Chromium tris((2-ethylhexanoate)

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

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

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

data from handbook or collection of data

Remarks:

collection of data

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2010

Materials and methods

Objective of study:

absorption

distribution

excretion

metabolism

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

Study was conducted in parallel of a 2-year oral carcinogenicity study. The purposes of this study is to determine the absorption of chromium picolinate into the systemic circulation, and the fate of both the chromium and the picolinate parts of chromium picolinate.

GLP compliance:

yes

Test material

Test material information

Constituent 1

Reference substance name:

Chromium picolinate monohydrate

Cas Number:

27882-76-4

Molecular formula:

C18-H12-Cr-N3-O6.H2-O

IUPAC Name:

Chromium picolinate monohydrate

Test material form:

solid

Details on test material:

Nonradiolabeled chromium picolinate was obtained from Spectrum Quality Products, Inc. (Gardena, CA - USA) in one lot (NG0569).
Radiolabeled chromium picolinate, labeled with 14C at multiple sites in the aromatic rings, was synthesized by Wizard Laboratories (West Sacramento, CA) at a specific activity of 52.0 mCi/mmole of chromium picolinate (17.3 mCi/mmole of each of the three picolinate ligands). The [14C]-chromium picolinate was supplied as a neat solid and its radiochemical purity was determined by HPLC.

Radiolabelling:

yes

Remarks:

14C for picolinate anion

Test animals

Species:

rat

Strain:

Fischer 344

Sex:

male

Details on test animals or test system and environmental conditions:

origin: Charles River Laboratories, Inc. (Raleigh, NC - USA)
acclimation period: at least one week
feed: Certfied Purina Rodent Chow #5002 and tap water ad libitum
housing: standard polycarbonate cages until they are used for an experiment, then individual glass metabolism chambers
body weight at initiation of the study: 206 - 233 grams
age at initiation of the study: 58 - 71 days old

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

other: water or propylene glycol

Duration and frequency of treatment / exposure:

single dose

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

15.3 mg/kg bw (total dose)

Remarks:

A dose formulation of [14C]-chromium picolinate dissolved in propylene glycol at a concentration of 2.84 mg (33.6 μCi) chromium picolinate per gram of dose preparation was prepared.

Doses / concentrations 2

Dose / conc.:

17.4 mg/kg bw (total dose)

Remarks:

A slurry of [14C]-chromium picolinate was prepared in water at an activity of 9.93 μCi per mg chromium picolinate.

No. of animals per sex per dose / concentration:

4 male rats per dose

Control animals:

no

Details on study design:

Urine and feces were collected until excretion was essentially complete (52 hours) and analyzed for total radiolabel by LSS and chromium. Exhaled organic volatiles and CO2 were collected for 24 and 48 hours, respectively. The animals were sacrificed at 52 hours postdosing. The
following tissues were collected: adipose (two sites), bladder, blood, brain, heart, kidney, liver, lung, muscle (two sites), skin (ear), spleen, testis, stomach (with contents), small intestine (with contents), large intestine (with contents), and cecum (with contents). The collected tissues were stored at approximately –20° C until analyzed for total radiolabel by tissue solubilization followed by LSS. Aliquots of the 8- and 24-hour urine collections were analyzed for chromium picolinate and metabolites by HPLC/LSS.

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on distribution in tissues:

15.3 mg/kg oral Dose of [14C]-Chromium Picolinate in Propylene Glycol to rats:
Less than 1% of 14C dose was found in tissues after 52 hours (adipose, bladder, blood, brain, heart, kidney, liver, lung, muscle, skin, spleen, testis, gastrointestinal tract).

17.4 mg/kg oral Dose of [14C]-Chromium Picolinate to rats as an Aqueous Slurry:
Less than 1% of the 14C dose administered was found in the non-gastrointestinal tract tissues at 48 hours; the gastrointestinal tract tissues and contents contained 0.15% of the administered radioactivity.

Details on excretion:

The rats dosed orally with [14C]-chromium picolinate dissolved in propylene glycol excreted an average of 53% of the 14C dose in urine, 39% in feces, and 1.5% as CO2 in breath in 24 hours. No measurable dose was collected as volatiles in breath. An additional 8% of the 14C dose was excreted during the collections at 48 and 52 hours.
An average of 1.25% ± 0.24% and 97.5% ± 7.4% of the chromium dose was excreted in urine and feces, respectively, in 48 hours.
An average of 49.0% ± 1.2% the 14C dose received was excreted in 24 hours as N-picolinoylglycine.
An average of 1.9% ± 0.4% and 1.1% ± 0.7% of the 14C dose received was excreted in 24 hours as picolinic acid and chromium picolinate, respectively.

The rats dosed orally with [14C]-chromium picolinate water slurry excreted an average of 41% of the 14C dose in urine, 47% in feces, and 1.4% as CO in breath in 24 hours. An additional 4% of the 14 2 C dose was excreted during the collections at 48 hours.
An average of 1.53% ± 0.51% and 97.6% ± 7.4% of the chromium dose was excreted in urine and feces, respectively, in 48 hours.

Metabolite characterisation studies

Metabolites identified:

yes

Details on metabolites:

Only a single radiolabeled metabolite (Ur1) was excreted in rat urine following an oral dose of [14C]-chromium picolinate. This metabolite was isolated and purified by HPLC. No apparent decomposition was observed during the purification process. Analysis of the isolated and purified metabolite for total chromium showed that Ur1 does not contain chromium. A sample of Ur1 that would have contained 75 μg-Eq/L of chromium based on the chromium/14C ratio in chromium picolinate was found to contain less than 10 μg/L chromium (the limit of quantitation of the method).

Any other information on results incl. tables

The poor bioavailability of chromium III, even though it has been proposed to be an essential element, is well

known. The poor bioavailability is little improved when chromium is complexed with picolinic acid or similar

complexing agents. Chromium picolinate has low water solubility. The rate of dissolution of the solid complex

could be slow enough to affect bioavailability. One of the goals of these studies was to establish the effect of

formulation on bioavailability. Propylene glycol was found to be a good solvent for the complex allowing

comparison of bioavailability of a homogenous formulation to an aqueous slurry. Comparing total chromium

excreted in urine following dosing with either the solution or slurry reveals little difference in rats.

A second question these studies sought to answer was the form of chromium in circulation. The analysis of urine

revealed that about 1% of the administered chromium picolinate is excreted unchanged in the urine of rats. Analysis of blood 1 hour following a 17.4 mg/kg oral dose indicated a concentration of 31 ng chromium picolinate/g of blood. At this same time the total radioactivity in blood was 290 ng-Eq of chromium picolinate, so no more than 10% of the chromium in the blood was associated with picolinate.

Picolinic acid represents about 83% of the mass of chromium picolinate. The fate of this part of the complex has

received little attention. Excretion of picolinate-derived radioactivity in rats is about equally divided between urine

and feces. Excretion of chromium, however, is nearly 100% in feces. This implies that much of the picolinate is

absorbed without the chromium attached. The major urinary metabolite is a glycine conjugate of picolinic acid.

Picolinic acid is cleared rapidly in rats with elimination being primarily by conjugation with glycine. There is little evidence for accumulation of picolinate-derived material in tissues. Less than 1% of the administered radioactivity remains in tissues after 48 hours.

Applicant's summary and conclusion

Conclusions:

Based on study results, the Chromium picolinate shows no bioaccumulation potential in rats tissue.