animals:

other: yes 0.9% saline treated animals

Details on dosing and sampling:

PHARMACOKINETIC STUDY
- Body fluids sampled: urine, faeces
- Time and frequency of sampling: daily

- Tissues sampled: Kindneys; 24 h after the last injection

Details on excretion:

- 66 - 92 % of the total dose incjected was recovered in urine within 24 h after application
- usually less than 5% of the dose was recovered in feces
- in 3 rats fecal excretion amounted to 8, 16.3 and 23.8 % of the dose. (In any individual animal the occurrence of a very high fecal excretion on a given day was invariably accompanied by a low urinary excretion and was considered to be due to intestinal puncture incident to the intraperitoneal injection)
- 24 h after the last application the kidneys showed less than 0.1 % aft the activity injected.
- DTPA showed the same excretion patterns

Metabolites identified:

not measured

CLINICAL OBSERVATIONS:

- 4.3 % weight loss

- dull, soiled coat

- diarrhea

HISTOLOGICAL CHANGES

- The histologic changes were grade 4 in the rat that received the largest dose of CaNa2EDTA, and grade 1 - 2 in the lower doses

grade 1: small, clear, randomly dispersed, well demarcated vacuoles in the cytoplasm of the epithelium of the proximal tubule

grade 2: an increased number of vacuoles, but the cytoplasm remained clearly visible

grade 3: larger vacuoles, presumably the product of coalescence, replaced the cytoplasm but did not displace the nucleus

grade 4: extrusion of cell contents through the disrupted apical border and cell nuclei were sometimes displaced

Reference 3

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Objective of study:

absorption

excretion

metabolism

toxicokinetics

Principles of method if other than guideline:

Metabolism studies were conducted on the rat. First distribution and balance studies were carried out with male animals. The animals were housed individually in metabolism cages for the separate collection of expired CO2, urine and feces. In a second series of experiments detailed studies on blood and urine were made on female animals. Studies were made after intraperitoneal, intravenous, intramuscular, and oral administration (intubation).

GLP compliance:

no

Radiolabelling:

yes

Remarks:

14C

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Weight at study initiation: 200 - 250 g

Route of administration:

other: i.p., i.v., i.m. and oral

Vehicle:

water

Duration and frequency of treatment / exposure:

single dose

Dose / conc.:

50 mg/kg bw (total dose)

Remarks:

(additionally one study was performed using 250 mg/kg bw for i.p. application)

No. of animals per sex per dose / concentration:

no data

Control animals:

no

Details on absorption:

Oral studies: 2-18 % (most of the value in the range of 2-4 %)

Details on distribution in tissues:

No organ retained more than 0.5 % of the dose.

Details on excretion:

ORAL
- 2-18 % are excreted in the urine
- 80-95 % are excreted via feces within 24 h
- less than 0.1 % of the dose is exhaled as CO2

PARENTERAL ADMINISTRATION
- 95 - 98 % dose appeared in the urine within 6 h (i.v.: 96.09 %; i.p.: 98.67 %; i.m.: 95.35 %)
- less than 0.1 % of the dose was exhaled as CO2
- the dose size 250 mg/kg bw vs 50 mg/kg bw had no effect on the excretion kinetics
(see table 1)

Toxicokinetic parameters:

half-life 1st: 32 min (i.m. application)

Toxicokinetic parameters:

half-life 1st: 31 min (i.v. application)

Toxicokinetic parameters:

half-life 1st: 35 min (i.p. application)

Toxicokinetic parameters:

half-life 1st: no data (oral)

Details on metabolites:

Chromatography provided evidence that EDTA is not metabolized but passes the body unchanged.

