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Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

There are 2 subchronic oral toxicity studies similar to OECD 408 guideline conducted with the source substance Chromium picolinate monohydrate (Rhodes et al, 2005). These studies also examined the potential effects of the substance on reproductive organs, sperm parameters and estrous cycle. None of these parameters were affected whatever the dose is, the maximum dose corresponds to 4683 mg/kg bw Chromium 2-ethylhexanoate (average daily dose) for rats. Therefore, it can be foreseen that Chromium 2-ethlyhexanoate will not affect fertility parameters.

Link to relevant study records

Referenceopen allclose all

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.
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.
Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

The acute and repeated-dose toxicity studies conducted on animals with both the target substance and the source substance reflect that Chromium (III) is poorly absorbed via oral route. No systemic effects were recorded. Therefore, additional testing into reproductive toxicity was deemed not necessary based on no systemic absorption occurring via the oral route.

Effects on developmental toxicity

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available

Justification for classification or non-classification

As per the 18th ATP of Regulation (EC) 1272/2008, Chromium 2-ethylhexanoate (metal salt of 2-ethylhexanoic acid) is legally classified for developmental effects as reprotoxic, cat. 1 - H360D: May damage the unborn child.

No classification for fertility according to Regulation (EC) 1272/2008 is required for Chromium 2-ethylhexanoate based on available data.

Additional information