Registration Dossier

Data platform availability banner - registered substances factsheets

Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.

The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.

Diss Factsheets

Toxicological information

Repeated dose toxicity: oral

Currently viewing:

Administrative data

Endpoint:
sub-chronic toxicity: oral
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:
comparable to guideline study with acceptable restrictions
Justification for type of information:
1. HYPOTHESIS FOR THE ANALOG APPROACH
The read across follows Scenario 2 - Different compounds have qualitatively similar properties: properties of the target substance predicted to be quantitatively equal to those of the source substance or prediction based on a worst-case approach (as described in the 2017 Read-Across Assessment Framework document).

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
TARGET: Chromium tris(2-ethylhexanoate) (EC 222-357-3, CAS 3444-17-5)
SOURCE: Chromium picolinate monohydrate (CAS n° 27882-76-4)

3. ANALOG APPROACH JUSTIFICATION
The target substance and the source substance are organic salts of Chromium (3+). The organic counter ion of the target and source substances are small (6-8 carbon) carboxylic acids of similar molecular weight and polarity. The biologically-reactive center of all the molecules would be predicted to be the Cr (3+).
4. DATA MATRIX
See Read Across document attached to CSR.
Cross-referenceopen allclose all
Reason / purpose for cross-reference:
reference to other study
Reference
Endpoint:
sub-chronic toxicity: oral
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:
comparable to guideline study with acceptable restrictions
Justification for type of information:
1. HYPOTHESIS FOR THE ANALOG APPROACH
The read across follows Scenario 2 - Different compounds have qualitatively similar properties: properties of the target substance predicted to be quantitatively equal to those of the source substance or prediction based on a worst-case approach (as described in the 2017 Read-Across Assessment Framework document).

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
TARGET: Chromium tris(2-ethylhexanoate) (EC 222-357-3, CAS 3444-17-5)
SOURCE: Chromium picolinate monohydrate (CAS n° 27882-76-4)

