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Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
26 to 29 April 1995
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: GLP study, similar to guidelines, with acceptable deviations; on related material
Cross-reference
Reason / purpose:
reference to same study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1995
Report Date:
1995

Materials and methods

Objective of study:
absorption
distribution
excretion
Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 417 (Toxicokinetics)
Deviations:
yes
Remarks:
only one low dose used
GLP compliance:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Type:
Constituent
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): radiolabelled-trisodium EDDS
- Molecular formula (if other than submission substance): C10-H13-N2-O8. 3Na
- Molecular weight (if other than submission substance): 358
- Smiles notation (if other than submission substance): [Na+].[Na+].[Na+].OC(=O)[C@H](CC([O-])=O)NCCNC(CC([O-])=O)C([O-])=O
- Substance type: technical product
- Physical state: clear liquid
- Radiochemical purity (if radiolabelling): 98.7%
- Specific activity (if radiolabelling): 16.1 uCi/mg
- Locations of the label (if radiolabelling): 14C
- Expiration date of radiochemical substance (if radiolabelling): 9 September 1993
- Stability under test conditions: no data
- Storage condition of test material: at about 4oC
Radiolabelling:
yes

Test animals

Species:
rat
Strain:
other: Crl: (WI)BR
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Canada, St-Constant, Quebec
- Age at study initiation: 6-8 weeks
- Weight at study initiation: males: 191-303 g; females 173-253 g
- Fasting period before study: no data
- Housing: in glass metabolism cages
- Individual metabolism cages: yes
- Diet (e.g. ad libitum): conventional, ad libitum
- Water (e.g. ad libitum): tap water, ad libitum
- Acclimation period: 7 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 3
- Humidity (%): 50 +/- 20
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12/12


IN-LIFE DATES: From: 26 April 1993 To: 29 April 1993

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: dosing solution pre-prepared at the appropriate concentration by the sponsor

HOMOGENEITY AND STABILITY OF TEST MATERIAL: no data
Duration and frequency of treatment / exposure:
single exposure
Doses / concentrations
Remarks:
Doses / Concentrations:
gavaged with 1 mL to give about 10 uCi/rat and 0.5 mg/rat (about 3 mg/kg bw) of 14C-[S,S]-EDDS trisodium salt
No. of animals per sex per dose:
5/sex
Control animals:
no
Positive control:
none
Details on study design:
- Dose selection rationale: selected to provide sufficient material to determine the distribution, elimination and mass balance of radioactivity
- Rationale for animal assignment (if not random): random
Details on dosing and sampling:
PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: urine, faeces, blood, plasma, cage washes, expired air, adipose tissue, brain, bone marrow (femur), femur bone, gonads, heart, GI (combined stomach, large and small intestine), GI contents, kidneys, liver, lungs, muscle (right leg adductor), pancreas, spleen, carcass
- Time and frequency of sampling: urine, faeces and cage washes were collected at 24, 48 and 72 h; expired air was trapped in potassium hydroxide and collected at 12, 24, 36, 48 and 72 h. Tissues and organs were sampled for radioactivity at study termination at 72 h.



Statistics:
Bartlett's test and t-tests were used to determine any gender differences in the recovery of radioactivity. A ln-transformation on the percent of dose was used to correct the non-homogeneity of the variances when appropriate.

Results and discussion

Preliminary studies:
none
Main ADME resultsopen allclose all
Type:
absorption
Results:
after 72 h, at least 5% of the dose was considered absorbed
Type:
distribution
Results:
after 72 h, a total of about 0.15% of the dose was recovered in the blood and organs (including carcass)
Type:
excretion
Results:
after 72 h, about 75% of the dose was excreted in the faeces, and about 2 and 3% in the urine and expired air, respectively

