Chromium trichloride

Repeated dose toxicity: oral

Administrative data

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1997

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: reliable report in peer reviewed Journal but only secondary literature available

Data source

Reference

Reference 1

Reference Type:

publication

Title:

Unnamed

Year:

1997

Reference 2

Reference Type:

publication

Title:

Chromium as an essential nutrient for humans

Author:

Anderson RA

Year:

1997

Bibliographic source:

Regulatory Toxicology and Pharmacology, 26:S35–41, 1997

Reference 3

Reference Type:

review article or handbook

Title:

Concise International Chemical Assessment Document 76 INORGANIC CHROMIUM(III) COMPOUNDS

Author:

Dr Tiina Santonen, Dr Antti Zitting, and Dr Vesa Riihimäki

Year:

2009

Bibliographic source:

International Programme on Chemical Safety (IPCS)

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:

20 weeks of exposure rather than only 13 weeks

GLP compliance:

not specified

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Chromium trichloride

EC Number:

233-038-3

EC Name:

Chromium trichloride

Cas Number:

10025-73-7

Molecular formula:

Cl3Cr

IUPAC Name:

chromium trichloride

Test material form:

solid: particulate/powder

Remarks:

migrated information: powder

Details on test material:

Reagent grade chromic chloride was purchased from Fisher Scientific Co. (Pittsburgh, PA)

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male

Details on test animals or test system and environmental conditions:

Four-week-old male Harlan Sprague-Dawley rats (eight per group)

Administration / exposure

Route of administration:

oral: feed

Vehicle:

other: diet

Details on oral exposure:

CrCl3 was fed a diet supplemented with 0, 5, 25, 50, or 100 mg Cr/kg as chromium chloride for a period of 20 weeks.

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

20 weeks

Frequency of treatment:

once daily

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 5, 25, 50, or 100 mg Cr/kg as chromium chloride, Daily Cr3+ intakes can be estimated to correspond to 0.35 – 7 mg/kg
Basis:
nominal in diet

No. of animals per sex per dose:

8

Control animals:

yes, plain diet

Details on study design:

Four-week-old male Harlan Sprague-Dawley rats (eight per group) were fed a diet supplemented with 0, 5, 25, 50, or 100 mg Cr/kg as chromium chloride for a period of 20 weeks (Anderson et al., 1997). Daily Cr3+ intakes can be estimated to correspond to 0.35 – 7 mg/kg bw (estimated on the basis of default reference values given in Appendix VI of European Commission [2003]). If 200 g is used as a mean body weight, the highest dose corresponds to 7 mg chromium/kg bw (corresponds to 21.3 mg CrCl3/kg bw).

Positive control:

none

Examinations

Observations and examinations performed and frequency:

Effects on body weights, selected organ weights, and the histology of liver and kidneys were evaluated.

Sacrifice and pathology:

Histopathological examination was performed on four high-dose and four control rats. Haematology and biochemical analyses of blood (serum glucose, cholesterol, triglycerides, liver enzymes, blood urea nitrogen, total protein, and creatinine) were performed on animals at 11, 17, and 24 weeks of age.

Other examinations:

Blood was collected from the tail after ll and l7 weeks and following decapitation after 24 weeks, allowed to clot 30 minutes at room temperature and then stored on ice prior to centrifugation at 4000 g for 30 minutes. Serum glucose, cholesterol, triglycerides, blood urea nitrogen, total protein, creatinine, .actate dehydrogenase, alanine amino transferase and aspartate amino transferase were determined using standard laboratory procedures on a Centrifichem 600 (Baker Instruments, Allentown, PA).

Statistics:

Statistical analyses of the data were performed by analysis of variance. Individual mean comparisons were identified with Duncan’s multiple range test. All values are mean ± SEM. There were eight animals per group. Using eight rats per group would be sufficient to detect a difference at the 0.05 level (power 0.9) with an expected difference between means of 0.4 and a standard deviation of 0.2 .

Results and discussion

Results of examinations

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

not specified

Haematological findings:

not specified

Clinical biochemistry findings:

effects observed, treatment-related

Description (incidence and severity):

Some sporadic, statistically significant changes were seen in some clinical chemistry parameters (lactate dehydrogenase, aspartate aminotransferase, serum creatinine levels), but no obvious effect on chromium concentration was stated by the authors.

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

not specified

Details on results:

No changes compared to control in body weights were observed in any dose group and all animals appeared normal with no visible differences amongst the groups. Weights of heart, liver, kidney, spleen, pancreas, testes and epididymal fat pad were not altered by dietary Cr. Hematocrit was also similar among all the groups. No changes in body or organ weights, no general signs of toxicity, and no changes in liver or kidney histopathology were seen. Some sporadic, statistically significant changes were seen in some clinical chemistry parameters (lactate dehydrogenase, aspartate aminotransferase, serum creatinine levels), but because these changes did not show any dose or time dependency, they were not considered to be treatment related. Glucose, cholesterol and triglycerides were similar for all groups at 11, 17 and 24 weeks.

Effect levels

1

Dose descriptor:

NOAEL

Effect level:

> 7 mg/kg bw/day (actual dose received)

Based on:

element

Remarks:

chromium

Sex:

male

Basis for effect level:

other: see 'Remark'

2

Dose descriptor:

NOAEL

Effect level:

> 21.3 mg/kg bw/day (actual dose received)

Based on:

test mat.

Remarks:

chromium chloride (anhydrous)

Sex:

male

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

Chromium concentrations in liver and kidneys were determined in four rats per group, showing a linear increase of chromium in liver and kidney tissue with doses received. Chromium picolinate resulted in significantly higher chromium concentrations in livers and kidneys, indicative of higher absorbtion rates compared to chromium trichloride. Values for Cr picolinate animals were consistently several-fold

higher than respective values for the Cr chloride supplemented animals.

Applicant's summary and conclusion

Conclusions:

Based on these results, the highest dose level (7 mg chromium (III)/kg bw/day ) can be considered as a no-observed-adverse-effect level (NOAEL) for repeated dose toxicity (using 200 g as a mean body weight). Accordingly, this relates to a NOAEL of 21.3 mg/kg bw/d based on chromium trichloride.

Executive summary:

This study was conducted to evaluate the toxicity of chromium chloride in rats exposed to 0, 5, 25, 50, or 100 mg Cr/kg chromium trichloride in the diet for 20 weeks (estimated to correspond to 0.35 – 7 mg/kg bw). No morphological changes of liver and renal damage were observed based on histopathological examination of kidneys and did not result in significant alterations in body weight gain at level of 15 mg chromium (III)/kg bw/day. However, in calculations, they used a rat body weight of only 100 g, which seems exceptionally low, because the normal weight of adult Sprague-Dawley rats is between 200 and 300 g. If 200 g is used as a mean body weight, the highest dose corresponds to 7 mg chromium/kg bw. Moreover no alterations in testers or epididymis weights were observed in rats at the highest dose.

Therefore, the no-observed-adverse-effects-level (NOAEL) of chromium trichloride is estimated to be 7 mg chromium (III)/kg bw/day. This value can be converted to a NOAEL of 21.3 mg/kg bw/d based on molecular mass of chromium trichloride (anhydrous) or to 35.9 mg chromium trichloride hexahydrate/kg bw/d respectively.