Table 1: Distribution of 14C activity following administration of Ca C14-EDTA to rats

	time after ip administration			oral administration
Tissue sample	1.5 h	6 h	24 h	24 h
Urine	85.2	95.7	94.6	10.3
Feces	0.5	2.0	3.6	88.3
Expired CO2		0.05	0.08
Skin	2.3	0.8	0.3	0.16
Kidney	1.4	0.3	0.3	0.04
GI tract	0.2	0.2	0.7	0.45
Liver	0.5	0.2	0.05	0.18
Skeleton		0.3	0.1	0.08
Muscle		0.1	0.3	0.36
Blood	1.7	0.1	0.01	0.04
Remains	8.1	0.03	0.01	0.03

Reference 4

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Objective of study:

other: Effects of CaNa2EDTA on the metabolism of Zn, Cu, Mn

Principles of method if other than guideline:

The effect of calcium disodium ethylenediaminetetraacetate (CaNa2EDTA) on the metabolism of Zn, Cu and Mn was investigated in mongrel female dogs. Dogs received either CaNa2EDTA subcutaneously or 0.9 % NaCl (controls). Urine was collected every 6 h. Tissue samples were obtained from liver, kidney, duodenum, muscle, hair, skin and bone post exsanguination.

GLP compliance:

no

Specific details on test material used for the study:

TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Preparation: disodium EDTA was mixed with equimolar quantities of CaCO3, in water and heated with constant stirring until excess CO2 was expelled and the final solution was adjusted to pH 7.4 with NaOH.

Radiolabelling:

no

Species:

dog

Strain:

other: Mongrel

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Canine Control Center
- Diet: Purina Dog Chow (concentration of Zn, Cu or Mn was 1.25; 0.16; or 0.98 mg/g dry weight, respectively)
- Water: ad libitum
- Acclimation period: 3-4 weeks

ENVIRONMENTAL CONDITIONS
- Temperature: 25 °C

Route of administration:

subcutaneous

Vehicle:

water

Duration and frequency of treatment / exposure:

54 h

Dose / conc.:

280 other: mg/kg/6 h

Remarks:

original data: 0.75 mmol/kg/6 h

No. of animals per sex per dose / concentration:

5

Control animals:

other: 0.9 % sterile NaCl

Details on dosing and sampling:

- Body fluids sampled: urine; every 6 h
- Tissues sampled: liver, kidney, upper duodenum (upper small intestine), muscle (thigh), bone (femur), hair and skin.

Statistics:

Analysis of variance (ANOVA) and Duncan’s new multiple range test were used to test for differences between groups. Differences between means were tested by two-way unpaired Student’s t-test.

Details on excretion:

- CaNa2EDTA to dogs caused a significant increase in urine flow when compared to controls

URINARY EXCRETION OF Zn
- significant increase in the excretion of Zn when compared to control (cumulative excretion within 54 h: 24.92 ± 0.346 mg compared to 1.58 ± 0.24 mg in the control)
- Maximal excretion of Zn occurred between 6 and 12 h of treatment (17 % of total Zn)

URINARY EXCRETION OF Cu
CaNa2EDTA treatment resulted in a significant increase in the excretion of Cu when compared to control (cumulative excretion within 54 h: 0.922 ± 0.24 mg compared to 0.12 ± 0.03 mg in the control)

URINARY EXCRETION OF Mn
CaNa2EDTA treatment resulted in a significant increase in the excretion of Mn when compared to control (cumulative excretion within 54 h: 0.582 ± 0.166 mg compared to 0.042 ± 0.01 mg in the control)

Metabolites identified:

no

TISSUE LEVELS OF Zn, Cu AND Mn

- statistically significant decrease in the tissue levels of Zn (small intestine, hair and skin) and Mn (hair) when compared to controls

- statistically significant increase in the concentration of Cu in the kidney when compared to controls

Reference 5

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Study meets generally accepted scientific principles

Objective of study:

excretion

Principles of method if other than guideline:

Rats were injected with a single dose of [14C]EDTA. The concentration of EDTA in urine and kidney homogenates was determined at several time points.