3. ANALOG APPROACH JUSTIFICATION
The target substance and the source substance are organic salts of Chromium (3+). The organic counter ion of the target and source substances are small (6-8 carbon) carboxylic acids of similar molecular weight and polarity. The biologically-reactive center of all the molecules would be predicted to be the Cr (3+).
4. DATA MATRIX
See Read Across document attached to CSR.
Reason / purpose for cross-reference:
reference to other study
Reason / purpose for cross-reference:
reference to same study
Reason / purpose for cross-reference:
reference to other study
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
Deviations:
yes
Remarks:
Examinations are limited compared to guideline requirements.
GLP compliance:
not specified
Limit test:
no
Species:
rat
Strain:
Fischer 344
Remarks:
F344/N
Sex:
male/female
Details on test animals or test system and environmental conditions:
origin: Taconic Laboratory Animals and Services, Germantown, NY, USA
age at initiation of the study: 6 weeks old
weight at initiation of the study: male = 91 - 92 g and female = 93 - 94 g
acclimatation period: 11-14 days
housing: 5 animals per cage
temperature: 72+/- 3°F
relative humidity: 50 +/- 15%
12 hours light/dark cycle
feed and water available at libitum
Route of administration:
oral: feed
Details on route of administration:
Dose formulations were prepared with irradiated NTP-2000 open formula diet (from Zeigle Brothers, Inc., Gardners, PA, USA).
Vehicle:
other: diet
Details on oral exposure:
Dose formulations were prepared 4 times thoughout the study.
Chromium picolinate monohydrate in feed was stable for at least 42 days when stored at room temperature, protected from light, and under simulated animal room conditions at a concentration of 82 ppm for 8 days at room temperature.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Dose formulations were analyzed 3 times during the study: all samples were within 10% of the target concentrations.
Duration of treatment / exposure:
93 days
Frequency of treatment:
ad libitum
Dose / conc.:
80 ppm
Dose / conc.:
240 ppm
Dose / conc.:
2 000 ppm
Dose / conc.:
10 000 ppm
Dose / conc.:
50 000 ppm
No. of animals per sex per dose:
10 male and 10 female per dose for core study
+ additonal groups for special studies
Control animals:
yes, plain diet
Details on study design:
Dose selection was based on the results of a 14-day palatability study with rat: 10 rats (5 male, 5 female) per group were administered the substance at concentrations of 1%, 3% and 5% of the diet. The chemical hd no effect on feed palatability an produced no sign of toxicity. The range of the doses for this sutdy were chosen based on the low adsorption of the substance by rats and the condition that the highest dose (50 000 ppm) did not exceed 5% of the diet, so as not to alter the nutritional value of the feed.
Positive control:
No
Observations and examinations performed and frequency:
- clinical findings recorded weekly for core study
- food consumption measured weekly by cage
- animals weight: day 1, weekly thoughout the study and at sacrifice
- hematology and clinical chemistry analyses: days 3, 21 (special study) and 93 (core study): rats were bled from the retroorbital sinus while under CO2/O2 anesthesia before sacrifice
- clinical chemistry parameters evaluated include sorbitol dehydrogenase, alkaline phosphatase, creatine kinase, creatinine, total protein,
albumin, blood urea nitrogen, total bile acids, and alanine aminotransferase
- hematology parameters evaluated include erythrocyte count, hemoglobin, packed cell volume (automated and spun hematocrit), mean orpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, platelet count, reticulocyte count, nucleated red blood cell
count, total leukocyte count, differential leukocyte counts, red blood cell morphology, and platelet morphology
- complete necropsy performed on all core study animals: liver, right kidney, heart, lungs, thymus and right testis (males) were weighed, microscopy examinations were carried out.
Sacrifice and pathology:
- complete necropsy performed on all core study animals
- liver, right kidney, heart, lungs, thymus and right testis (males) were weighed
- microscopy examinations were carried out
- gross lesions examined
Other examinations:
- sperm count and motility from male exposed to 0, 2000, 10000, 50000 ppm
- vaginal cytology evaluations performed the last 12 days of the study from female exposed to 0, 2000, 10000, 50000 ppm
Statistics:
