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Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics
Type of information:
migrated information: read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
This study is used for read-across and therefore has been assigned a reliability of 2 (reliable with restrictions). The study, if used in support of terephthalic acid, has a reliability of 1 (reliable without restriction). This study was selected as the key study because the information provided for the hazard endpoint is sufficient for the purpose of classification and labelling and/or risk assessment. Recent study performed to appropriate guidelines under GLP.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2006
Report Date:
2006

Materials and methods

Objective of study:
distribution
excretion
metabolism
Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 417 (Toxicokinetics)
GLP compliance:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
The unlabelled test substance used was terephthalic acid;
- Molecular weight; 166
-Colour; White
-Physical State; Solid
-Batch HHAS116
-Purity (%w/w) 99.9%

The radiolabelled test substance used was;
Source; Amersham
CTL test substance reference number; Y00751/006
Specific activity; 4.51 GBq/mmol; 26.6 MBq/mg
Radiochemical purity; 99.2%
Storage conditions; -20 degC.
Radiolabelling:
yes
Remarks:
14C

Test animals

Species:
mouse
Strain:
CD-1
Sex:
male
Details on test animals and environmental conditions:
The test animals were obtained from Charles River. At the time of dosing, the mice were required to be 27-32 g in weight.

The animals were housed up to 3 per cage, sexes separately, in multiple mouse racks. Diet was supplied by Special Diet Services Ltd, Stepfield, Witham, Essex and mains water supplied by plastic water bottles were available ad libitum.

ENVIRONMENTAL CONDITIONS
- Temperature 22 ±3 °C
- Humidity 30-70%
- Air changes (per hr): at least 15 changes/hour
- Photoperiod (hrs dark / hrs light):Artificial giving 12 hours light, 12 hours dark.

Administration / exposure

Route of administration:
intraperitoneal
Vehicle:
CMC (carboxymethyl cellulose)
Details on exposure:
Each mouse was given a single intraperitoneal dose of 800 mg [14C]-terephthalic acid/kg.

The dose preparation was formulated by mixing a total weight of 756.2 mg terephthalic acid, including 6.536 MBq of radiolabelled test substance in an agate pestle and mortar bowl. The resulting material was then suspended in the dose vehicle to give 9.4456 g of dose preparation. Triplicate aliquots of each dilution were taken and analysed by liquid scintillation.
Duration and frequency of treatment / exposure:
Single i.p. dose
Doses / concentrations
Remarks:
Doses / Concentrations:
800 mg [14C]-terephthalic acid/kg
No. of animals per sex per dose:
19 males mice were used (single dose level).

Control animals:
no
Positive control:
No positive control: not relevant

Details on study design:
A single intraperitoneal dose of 800 mg [14C]-terephthalic acid/kg was administered to a group of 18 male mice. Sub-groups of three mice were terminated at 2, 4, 6, 12, 24 and 48 hours after dosing and blood and tissue samples taken.
Details on dosing and sampling:
A single intraperitoneal dose of 800 mg [14C]-terephthalic acid/kg was administered. Sub groups of three animals were terminated at 2, 4, 6, 12, 24 and 48 hour after dosing and blood and tissue samples taken.

Triplicate weighed aliquots of the dose preparation were taken before during and after dosing and diluted volumetrically in DMSO:methanol:water (7:2:1). Triplicate aliquots of each dilution were then taken and analysed by liquid scintillation counting.
Statistics:
Means and standard deviations are reported.

Results and discussion

Preliminary studies:
No preliminary studies.

Toxicokinetic / pharmacokinetic studies

Details on absorption:
Rapid and extensive; > 80%, based on the level of urinary excretion.

Details on distribution in tissues:
Highest in the kidney two hours after dosing: 563 μg equiv/g (~ 1% of administered dose). Concentration in blood, plasma and bone marrow at two hours was 167, 221 μg, and ≤ 40 μg equiv/g, respectively. Bone contained 74 μg equiv/g. Group mean concentrations of radioactivity in all other tissues measured ≤ 40 μg equiv/g.
Details on excretion:
Rapid and by 48 hours only the brain contained radioactivity above the limit of detection. 92% excreted in urine and faeces (urinary excretion, plus cage wash: 81%; faecal excretion:11%). Radioactivity in gastrointestinal tract contents at termination < 0.1%.

Metabolite characterisation studies

Metabolites identified:
yes
Details on metabolites:
sulphate conjugate of terephthalic acid

Any other information on results incl. tables

Absorption was rapid and extensive and is estimated to be in excess of 80%, based on the level of urinary excretion.

The highest tissue concentration was found in the kidney two hours after dosing; 563 μg equiv/g representing approximately 1% of the administered dose. At the same time point the concentration of radioactivity in blood and plasma was 167 and 221 μg equiv/g respectively. Bone contained the next highest concentration of radioactivity; 74 μg equiv/g. Bone marrow was difficult to isolate from mouse femur but a sample isolated 2 hours after dosing showed a concentration of 92 μg equiv/g. Group mean concentrations of radioactivity in all other tissues measured was 40 μg equiv/g or less.

Elimination of radioactivity from the tissues was rapid and by 48 hours after dosing only the brain contained radioactivity above the limit of detection.

 

Over 48 hours, male mice excreted mean totals of approximately 92% of administered radioactivity in urine and faeces. Urinary excretion, plus cage wash, accounted for a mean total of 81% and faecal excretion for 11%. The percentage of radioactivity present in the gastrointestinal tract contents at termination was less than 0.1%.