GLP compliance:

no

Specific details on test material used for the study:

RADIOLABELLING INFORMATION
- Specific activity (if radiolabelling): 5 µCi/100 mg

Radiolabelling:

yes

Remarks:

14C

Species:

rat

Strain:

other: CD

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River
- Weight at study initiation: 200 - 300 g
- Individual metabolism cages: yes
- Diet: NIH-31 rat food ad libitum
- Water: tap water ad libitum

Route of administration:

intraperitoneal

Vehicle:

not specified

Duration and frequency of treatment / exposure:

single treatment

Dose / conc.:

400 mg/kg bw (total dose)

No. of animals per sex per dose / concentration:

18

Control animals:

other: yes, 0.9 % saline treated animals

Details on study design:

18 rats were each injected with a single dose of [14C]EDTA and placed in plastic metabolic cages for urine collection. Six were killed at 16, 22, or 28 h after the injection. One control rat was killed at each time point. Kidneys were removed, weight and homogenized. Radioactivity in the urine and kidney homogenates was measured by scintillation counting in order to calculate EDTA concentrations.

Details on dosing and sampling:

PHARMACOKINETIC STUDY
- Body fluids sampled: urine
- Tissues sampled: Kidneys
- Time and frequency of sampling: urine: 16, 22, 28 h
- Method type for identification: Liquid scintillation counting

Statistics:

Student's t-test, ANOVA and Dunnett's test

Details on distribution in tissues:

- During the 22 h period, the renal EDTA concentration was about 80 µg/g kidney homogenate. This equals 0.1-0.2 % of the EDTA injected.

Details on excretion:

- By 22 h, 80 ± 3 % of the injected dose had been collected in the urine. This amount stayed approximately the same until 28 h after application.

Metabolites identified:

not measured

Reference 6

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

3 (not reliable)

Rationale for reliability incl. deficiencies:

other: Unsuitable test method

Objective of study:

excretion

Qualifier:

no guideline followed

Principles of method if other than guideline:

At regular intervals up to 32 h after a single dose of 95 mg Na2EDTA the gastrointestinal tract was removed and the stomach, small intestine and colon were subjected to thorough washing before determining the EDTA concentrations of each of these sections.

GLP compliance:

no

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Source of test material: Sequestrene NA2, Alrose Chemical Co., Providence, RI, USA

Radiolabelling:

not specified

Species:

rat

Strain:

not specified

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: adult
- Weight at study initiation: 200 g

Route of administration:

oral: gavage

Vehicle:

not specified

Details on exposure:

PREPARATION OF DOSING SOLUTIONS: 100 mg Sequestrene NA2 suspended in 7 mL distilled water.

Duration and frequency of treatment / exposure:

one application

Dose / conc.:

95 other: mg/animal

Remarks:

corresponding to 475 mg/kg bw; assuming a body weight of 200 g

No. of animals per sex per dose / concentration:

no data

Control animals:

not specified

Details on study design:

no data

Details on dosing and sampling:

no data

Statistics:

no data

Details on absorption:

All EDTA had passed through the stomach within 12 h and 93 % of the dose was recovered in the colon after 32 h, which demonstrated a poor absorption from GI tract.

Details on distribution in tissues:

The distribution pattern in the gastrointestinal tract is as follows: A maximum urinary excretion of EDTA was reached 4 hours after administration, then gradually decreasing in concentration, and ending by 32 hours with a total of about 6 % of the ingested dose. In the stomach, no EDTA could be found by 12 hours. In the small intestines, the maximum EDTA peak was reached during the 4th hour, gradually tapering off and terminating at the end of 32 hours. In the colon (including caecum), about 90 % of the administered dose was recovered by 24 hours, with 93 % in 32 hours.

Details on excretion:

Urinary excretion over the period of 32 h cumulated to 6 % of the dose, the excretion via feces over 32 h cumulated to 93 %.

Details on metabolites:

no data

- When adults received daily doses of 95 mg Na2EDTA for 7 days the percentage of daily excretion in urine and feces was similar.

Reference 7

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

other: Documentation insufficient for assessment

Objective of study:

excretion

Qualifier:

no guideline followed

Principles of method if other than guideline:

Single doses of Na2EDTA were administered and the amount excreted in urine determined (method unknown).