Toxicokinetic / pharmacokinetic studies

Details on absorption:
Only about 5% of the dose was absorbed from the gastrointestinal tract as shown by the radioactivity recovered from urine, expired air and recovered in the tissues during the 72 h exposure period. The cage wash may have contained some further absorbed material (excreted as urine). See Tables 1 and 2 for further details.
Details on distribution in tissues:
The total radioactivity recovered from the organs and tissues examined are given in Table 1. The combined mean radioactivity content of blood and tissues (including carcass) was 0.136 and 0.153% in males and females, respectively.
Details on excretion:
Radioactivity was excreted mainly in the faeces and occurred rapidly with about 62% and 71% of the dose being recovered in faeces in males and females, respectively, during the first 24 h. In total, during the 72-h collection period, faecal excretion accounted for about 75% of the administered dose in males and females. Only a small fraction of the dose was recovered in the urine (about 1.7%) and expired air (3.25%). See Tables 1 and 2 for further details.

Metabolite characterisation studies

Metabolites identified:
not measured

Any other information on results incl. tables

Table 1. Total recovery (mass balance) of radioactivity in excreta and tissues

 Sample Males (% of dose)  Females (% of dose) 
Urine  1.87 ± 1.58 1.49 ± 0.200
Faeces 

75.6 ± 6.91

75.2 ± 7.92

Expired air  3.35 ± 2.21 3.19 ± 0.803
Cage wash  3.37 ± 2.86

9.38 ± 7.55

Blood  0.0041 ± 0.0093 0.000 ± 0.000
Liver  0.0424 ± 0.0353 0.037 ± 0.014
Kidneys  0.0092 ± 0.0084 0.004 ± 0.001
Heart  0.0003 ± 0.0008 0.000 ± 0.001 
Lungs  0.0007 ± 0.0015 0.000 ± 0.000
Pancreas  0.0007 ± 0.0016 0.001 ± 0.002 
Spleen   0.005 ± 0.0011 0.001 ± 0.002
Brain  0.0015 ± 0.0034 0.000 ± 0.000
Testes/ovaries  0.0010 ± 0.0023 0.000 ± 0.000
Muscle  0.0000 ± 0.0000 0.000 ± 0.000
 Adipose tissue 0.0283 ± 0.0127 0.017 ± 0.026
 Bone marrow 0.0000 ± 0.0000 0.000 ± 0.000
 Bone femur 0.0000 ± 0.0000 0.000 ± 0.000 
 GI tract 0.0358 ± 0.0478 0.013 ± 0.012 
 GI contents 0.0345 ± 0.0771 0.000 ± 0.000 
 Carcass 0.114 ± 0.141 0.080 ± 0.083 
 Total 84.4 ± 1.52  89.5 ± 2.76

Table 2. Percentage recovery of radioactivity in excreta

 

% of dose

Cumulative % of dose

Period (h)

Urine

Faeces

Cage wash

Expired air

Total

Urine

Faeces

Cage wash

Expired air

Total

Males

 

 

 

 

 

 

 

 

 

 

0-12

a

a

a

1.2228 ± 0.2709

1.2228 ± 0.2709

a

a

a

1.2228 ± 0.2709

1.2228 ± 0.2709

12-24

1.3003 ± 0.4784

62.2836 ± 26.9438

2.2841 ± 2.1168

0.7793 ± 0.3835

66.6474 ± 26.2117

1.3003 ± 0.4784

62.2836 ± 26.9438

2.2841 ±

2.1168

2.0021 ± 0.1764

67.8702 ±

26.3440

24-36

a

a

a

0.6048 ±

0.8138

0.6048 ± 0.8138

1.3003 ± 0.4784

62.2836 ± 26.9438

2.2841 ± 2.1168

2.6069 ± 0.9824

68.4750 ± 25.5306

36-48

0.4169 ± 0.8032

8.7869 ± 11.8536

0.4881 ± 0.6665

0.4913 ± 0.7762

10.2732

± 13.9894

1.7173 ± 1.2524

71.1606 ± 15.3503

2.7722 ± 2.4431

3.0982 ± 1.7566

78.7482 ± 12.0645

48-72

0.1532 ±

0.3335

4.3958 ± 8.6421

0.5985 ± 1.3383

0.2484 ± 0.4581

5.3959 ± 10.7689

1.8705 ± 1.5803

75.5564 ± 6.9090

3.3707 ± 2.8555

3.3466 ± 2.2133

84.1441 ± 1.7590

Females

 