The single metabolite was identified as the sulphate conjugate of terephthalic acid. The HPLC radiochromatogram of the pooled urine sample and cage wash contained a single, broad peak eluting at approximately 10 minutes. The negative mode mass spectra of this peak contained a base peak which was also the molecular ion [M-1] at 245 m/z.

Table 1 Excretion of Radioactivity by Male Mice

Time after dosing (hours)

Faeces

Urine

Cage Wash

Mean

SD

Mean

SD

Mean

SD

0-24

11.161

6.949

69.095

14.704

10.325

5.508

24-48

0.297

0.275

0.559

0.309

0.796

0.436

0-48

11.458

6.707

69.654

15.005

11.121

5.114

 

 

Mean

SD

Total excreted

92.233

4.700

GI tract contents at study termination

0.047

0.029

Table 2 Concentration of Radioactivity in the Blood following a Single Oral Dose of 800 mg of14C Terephthalic Acid/kg

Time (hours)

Mean

SD

2

166.843

129.342

4

21.107

8.494

6

8.764

5.644

12

37.411

48.761

24

4.077

5.023

48

<LOD

-

Table 3 Concentration of Radioactivity in Tissues of the Male Mouse following a Single Oral Dose of 800 mg of14C Terephthalic Acid/kg

Tissue

2 hours

4 hours

6 hours

12 hours

24 hours

48 hours

Mean

SD

Mean

SD

Mean

SD

Mean

SD

Mean

SD

Mean

SD

Adrenals

34.414

27.360

<LOD

-

<LOD

-

<LOD

-

<4.532

-

<LOD

-

Brain

7.244

3.268

3.705

0.318

3.854

0.732

4.361

0.663

3.389

0.577

0.281 

0.102

Heart

15.935

12.603

1.941

0.802

<0.693

-

<1.489

-

<LOD

-

<LOD

-

Kidneys

562.553

425.687

104.452

65.061

106.984

69.720

136.620

41.733

37.500

51.468

 <0.249

-

Liver

37.437

29.225

5.886

1.946

3.841

3.507

7.774

4.645

5.579

5.498

<LOD

-

Lungs

24.677

18.776

2.707

1.106

1.067

0.960

4.765

6.237

<0.612

-

<LOD

-

Pancreas

39.402

30.124

3.506

0.437

<1.113

-

2.008

1.188

<1.430

-

<LOD

-

Spleen

21.876

16.079

4.334

0.505

1.074

0.176

<14.021

-

<0.707

-

<LOD

-

Thymus

36.162

31.077

<1.969

-

<1.049

-

<1.377

-

<LOD

-

<LOD

-

Thyroid

<45.618

-

<LOD

-

<LOD

-

<LOD

-

<LOD

-

<LOD

-

Testes

18.116

12.803

5.982

1.685

1.800

0.433

1.483

0.844

<0.708

-

<LOD

-

Abdominal Fat

29.168

29.113

<4.771

-

<1.413

-

<LOD

-

<LOD

-

<LOD

-

Bone

74.451

52.951

9.775

3.485

3.633

1.765

4.395

1.909

<1.239

-

<LOD

-

Bone Marrow

<143.8

-

<LOD

-

<LOD

-

<LOD

-

<LOD

-

<LOD

-

Muscle

20.807

15.173

1.376

0.200

<0.723

-

<0.665

-

<0.538

-

<LOD

-

Blood

166.843

129.342

21.107

8.494

8.764

5.644

37.411

48.761

4.077

5.023

<LOD

-

Plasma

220.763

186.296

19.165

14.331

9.059

11.410

12.431

7.121

7.994

9.927

<LOD

-

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): no bioaccumulation potential based on study results
The study and the conclusions which are drawn from it fulfil the quality criteria (validity, reliability, repeatability).
The test substance was extensively absorbed into systemic circulation following the administration of a single intraperitoneal dose and widely distributed to all tissues including bone and bone marrow and was rapidly excreted via urine as the sulphate conjugate.
Executive summary:

A single intraperitoneal dose of 800 mg [14C]-test substance/kg bw was administered to a group of 18 male CD-1 mice. Urine and faeces were collected. Sub-groups of three mice were terminated at 2, 4, 6, 12, 24 and 48 hours after dosing. At each time interval, blood and tissue samples were taken.

The administered dose was extensively absorbed into systemic circulation, widely distributed and rapidly excreted. The major route of excretion was via urine, which accounted for at least 70% of the administered dose within 24 hours after dosing. A large amount of radioactivity was also recovered from the floor of the cage which is most likely to be from urinary origin. In total, approximately 80% of the administered dose was estimated to have been excreted via urine. The highest tissue concentration of radioactivity was detected in the kidney, reflecting the extensive urinary excretion. Some radioactivity was present in the bone marrow at 2 hours after dosing, but by 4 hours it was at levels below the calculated limit of detection. Intact bone samples (femur) contained higher concentrations of radioactivity than most of the tissues that were analysed and it is considered that given the structure of bone and the timescales of the experiment, this radioactivity must be present mainly in the bone marrow. Radioactivity in all tissues declined rapidly and by 48 hours after dosing most were below the level of detection indicating that there is no potential for accumulation. Analysis of urine showed the presence of a single radiolabelled peak which was identified as the sulphate conjugate of the acid moiety.