Chromium

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

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

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Acceptable, well-documented publication which meets basic scientific principles

Data source

Reference

Reference Type:

publication

Title:

Development of a pharmacokinetic model for chromium in the rat following subchronic exposure

Author:

Thomann R.V, Snyder C.A, Squibb K.S

Year:

1994

Bibliographic source:

Toxicol Appl Pharmacol 128, 189-198

Materials and methods

Objective of study:

toxicokinetics

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

Rats were exposed to 100 ppm of the test substance in drinking water for up to 6 weeks, followed by a depuration period of of 12 or 20 weeks. After sacrifice, Cr accumulation into tissues was analysed.

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

Potassium chromate

EC Number:

232-140-5

EC Name:

Potassium chromate

IUPAC Name:

Potassium chromate

Details on test material:

Potassium chromate from Baker Chemical Co, Phillipsburg, NJ, USA
No other data .

Radiolabelling:

no

Test animals

Species:

rat

Strain:

Fischer 344

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Male Fischer-344 rats obtained from the Charles River Breeding Laboratories (Kingston, NY, USA)
- Age at study initiation: 6 weeks
- Weight at study initiation: ca 200 g
- Fasting period before study: no data
- Housing: housed in pairs in wire mesh cages
- Individual metabolism cages: no
- Diet (e.g. ad libitum): yes, Purina Lab Chow
- Water (e.g. ad libitum): yes
- Acclimation period: 2 weeks


ENVIRONMENTAL CONDITIONS
- Temperature (°C): no data
- Humidity (%): no data
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): no data


IN-LIFE DATES: From: 6 hrs to 20 weeks

Administration / exposure

Route of administration:

oral: drinking water

Vehicle:

water

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:

VEHICLE
- Justification for use and choice of vehicle (if other than water): water
- Concentration in vehicle: 100 ppm



HOMOGENEITY AND STABILITY OF TEST MATERIAL:
The drinking water solutions were changed weekly. Montoring the chromate concentrations in water samples indicated that the total Cr concentrations did not change and Cr(VI) was not significantly reduced to Cr(III) during this time period.

Duration and frequency of treatment / exposure:

Cr was given in drinking water during a period of 6 weeks. In addition to the groups treated for 6 weeks, groups of three rats each were euthanised after 1, and 3 weeks of exposure.

Doses / concentrations

Remarks:

Doses / Concentrations:
100 ppm Cr (as potassium chromate) in drinking water (ad libitum) (corresponding to approximately 16 ml * 100 µg/ml = 1600 µg/day

No. of animals per sex per dose / concentration:

Experiment 1: 57 males (100 ppm) and 12 controls.
Experiment 2: 62 males (100 ppm)

Control animals:

yes, concurrent vehicle

Positive control reference chemical:

No

Details on study design:

- Dose selection rationale: no data
- Rationale for animal assignment (if not random): no data

Details on dosing and sampling:

PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled : blood, liver, kidney, spleen (both in experiment 1 and 2); bone (right femur), bone marrow, total remaining carcass
- Time and frequency of sampling: tissues collected at sacrifice and frozen for Cr analysis
- Other:

Statistics:

No data

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:

A three-compartment model was devised, assuming that diffusion limited Cr uptake. Compartment 1 was blood, from which plasma exchanged Cr with compartment 2 (storage in bone and carcass) as well as with compartment 3 (liver, kidney, spleen) from whicg Cr was lost by excretion.

Details on distribution in tissues:

After the 12 week period, the total Cr concentrations were greatest in the kidney, followed by the spleen, liver and blood.
In experiment 2 it was seen that at the end of the 20 week period the main part (about 87%) of the body burden was in the carcass and bone.

Details on excretion:

Elimination from the liver was biphasic, whereas it was monophasic in the spleen, kidney and bone.
The elimination of Cr from the bones and carcass was vey slow (half-time >100 days). The half-time for elimination from whole body was about 80 days, and from liver, kidney and spleen about 10 days.

Toxicokinetic parameters

Toxicokinetic parameters 1

Toxicokinetic parameters:

half-life 1st: from liver, kidney and spleen 10 days

Toxicokinetic parameters 2

Toxicokinetic parameters:

half-life 2nd: from whole body 80 days

Toxicokinetic parameters 3

Toxicokinetic parameters:

half-life 3rd: from bone and carcass >10 days

Applicant's summary and conclusion

Conclusions:

Using a pharmacokinetic model slow overall kinetis of Cr depuration from the tissues were identified. The main part of orally dosed Cr binds to bone (half-life >100 days). Cr may thus be sequestered and released by the storage compartment over an extended time period.

Executive summary:

Rats were exposed to 100 ppm of the test substance in drinking water for up to 6 weeks, followed by a depuration period of of 12 or 20 weeks. After sacrifice, Cr accumulation into tissues was analysed.

Using a pharmacokinetic model slow overall kinetis of Cr depuration from the tissues were identified. The main part of orally dosed Cr binds to bone (half-life >100 days). Cr may thus be sequestered and released by the storage compartment over an extended time period.