GLP compliance:

no

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Source of test material: Sequestrene NA2, Alrose Chemical Co., Providence, RI, USA

Radiolabelling:

not specified

Species:

rat

Strain:

not specified

Sex:

not specified

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: adult rats
- Weight at study initiation: 200 g
- Housing: individual
- Individual metabolism cages: yes

Route of administration:

oral: gavage

Vehicle:

not specified

Details on exposure:

no data

Duration and frequency of treatment / exposure:

no data

Dose / conc.:

47.5 other: mg/animal

Remarks:

corresponding to 237.5 mg/kg bw; assuming a body weight of 200 g

Dose / conc.:

95 other: mg/animal

Remarks:

corresponding to 475.0 mg/kg bw; assuming a body weight of 200 g

Dose / conc.:

142.5 other: mg/animal

Remarks:

corresponding to 712.5 mg/kg bw; assuming a body weight of 200 g

No. of animals per sex per dose / concentration:

no data

Control animals:

not specified

Details on study design:

no data

Details on dosing and sampling:

no data

Statistics:

no data

Details on absorption:

no data

Details on distribution in tissues:

no data

Details on excretion:

The amount of EDTA excreted in urine was directly proportional to the amount ingested. The peak urinary excretion was after 4 h. The authors concluded that due to the linear relationship EDTA is most likely absorbed by diffusion.

Details on metabolites:

no data

Reference 8

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

3 (not reliable)

Rationale for reliability incl. deficiencies:

other: Significant methodological deficiencies

Objective of study:

excretion

Qualifier:

no guideline followed

Principles of method if other than guideline:

After oral administration of Na2EDTA or Na2CaEDT to rats, feces and urine was collected for 48 hours and the percentage of the administered dose excreted as EDTA was determined.

GLP compliance:

no

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Source of test material: Sequestrene NA2, Alrose Chemical Co., Providence, RI, USA

Radiolabelling:

no

Species:

rat

Strain:

not specified

Sex:

not specified

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: weanlings and adults were tested
- Metabolism cages: yes

Route of administration:

oral: gavage

Vehicle:

not specified

Details on exposure:

no further data

Duration and frequency of treatment / exposure:

single exposure

Dose / conc.:

600 mg/kg bw (total dose)

Remarks:

- equivalent to 1% EDTA in diet (conversion according to EU risk assessment)

No. of animals per sex per dose / concentration:

no data

Control animals:

no

Positive control reference chemical:

none

Details on study design:

no further data

Details on dosing and sampling:

PHARMACOKINETIC STUDY (excretion)
- Tissues and body fluids sampled: urine, feces
- Time and frequency of sampling: Urine and feces were collected for 2 days
- Other: Determination of EDTA was performed by the Modified Darbey's Colorimetric Method (1952)

Details on excretion:

see "Any other information on results incl. tables"

Metabolites identified:

no

Table 1: Metabolic recovery of EDTA from the urine and the feces of weanling and adult rats ingesting Sequestrene NA2 or Sequestrene NA2Ca in 48 hours.

Test Groups(age of animals)	Amount ingested		EDTA recovered from
	Sequestrene	EDTA	Urine		Feces		Total
	mg	mg	mg	%	mg	%	mg	%
Sequestrene NA2
Weanling	95.0	74.1	6.3	8.5	65.7	88.6	72.0	97.1
4-month	85.6	66.8	3.4	5.1	59.5	89.2	62.9	94.3
8-month	104.9	81.8	4.4	5.4	74.2	90.7	78.6	96.1
Sequestrene NA2Ca
4-month	136.4	96.2	4.4	4.6	84.1	87.4	88.5	92.0
8-month	143.7	101.3	4.5	4.5	90.7	89.6	95.2	94.1

Reference 9

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

3 (not reliable)

Rationale for reliability incl. deficiencies:

other: Inconsistent results; documentation insufficient

Objective of study:

excretion

Qualifier:

no guideline followed

Principles of method if other than guideline:

Rats were fed Sequestrene NA2 (=Na2 EDTA). The excreted amount of the test substance in the urine and faeces was investigated. The method used for the determination of the amount of Sequestrene NA2 present (= Na2 EDTA) in urine and feces of experimental animals was that described by Darbey (1952). The principle of this method is based on the formation of the stable soluble nickel complex of EDTA at an alkaline pH, precipitating the uncomplexed nickel, filtering and then releasing the nickel from the EDTA complex by dilute mineral acid. The released nickel is then determined colorimetrically with potassium dithio-oxalate.