Organ and bodyweight data were analyzed with analysis of variance followed by the parametric multiple comparison procedures of Dunnett and Williams. Hematologyand clinical chemistry data were analyzed using Kruskal–Wallis analysis of variance by the nonparametric multiple omparison methods of Shirley and Dunn. Jonckheere's test was used to assess the significance of dose–response trends. Extreme values were identified by the outlier test of Dixon and Massey. The Cochran–Armitage and Fisher's exact tests were used to assess nonneoplastic lesion prevalence.
Clinical signs:
no effects observed
Description (incidence and severity):
Administration of Chromium picolinate monohydrate produced no clinical signs of toxicity.
Mortality:
no mortality observed
Description (incidence):
All rats survived to the end of the study.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
No significant compound-related effects on growth or final mean body weights of rats were observed.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
Feed consumption by exposed rats was similar to that by the control group
Food efficiency:
not specified
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Description (incidence and severity):
There were no statistically significant hematological changes.
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
There were no statistically significant clinical chemistry changes.
Urinalysis findings:
not examined
Behaviour (functional findings):
not specified
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, non-treatment-related
Description (incidence and severity):
Organ weights showed slight alterations in exposed animals. Male heart and liver weights showed significant dose-related negative trends (6–8% less than controls). Female right kidneyweights displayed trends toward significant increases in exposed animals (7–13% greater than controls).
These effects were not considered to be compound-related due to the small magnitude of the changes in conjunction with the lack of any clear
dose–response.
Gross pathological findings:
not specified
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, non-treatment-related
Description (incidence and severity):
Histopathological lesions were considered spontaneous or incidental and not related to substance's exposure.
Histopathological findings: neoplastic:
not specified
Description (incidence and severity):
Effects on reproduction:
Sperm motility, number of sperm per mg cauda, total number of sperm per cauda, number of spermatids permg testis, and total number of spermatids per testis of animals exposed to the substance were similar to those of control animals.
Evaluation of vaginal smears did not reveal anysignifi cant differences among the females in the amount of time spent in different estrous
stages, the cycle length, or the number of cycles.
There was an increase in the number of females with regular cycles in the group exposed to 50000 ppm of substance.
Dose descriptor:
NOAEL
Effect level:
50 000 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
body weight and weight gain
clinical biochemistry
clinical signs
food consumption and compound intake
haematology
histopathology: non-neoplastic
mortality
organ weights and organ / body weight ratios
Remarks on result:
other: expressed as Chromium picolinate monohydrate
Dose descriptor:
NOAEL
Effect level:
4 243 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
body weight and weight gain
clinical biochemistry
clinical signs
food consumption and compound intake
haematology
histopathology: non-neoplastic
mortality
organ weights and organ / body weight ratios
Remarks on result:
other: expressed as Chromium picolinate monohydrate
Key result
Dose descriptor:
NOAEL
Effect level:
4 683 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
body weight and weight gain
clinical biochemistry
clinical signs
food consumption and compound intake
haematology
histopathology: non-neoplastic
mortality
organ weights and organ / body weight ratios
Remarks on result:
other: expressed as Chromium 2-ethylhexanoate
Critical effects observed:
not specified
Conclusions:
In the experimental conditions of a test equivalent to OECD 408 guideline, subchronic exposure to Chromium picolinate monohydrate did not cause any toxic effects in rats.
Reason / purpose for cross-reference:
reference to same study
Reference
Endpoint:
reproductive toxicity, other
Remarks:
effects on sperm parameters and estrous cycle
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:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Justification for type of information:
1. HYPOTHESIS FOR THE ANALOG APPROACH
The read across follows Scenario 2 - Different compounds have qualitatively similar properties: properties of the target substance predicted to be quantitatively equal to those of the source substance or prediction based on a worst-case approach (as described in the 2017 Read-Across Assessment Framework document).