 

 

 

 

 

 

 

 

 

0-12

a

a

a

1.1357

± 0.1808

1.1357

± 0.1808

a

a

a

1.1357

± 0.1808

1.1357

± 0.1808

12-24

1.2509 ± 0.1869

70.6335

± 5.9226

9.0715 ± 7.3306

1.4762 ± 0.4461

82.4320 ± 3.5779

1.2509 ± 0.1869

70.6335

± 5.9226

9.0715 ± 7.3306

2.6119 ± 0.5366

83.5677 ± 3.6176

24-36

a

a

a

0.3144 ± 0.1596

0.3144 ± 0.1596

1.2509 ± 0.1869

70.6335

± 5.9226

9.0715 ± 7.3306

2.9263 ± 0.6461

83.8821 ±

3.5258

36-48

0.2609 ± 0.2946

3.9687 ± 3.8809

0.2423 ± 0.3216

0.2029 ± 0.1229

4.6226 ± 3.8030

1.4596 ± 0.1392

74.6022 ± 7.7342

9.3138 ± 7.5307

3.1292 ± 0.7494

88.5047 ± 2.7321

48-72

0.0289 ± 0.0647

0.6468 ± 0.2785

0.0622 ± 0.0956

0.0614 ± 0.0666

0.7993 ± 0.3595

1.4885 ± 0.2003

75.2490 ± 7.9168

9.3760 ± 7.5495

3.1906 ± 0.8025

89.3041 ± 2.7273

a: not sampled

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): no bioaccumulation potential based on study results
In a GLP study, similar to OECD Guideline 417, a single dose of radiolabelled trisodium EDDS (about 2-3 mg/kg bw/day) administered by gavage to male and female rats was rapidly eliminated, mainly in the faeces (about 75% of the administered dose), with at least 5% considered absorbed from the gastrointestinal tract.
Executive summary:

In a GLP study conducted according to a protocol similar to OECD Guideline 417, the absorption, distribution and elimination of 14C-labelled trisodium EDDS was determined in male and female Wistar rats. The radiolabelled test substance was administered by single oral gavage (in water) to five rats of each sex at a dose level of 0.5 mg/rat (about 2-3 mg/kg bw) and the animals placed in individual metabolism cages. Urine, faeces and cage washes were collected at 24, 48 and 72 h and expired air was collected in 12, 24, 36, 48 and 72 h samples. At study termination (72 h), blood samples were taken and plasma separated and selected tissues and gastrointestinal contents were collected and the levels of radioactivity were determined by liquid scintillation counting (after solubilising the tissues as necessary).

Trisodium EDDS was rapidly excreted, mainly in the faeces. In the first 24 h, approximately 62 and 71% of the administered dose, respectively in males and females, was excreted in the faeces, and after 72 h about 75% was excreted in the faeces. Overall, at least 5% of the test substance was absorbed from the GI tract as determined by the amount of radioactivity in urine, expired air and in the tissues. Some further absorbed material may have been found in the cage wash and possibly any faeces produced after 36 hr. The combined mean radioactivity content of blood and tissues (including carcass) was 0.136 and 0.153% of the administered dose in males and females, respectively. No statistically significant gender differences were evident in the absorption, distribution or excretion patterns.

In conclusion, at least 5% of an administered dose of trisodium EDDS was considered absorbed from the gastrointestinal tract, with most being excreted in the faeces within the first 24 h after administration.

[Data on trisodium EDDS is considered relevant to use for understanding the basic toxicokinetics of EDDS acid, and is acceptable for using as read-across information.]