GLP compliance:

no

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Source of test material: Sequestrene NA2, Alrose Chemical Co., Providence, RI, USA

Radiolabelling:

no

Species:

rat

Strain:

Wistar

Sex:

not specified

Details on test animals or test system and environmental conditions:

no data

Route of administration:

oral: feed

Vehicle:

not specified

Details on exposure:

no data

Duration and frequency of treatment / exposure:

no data

Dose / conc.:

300 mg/kg bw/day

Remarks:

original data: 0.5% of the diet, conversion according to EU risk assessment)

Dose / conc.:

600 mg/kg bw/day

Remarks:

original data: 1.0% of the diet, conversion according to EU risk assessment

Dose / conc.:

3 000 mg/kg bw/day

Remarks:

original data: 5.0% of the diet, conversion according to EU risk assessment

No. of animals per sex per dose / concentration:

no data

Control animals:

not specified

Details on study design:

no data

Details on dosing and sampling:

no data

Statistics:

no data

Details on absorption:

no data

Details on distribution in tissues:

no data

Details on excretion:

- 82.2 % of the ingested 0.5 % in diet dose was excreted in urine and feces thereof 99.4 % were recovered from feces and 0.6 % in urine.
- 44.5 % of the ingested 1.0 % in diet dose was excreted in urine and feces thereof 98.2 % were recovered from feces and 1.8 % in urine.
- 45.4 % of the ingested 5.0 % in diet dose was excreted in urine and feces thereof 97.5 % were recovered from feces and 2.5 % in urine.

Details on metabolites:

no data

Description of key information

In rat as well as in human studies CaNa2EDTA and Na2EDTA is poorly absorbed from the GI tract and the absorbed part rapidly excreted by urine. Therefore, one can rule out the danger of bioaccumulation. However, administration of EDTA salts results in an increased excretion of necessary ions like Zn, Mn or Ca. Short description of key information on absorption rate:

- CaNa2EDTA does not penetrate the skin.

Additional information

Some poorly reported toxicokinetics studies using the disodium salt of EDTA have been performed. Additionally studies using Ca and Na salts of EDTA are available. According to the dissociation equilibrium of edetic acid, administration of different sodium salts will result in the formation of various anionic species of EDTA in dependence on the intestinal pH value. In whatever salt EDTA is administered, it is likely to chelate metal ions in vivo. Therefore, the studies using CaNa2EDTA have been used as read-across (see chapter 13 for read-across justification). It can be assumed that the systemic absorption from the intestinal tract is low. The obtained data can be used to predict that dermal absorption should be even lower. Additionally absorbed EDTA does not undergo any biotransformation and is excreted unchanged.

In toxicokinetics studies on humans as well as rats the CaNa2 and Na salts of EDTA are poorly absorbed from the gastrointestinal tract (2 to 18 % in rats; less than 5 % in humans) CaNa2EDTA does not penetrate the skin, only 0.001 % were absorbed within 24 h of administration. Intravenously applied EDTA is rapidly excreted in urine (humans 50.% within the first hour 98 % within 24 h; rats: 95 % to 98 % within 6 h). These data were also confirmed by the independent evaluation of the MAK Commission for the Investigation of Health Hazards of Chemical Compounds in the work area (MAK, 46. Lieferung, 2009).