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
TARGET: Chromium tris(2-ethylhexanoate) (EC 222-357-3, CAS 3444-17-5)
SOURCE: Chromium picolinate monohydrate (CAS n° 27882-76-4)

3. ANALOG APPROACH JUSTIFICATION
The target substance and the source substance are organic salts of Chromium (3+). The organic counter ion of the target and source substances are small (6-8 carbon) carboxylic acids of similar molecular weight and polarity. The biologically-reactive center of all the molecules would be predicted to be the Cr (3+).
4. DATA MATRIX
See Read Across document attached to CSR.
Reason / purpose for cross-reference:
reference to same study
Reason / purpose for cross-reference:
reference to other study
Reason / purpose for cross-reference:
reference to other study
Qualifier:
no guideline followed
Principles of method if other than guideline:
At the end of a 3-month study equivalent to an OECD 408 guideline study, samples were collected for sperm count and motility from male rats. Vaginal cytology evaluations were also performed on the last 12 days of the study from female rats.
GLP compliance:
not specified
Limit test:
no
Species:
mouse
Strain:
B6C3F1
Sex:
male/female
Details on test animals or test system and environmental conditions:
origin: Taconic Laboratory Animals and Services, Germantown, NY, USA
age at initiation of the study: 6 weeks old
weight at initiation of the study: male = 19.4 - 19.6 g and female = 16.7 - 16.9 g
acclimatation period: 11-14 days
housing: 5 female animals per cage and 1 male animal per cage
temperature: 72+/- 3°F
relative humidity: 50 +/- 15%
12 hours light/dark cycle
feed and water available at libitum
Route of administration:
oral: feed
Vehicle:
other: diet
Details on exposure:
Dose formulations were prepared with irradiated NTP-2000 open formula diet (from Zeigle Brothers, Inc., Gardners, PA, USA).
Dose formulations were prepared 4 times thoughout the study.
Chromium picolinate monohydrate in feed was stable for at least 42 days when stored at room temperature, protected from light, and under simulated animal room conditions at a concentration of 82 ppm for 8 days at room temperature.
Details on mating procedure:
No mating procedure.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Dose formulations were analyzed 3 times during the study: all samples were within 10% of the target concentrations.
Duration of treatment / exposure:
93 days
Frequency of treatment:
ad libitum
Dose / conc.:
2 000 ppm
Dose / conc.:
10 000 ppm
Dose / conc.:
50 000 ppm
No. of animals per sex per dose:
10 male and 10 female per dose
Control animals:
yes, plain diet
Parental animals: Observations and examinations:
Clinical findings recorded weekly
Food consumption measured weekly by cage
Animals weight: day 1, weekly thoughout the study and at sacrifice
Hematology and clinical chemistry analyses: days 3, 21 (special study) and 93 (core study): rats were bled from the retroorbital sinus while under CO2/O2 anesthesia before sacrifice
Clinical chemistry parameters evaluated include sorbitol dehydrogenase, alkaline phosphatase, creatine kinase, creatinine, total protein,
albumin, blood urea nitrogen, total bile acids, and alanine aminotransferase
Hematology parameters evaluated include erythrocyte count, hemoglobin, packed cell volume (automated and spun hematocrit), mean orpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, platelet count, reticulocyte count, nucleated red blood cell
count, total leukocyte count, differential leukocyte counts, red blood cell morphology, and platelet morphology
Oestrous cyclicity (parental animals):
Evaluation of vaginal smears, cycle length and number of cycles
Sperm parameters (parental animals):
Sperm motility, number of sperm per mg cauda, total number of sperm per cauda, number of spermatids per mg testis, total number of spermatids per testis, weight of right testis
Postmortem examinations (parental animals):
Surviving animals (all) were sacrified and examined. Complete necropsy performed on all study animals: liver, right kidney, heart, lungs, thymus and right testis (males) were weighed, microscopy examinations were carried out.
Statistics:
Organ and bodyweight data were analyzed with analysis of variance followed by the parametric multiple comparison procedures of Dunnett and Williams.
Clinical signs:
no effects observed
Description (incidence and severity):
Administration of Chromium picolinate monohydrate produced no clinical signs of toxicity.
Mortality:
no mortality observed
Description (incidence):
All mice survived to the end of the study.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
Final mean body weights of mice were similar to those of the controls.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
Feed consumption by exposed rats was similar to that by the vehicule controls.
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Description (incidence and severity):
No changes in hematology variables occured in mice administered Chromum picolinate monohydrate.
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
There were no statistically significant clinical chemistry changes observed in rats exposed to the substance.
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, non-treatment-related
Histopathological findings: non-neoplastic:
effects observed, non-treatment-related
Description (incidence and severity):
Histopathological lesions were considered spontaneous or incidental and not related to substance's exposure.
Reproductive function: oestrous cycle:
effects observed, non-treatment-related
Description (incidence and severity):
Evaluation of vaginal smears did not reveal any significant differences among the females in the amount of time spent in different estrous stages, the number of cycles, or the number of females with regular cycles. Estrous cycle length increased by 31% in females exposed to 10,000 ppm of Chromium picolinate monohyrate (5.1 ± 0.5 in exposed mice versus 3.9 ± 0.2 in controls), primarily due to 2 individual animals who had 8-daycy cles. This was not considered to be indicative of reproductive toxicity because all other parameters were normal, the other animals in the group had cycles of normal length, and no corresponding changes occurred in females exposed to 50,000 ppm of Chromium picolinate monohydrate.
Reproductive function: sperm measures:
no effects observed
Description (incidence and severity):
There were no alterations in sperm motility, number of sperm per mg cauda, total number of sperm per cauda, number of spermatids per mg testis, and total numbers of spermatids per testis in exposed animals.
Reproductive performance:
not examined
Dose descriptor:
NOAEL
Remarks on result:
not determinable because of methodological limitations
Remarks:
no NOAEL identified - generation not specified
Dose descriptor:
NOAEL
Remarks on result:
not determinable because of methodological limitations
Remarks:
no NOAEL identified - generation not specified
Reproductive effects observed:
not specified
Conclusions:
In this study similar to OECD 408 guideline study conducted with mice exposed to Chromium picolinate monohydrate, no changes in absolute or relative reproductive organ weights were noted and no gross and histopathological findings were observed. Investigations of sperm parameters, vaginal smears and female cycle length/number of cycles revealed no treatment-related effects.
Reason / purpose for cross-reference:
reference to other study
Reference
Endpoint:
reproductive toxicity, other
Remarks:
effects on sperm parameters and estrous cycle
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:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Justification for type of information:
1. HYPOTHESIS FOR THE ANALOG APPROACH
The read across follows Scenario 2 - Different compounds have qualitatively similar properties: properties of the target substance predicted to be quantitatively equal to those of the source substance or prediction based on a worst-case approach (as described in the 2017 Read-Across Assessment Framework document).

