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Toxicological information

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
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: GLP study according to modern scientific standards, minor deviations from applicable guidelines
Cross-reference
Reason / purpose:
reference to same study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2008

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 417 (Toxicokinetics)
GLP compliance:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Chromium Picolinate Monohydrate
- Molecular formula (if other than submission substance): Cr(C5H4NCO2) x H2O
- Molecular weight (if other than submission substance): 436.6 g/mol
- Smiles notation (if other than submission substance): O.O=C(O[Cr](OC(=O)c1ccccn1)OC(=O)c2ccccn2)c3ccccn3
- Physical state: reddish-purple crystalline powder
- Lot/batch No.: NG0569
Radiolabelling:
yes
Remarks:
14C-labelling of the picolinate anion

Test animals

Species:
rat
Strain:
Fischer 344
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Inc. (Raleigh, NC, USA)
- Age at study initiation: 8-10 weeks
- Weight at study initiation: 200-230 g
- Housing: polycarbonate cages
- Individual metabolism cages: yes
- Diet (e.g. ad libitum): Certified Purina Rodent Chow #5002 ad libitum
- Water (e.g. ad libitum): tap water ad libitum
- Acclimation period: 1 week

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
propylene glycol
Details on exposure:
VEHICLE
- Justification for use and choice of vehicle (if other than water): the test material was administered in propylene glycol as well as in water
Duration and frequency of treatment / exposure:
Single adminsitration
Doses / concentrations
Remarks:
Doses / Concentrations:
15.3 mg/kg bw (propylene gylcol)
17.4 mg/kg bw (as an aqueous slurry)
No. of animals per sex per dose:
4
Control animals:
no
Details on dosing and sampling:
PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: 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).
- Time and frequency of sampling: Urine and feces were collected until excretion was essentially complete (52 hours) and analyzed for total radiolabel by LSS and chromium by the method described below. Exhaled organic volatiles and CO2 were collected for 24 and 48 hours, respectively. The animals were sacrificed at 52 hours postdosing.
- Other: Aliquots of urine and feces from animals receiving [14C]-chromium picolinate were analyzed for total chromium. The fecal samples were prepared for analysis as described above. The resulting solutions were analyzed for chromium using a PerkinElmer Optima 4300 DV inductively coupled plasma-atomic emission spectrometer.

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:
1.3-1.5%, judging from urinary excretion
Details on distribution in tissues:
see tissue distribution study
Details on excretion:
Propylene glycol: 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.
Aqueous slurry: 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:
Cr(III) is not metabolised. The metabolism of the picolinate ion was investigated, but the anion is out of the scope for this dossier.
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 (data not shown). 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.

Any other information on results incl. tables

15.3 mg/kg Oral Dose of [14C]-Chromium Picolinate in Propylene Glycol to Rats

The results of the assay of total chromium excreted in urine and feces collected from the animals are shown in Table 1. 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.

17.4 mg/kg Oral Dose of [14C]-Chromium Picolinate to Rats as an Aqueous Slurry

Excretion of total chromium from rats sacrificed at 48 hours following administration of chromium picolinate is also shown in Table 1. 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.

Table 1: Excretion of Total Chromium by Male Rats

Time (hours)

Urine

Faeces

Total


Vehicle:
Propylene Glycol a

8

0.97 ± 0.26

0.97 ± 0.26

24

1.18 ± 0.24

82.5 ± 12.2

83.7 ± 12.1

48

1.25 ± 0.24

97.5 ± 7.4

98.8 ± 7.3


Vehicle:
Water a

2

0.16 ± 0.14

0.18 ± 0.14

4

0.34 ± 0.04

0.0 ± 0.0

0.34 ± 0.04

8

0.66 ± 0.05

7.64 ± 15.3

8.30 ± 15.3

12

0.84 ± 0.05

13.7 ± 11.5

14.6 ± 11.5

24

1.16 ± 0.34

92.9 ± 8.9

94.1 ± 8.8

48

1.53 ± 0.51

97.6 ± 7.4

99.2 ± 7.2

a Values are presented as cumulative percent of dose (mean ± standard) deviation for four rats at each timepoint.

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): no bioaccumulation potential based on study results
Poor absorption. Complete excretion within 48 h, almost quantitatively in faeces. Comparing total chromium excreted in urine following dosing with either the solution or slurry reveals little difference in rats.
Executive summary:

The poor bioavailability of chromium III, even though it is an essential mineral, 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 (data not shown). 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.