 

Discussion on bioaccumulation potential result:

In a study conducted by Foreman et al. (1953), 50 mg/kg bw of 14C-labelled calcium salt of EDTA were administered to rats orally (gavage), intraperitoneally, intravenously or intramuscularly. After oral application calcium EDTA was poorly absorbed from gastrointestinal tract (2 - 18 % within 24 h). Most of the administered dose was excreted by feces 80 - 95 % and much less in urine (2 - 18 %). After parenteral application 95 - 98 % (i.v.: 96.09 %; i.p.: 98.67 %; i.m.: 95.35 %) of the radioactivity was excreted in urine within 6 h after application, while less than 0.1 % was exhaled as CO2. None of these tissues contained at this time point more than 0.5 % of the radioactivity administered.

Two additional studies on the toxicokinetics of CaNa2EDTA after i.p. application are available. In one study rats got 10 injections of 300 - 436 mg/kg bw/day 14 C-labelled CaNa2EDTA. 66 to 92 % of the administered dose were recovered in urine while generally less than 5 % were excreted by feces. 24 h after the last injection kidneys showed less than 0.1 % of the radioactivity (Doolan, 1967). In the other study, 18 rats got a single i.p. application of 400 mg/kg bw 14[C]CaNa2EDTA. Within 22 h, 80 % of the radioactivity were excreted in urine, while the concentration in kidney homogenate was approximately 0.1 - 0.2 % during this time period (Miller, 1986).

The effects of s.c. application of CaNa2EDTA on Zn, Cu and Mn metabolism were investigated in female dogs. CaNa2EDTA was applied with a dose of 280 mg/kg bw/ every 6 hours for 54 h. Urine was collected every 6 h and the Zn, Cu and Mn content analysed. CaNa2EDTA application increased the urinary excretion of Zn, Cu and Mn significantly (Ibim, 1992).

In addition, in poorly documented studies by Yang (1964) the toxicokinetics of Na2EDTA were analysed in rats. After gavage application of 47.5, 95 and 142.5 mg/kg bw the amount of EDTA ingested was proportional to the amount of urinary excretion with a peak excretion 4 h after application. After gavage administration of 400 mg/kg bw to weanling and adult rats roughly 90 % of the dose were recovered in feces, while only 5.3 % (adults) - 8.6 % (weanlings) were recovered in urine within 48 h. It was therefore assumed that most of the orally applied EDTA is not absorbed. After a single gavage application of ca. 475 mg/kg bw to rats, the gastrointestinal tract was removed in intervals up to 32 h and the EDTA content analysed. All EDTA passed through the stomach within 12 h and 93 % of the dose was recovered in the colon after 32 h, which demonstrated a poor absorption from GI tract. The EDTA contents of the small intestine and urine reached a maximum about 4 h after dosage. Urinary excretion over the period of 32 h cumulated to 6 % of the dose. In an additional study, Yang stated that of a dietary dose of 300, 600 and 3000 mg/kg bw 82 %, 44 % and 45 % could be recovered in urine and feces. However, it is unclear were the residual percentage of Na2EDTA remained.

Foreman & Trujillo (1954) studied the toxicokinetics of 14C-CaNa2EDTA in young, healthy male volunteers. 4.2 mg/person were applied i.v. or i.m. 50 % of the dose was excreted in urine within 1 h (i.v.) or 2.5 h (i.m.). Within 24 h, > 98 % of the dose was excreted in urine after both applications. The half-live blood clearance was 1 h 5 min (i.v.) or 1.5 h (i.m.) respectively. Additionally, Foreman administered 14C-CaNa2EDTA orally at a dose of 1.5 mg/person. CaNa2EDTA was poorly absorbed from gastrointestinal tract. Within 72 h, 91 % of the dose was excreted in feces and 4.2 % in urine. No test substance could be detected in blood.

Discussion on absorption rate:

In a study on young, healthy, male volunteers Foreman & Trujillo (1954) investigated the dermal absorption of CaNa2EDTA. 3 mg of a mixture of 14C-labelled and unlabelled substance was prepared in water soluble base. The past was applied over an area of 100 cm² for 24 h under occlusive conditions. In one study Na salt was used instead of Ca salt. The maximum activity in the urine was 0.001 % of the administered dose.