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
TARGET: Chromium tris(2-ethylhexanoate) (EC 222-357-3, CAS 3444-17-5)
SOURCE: Chromium picolinate monohydrate (CAS n° 27882-76-4)

3. ANALOG APPROACH JUSTIFICATION
The target substance and the source substance are organic salts of Chromium (3+). The organic counter ion of the target and source substances are small (6-8 carbon) carboxylic acids of similar molecular weight and polarity. The biologically-reactive center of all the molecules would be predicted to be the Cr (3+).
4. DATA MATRIX
See Read Across document attached to CSR.
Reason / purpose for cross-reference:
reference to same study
Reason / purpose for cross-reference:
reference to other study
Reason / purpose for cross-reference:
reference to other study
Qualifier:
no guideline followed
Principles of method if other than guideline:
At the end of a 3-month study equivalent to an OECD 408 guideline study, samples were collected for sperm count and motility from male rats. Vaginal cytology evaluations were also performed on the last 12 days of the study from female rats.
GLP compliance:
not specified
Limit test:
no
Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals or test system and environmental conditions:
origin: Taconic Laboratory Animals and Services, Germantown, NY, USA
age at initiation of the study: 6 weeks old
weight at initiation of the study: male = 91 - 92 g and female = 93 - 94 g
acclimatation period: 11-14 days
housing: 5 animals per cage
temperature: 72+/- 3°F
relative humidity: 50 +/- 15%
12 hours light/dark cycle
feed and water available at libitum
Route of administration:
oral: feed
Vehicle:
other: diet
Details on exposure:
Dose formulations were prepared with irradiated NTP-2000 open formula diet (from Zeigle Brothers, Inc., Gardners, PA, USA).
Dose formulations were prepared 4 times thoughout the study.
Chromium picolinate monohydrate in feed was stable for at least 42 days when stored at room temperature, protected from light, and under simulated animal room conditions at a concentration of 82 ppm for 8 days at room temperature.
Details on mating procedure:
No mating procedure.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Dose formulations were analyzed 3 times during the study: all samples were within 10% of the target concentrations.
Duration of treatment / exposure:
93 days
Frequency of treatment:
ad libitum
Dose / conc.:
2 000 ppm
Dose / conc.:
10 000 ppm
Dose / conc.:
50 000 ppm
No. of animals per sex per dose:
10 male and 10 female per dose
Control animals:
yes, plain diet
Parental animals: Observations and examinations:
Clinical findings recorded weekly
Food consumption measured weekly by cage
Animals weight: day 1, weekly thoughout the study and at sacrifice
Hematology and clinical chemistry analyses: days 3, 21 (special study) and 93 (core study): rats were bled from the retroorbital sinus while under CO2/O2 anesthesia before sacrifice
Clinical chemistry parameters evaluated include sorbitol dehydrogenase, alkaline phosphatase, creatine kinase, creatinine, total protein,
albumin, blood urea nitrogen, total bile acids, and alanine aminotransferase
Hematology parameters evaluated include erythrocyte count, hemoglobin, packed cell volume (automated and spun hematocrit), mean orpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, platelet count, reticulocyte count, nucleated red blood cell
count, total leukocyte count, differential leukocyte counts, red blood cell morphology, and platelet morphology
Oestrous cyclicity (parental animals):
Evaluation of vaginal smears, cycle length and number of cycles
Sperm parameters (parental animals):
Sperm motility, number of sperm per mg cauda, total number of sperm per cauda, number of spermatids per mg testis, total number of spermatids per testis, weight of right testis
Postmortem examinations (parental animals):
Surviving animals (all) were sacrified and examined. Complete necropsy performed on all study animals: liver, right kidney, heart, lungs, thymus and right testis (males) were weighed, microscopy examinations were carried out.
Statistics:
Organ and bodyweight data were analyzed with analysis of variance followed by the parametric multiple comparison procedures of Dunnett and Williams.
Clinical signs:
no effects observed
Description (incidence and severity):
Administration of Chromium picolinate monohydrate produced no clinical signs of toxicity.
Mortality:
no mortality observed
Description (incidence):
All rats survived to the end of the study.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
No significant compound-related effects on growth and final mean body weights of rats were observed.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
Feed consumption by exposed rats was similar to that by the vehicule controls.
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Description (incidence and severity):
There were no statistically significant hematological changes observed in rats exposed to the substance.
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
There were no statistically significant clinical chemistry changes observed in rats exposed to the substance.
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, non-treatment-related
Histopathological findings: non-neoplastic:
effects observed, non-treatment-related
Description (incidence and severity):
Histopathological lesions were considered spontaneous or incidental and not related to substance's exposure.
Reproductive function: oestrous cycle:
effects observed, non-treatment-related
Description (incidence and severity):
Evaluation of vaginal smears did not reveal any significant differences among the females in the amount of time spent in different estrous
stages, the cycle length, or the number of cycles. There was an increase in the number of females with regular cycles in the group exposed to 50,000 ppm of Chromium picolinate monohydrate.
Reproductive function: sperm measures:
no effects observed
Description (incidence and severity):
Sperm motility, number of sperm per mg cauda, total number of sperm per cauda, number of spermatids per mg testis, and total number of spermatids per testis of animals exposed to Chromium picolinate monohydrate were similar to those of control animals.
Reproductive performance:
not examined
Dose descriptor:
NOAEL
Remarks on result:
not determinable because of methodological limitations
Remarks:
no NOAEL identified - generation not specified
Dose descriptor:
NOAEL
Remarks on result:
not determinable because of methodological limitations
Remarks:
no NOAEL identified - generation not specified
Reproductive effects observed:
not specified
Conclusions:
In this study similar to OECD 408 guideline study conducted with rats exposed to Chromium picolinate monohydrate, no changes in absolute or relative reproductive organ weights were noted and no gross and histopathological findings were observed. Investigations of sperm parameters, vaginal smears and female cycle length/number of cycles revealed no treatment-related effects.

Data source

Reference
Reference Type:
publication
Title:
Absence of toxic effects in F344/N rats and B6C3F1 mice following subchronic administration of chromium picolinate monohydrate
Author:
Rhodes, M.C. et al.
Year:
2005
Bibliographic source:
Food and Chemical Toxicology 43 (2005), 21-29

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)
Deviations:
yes
Remarks:
Examinations are limited compared to guideline requirements.
GLP compliance:
not specified
Limit test:
no

Test material

Constituent 1
Chemical structure
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:
not specified
Details on test material:
origin: TCU America - Portland (OR) - USA

Test animals

Species:
mouse
Strain:
B6C3F1
Sex:
male/female
Details on test animals or test system and environmental conditions:
origin: Taconic Laboratory Animals ans Services, Germantown, NY, USA
age at initiation of the study: 6 weeks old
weight at initiation of the study: male = 19.4 - 19.6 g and female = 16.7 - 16.9 g
acclimatation period: 11-14 days
housing: 5 female per cage, male housed individually
temperature: 72+/- 3°F
relative humidity: 50 +/- 15%
12 hours light/dark cycle
feed and water available at libitum

Administration / exposure

Route of administration:
oral: feed
Details on route of administration:
Dose formulations were prepared with irradiated NTP-2000 open formula diet (from Zeigle Brothers, Inc., Gardners, PA, USA).
Vehicle:
other: diet
Details on oral exposure:
Dose formulations were prepared 4 times thoughout the study.
Chromium picolinate monohydrate in feed was stable for at least 42 days when stored at room temperature, protected from light, and under simulated animal room conditions at a concentration of 82 ppm for 8 days at room temperature.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Dose formulations were analyzed 3 times during the study: all samples were within 10% of the target concentrations.
Duration of treatment / exposure:
93 days
Frequency of treatment:
ad libitum
Doses / concentrationsopen allclose all
Dose / conc.:
80 ppm
Dose / conc.:
240 ppm
Dose / conc.:
2 000 ppm
Dose / conc.:
10 000 ppm
Dose / conc.:
50 000 ppm
No. of animals per sex per dose:
10 male and 10 female per dose for core study
+ additonal groups for special studies
Control animals:
yes, plain diet
Details on study design:
Dose selection was based on the results of a 14-day palatability study with rat: 10 rats (5 male, 5 female) per group were administered the substance at concentrations of 1%, 3% and 5% of the diet. The chemical hd no effect on feed palatability an produced no sign of toxicity. The range of the doses for this sutdy were chosen based on the low adsorption of the substance by rats and the condition that the highest dose (50 000 ppm) did not exceed 5% of the diet, so as not to alter the nutritional value of the feed.
Positive control:
No

Examinations

Observations and examinations performed and frequency:
- clinical findings recorded weekly for core study
- food consumption measured weekly by cage
- animals weight: day 1, weekly thoughout the study and at sacrifice
- hematology and clinical chemistry analyses: days 3, 21 (special study) and 93 (core study): rats were bled from the retroorbital sinus while under CO2/O2 anesthesia before sacrifice
- clinical chemistry parameters evaluated include sorbitol dehydrogenase, alkaline phosphatase, creatine kinase, creatinine, total protein,
albumin, blood urea nitrogen, total bile acids, and alanine aminotransferase
- hematology parameters evaluated include erythrocyte count, hemoglobin, packed cell volume (automated and spun hematocrit), mean orpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, platelet count, reticulocyte count, nucleated red blood cell
count, total leukocyte count, differential leukocyte counts, red blood cell morphology, and platelet morphology
- complete necropsy performed on all core study animals: liver, right kidney, heart, lungs, thymus and right testis (males) were weighed, microscopy examinations were carried out.
Sacrifice and pathology:
- complete necropsy performed on all core study animals
- liver, right kidney, heart, lungs, thymus and right testis (males) were weighed
- microscopy examinations were carried out
- gross lesions examined
Other examinations:
- sperm count and motility from male exposed to 0, 2000, 10000, 50000 ppm
- vaginal cytology evaluations performed the last 12 days of the study from female exposed to 0, 2000, 10000, 50000 ppm
Statistics:
Organ and bodyweight data were analyzed with analysis of variance followed by the parametric multiple comparison procedures of Dunnett and Williams. Hematologyand clinical chemistry data were analyzed using Kruskal–Wallis analysis of variance by the nonparametric multiple omparison methods of Shirley and Dunn. Jonckheere's test was used to assess the significance of dose–response trends. Extreme values were identified by the outlier test of Dixon and Massey. The Cochran–Armitage and Fisher's exact tests were used to assess nonneoplastic lesion prevalence.

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Description (incidence and severity):
Administration of Chromium picolinate monohydrate produced no clinical signs of toxicity.
Mortality:
no mortality observed
Description (incidence):
All mice survived until the end of the study.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
Final mean body weights of mice were similar to those of the controls.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
Feed consumption by exposed mice was similar to that of controls.
Food efficiency:
not specified
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Description (incidence and severity):
No changes in hematology variables occurred in mice administered Chromium picolinate monohydrate.
Clinical biochemistry findings:
not specified
Urinalysis findings:
not examined
Behaviour (functional findings):
not specified
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, non-treatment-related
Description (incidence and severity):
Organ weights and organ/bodyweight ratios of exposed animals were generally unaffected. Females displayed significantly decreased trends in right kidney and thymus weights. However, pair-wise comparisons did not reveal any significant differences between treated and control groups.
Gross pathological findings:
not specified
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, non-treatment-related
Description (incidence and severity):
Histopathological lesions were considered spontaneous or incidental and not related to substance's exposure.
Histopathological findings: neoplastic:
not specified
Description (incidence and severity):
Effects on reproduction:
Sperm motility, number of sperm per mg cauda, total number of sperm per cauda, number of spermatids permg testis, and total number of spermatids per testis of animals exposed to the substance were similar to those of control animals.
Evaluation of vaginal smears did not reveal anysignifi cant differences among the females in the amount of time spent in different estrous
stages, the number of cycles, or the numberof females with regular cycle.
Estrous cycle length increased by 31% in females exposed to 10000 ppm (5.1 ± 0.5 in exposed mice versus 3.9 ± 0.2 in controls), primarily due to 2 individual animals who had 8-day cycles. This was not considered to be indicative of reproductive toxicity because all other parameters were normal, the other animals
in the group had cycles of normal length, and no corresponding changes occurred in females exposed to 50000 ppm.

Effect levels

open allclose all
Dose descriptor:
NOAEL
Effect level:
50 000 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
body weight and weight gain
clinical biochemistry
clinical signs
food consumption and compound intake
haematology
histopathology: non-neoplastic
mortality
organ weights and organ / body weight ratios
Remarks on result:
other: expressed as Chromium picolinate monohydrate
Dose descriptor:
NOAEL
Effect level:
9 141 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
body weight and weight gain
clinical biochemistry
clinical signs
food consumption and compound intake
haematology
histopathology: non-neoplastic
mortality
organ weights and organ / body weight ratios
Remarks on result:
other: expressed as Chromium picolinate monohydrate
Key result
Dose descriptor:
NOAEL
Effect level:
10 089 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
body weight and weight gain
clinical biochemistry
clinical signs
food consumption and compound intake
haematology
histopathology: non-neoplastic
mortality
organ weights and organ / body weight ratios
Remarks on result:
other: expressed as Chromium 2-ethylhexanoate

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
In the experimental conditions of a test equivalent to OECD 408 guideline, subchronic exposure to Chromium picolinate monohydrate did not cause any toxic effects in mice.