Dichromium trioxalate

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

The results presented in various publications (including UN CICAD and European Food Scientific Committe on Food are used) suggest that trivalent chromium has no effect on fertility at tolerated levels of exposure.

The results of work with high doses showed mixed results with some parameters such as viablity of implants possibly reduced (sample sizes too small for reliable statistics) and reduced mating performance that may be in relation to reduced body weights - ie secondary effects to other adverse parental toxicity.

Ingestion of oxalate as oxalic acid did not cause adverse effects general health, mating or fertility, although there was a significant reduction in water consumption at top dose levels.

Treatment with 162 mg/kg/day resulted in a significant decrease of average number of litters

Adjusted kidney weight increased by nearly 10%in high dose females.

For the second generation, there was a decrease at the high dose level of average number of live pups per litter.

At necropsy, kidney weight was significantly increased by about 10% in high dose males and females.

A no observed adverse effect concentration is considered to be 162 mg/kg/day

Ultimately, it needs to be realised that Cr3+ is an essential element in diet and occurs in food and natural water. It is readily excreted and is non-accumulative. Oxalic acid is a natural metabolite formed in all cells and is excreted in the urine.

Link to relevant study records

Reference

Endpoint:

screening for reproductive / developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

test procedure in accordance with generally accepted scientific standards and described in sufficient detail

Justification for type of information:

The test was performed on a bio-available salt of chromium III that is commonly used in dietary supplements. The counter ion, picolinate, is itself under checks for possible reproductive effects, but a negative response in this study means that it is good evidence that neight chromium III or picolinate are hazarous for reproduction.

Qualifier:

equivalent or similar to guideline

Guideline:

EPA OPPTS 870.3800 (Reproduction and Fertility Effects)

Principles of method if other than guideline:

Four weeks prior to mating, the males were fed a diet providing 200 mg/kg/day [Cr(pic)3] for comparison with untreated controls. Females were not treated. Each male was mated with two females, which were sacrificed on gestation day 17, and their litters were examined for adverse effects.

GLP compliance:

no

Limit test:

yes

Justification for study design:

Valid assessment method to examine potential effects on fertility.

Species:

mouse

Strain:

CD-1

Details on species / strain selection:

Charles River Breeding Laboratories, International (Wilmington, MA)

Sex:

male/female

Details on test animals or test system and environmental conditions:

22±2°C, with 40–60% humidity and a 12-h photoperiod

Route of administration:

oral: feed

Details on exposure:

200 mg/kg body mass per day (25 mg Cr per kilogram body mass per day) mixed into feed, based on data from previous studies, which indicated that CD-1 mice consume an average of 7 g diet per day

Details on mating procedure:

Animals were mated naturally, two females with one male, for 1 week.Observation of a copulation plug in the vagina designated gestation day 0 (GD 0). Mated females were individually housed in shoe box-type cages with hardwood bedding and given Harlan Teklad rodent chow and water ad libitum.

Details on analytical verification of doses or concentrations:

Males were fed the appropriate test diet for 4 weeks prior to mating

Duration of treatment / exposure:

4 weeks

Frequency of treatment:

Diet

Dose / conc.:

200 mg/kg bw/day (nominal)

Remarks:

Of the test substance in feed

Dose / conc.:

25 mg/kg bw/day (nominal)

Remarks:

Cr 3+ equivalent

No. of animals per sex per dose:

24 females, 12 males

Control animals:

yes, plain diet

Litter observations:

Yes

Reproductive indices:

Yes

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

not examined

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

not examined

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

not examined

Ophthalmological findings:

not examined

Behaviour (functional findings):

no effects observed

Organ weight findings including organ / body weight ratios:

not examined

Histopathological findings: non-neoplastic:

not examined

Histopathological findings: neoplastic:

not examined

Reproductive performance:

no effects observed

Description (incidence and severity):

The mating indices for control and treated males were identical

Key result

Dose descriptor:

NOAEL

Effect level:

> 25 mg/kg bw/day (nominal)

Based on:

element

Remarks:

Chromium III

Sex:

male

Remarks on result:

not determinable due to absence of adverse toxic effects

Key result

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

> 25 mg/kg bw/day (nominal)

Based on:

element

Remarks:

Cr3+

Remarks on result:

not determinable due to absence of adverse toxic effects

Key result

Reproductive effects observed:

no

Lowest effective dose / conc.:

25 mg/kg bw/day (nominal)

An increase in the average number of total resorbed or dead fetuses was observed in the treated group as compared to controls; however, the increase was not statistically significant. No significant effect of exposure was seen on gross or skeletal malformations (split cervical arch) or skeletal variations (rudimentary or supernumerary ribs). Fetuses sired by exposed males weighed significantly more than fetuses of unexposed males. However, this difference is extremely small and is probably a statistical anomaly.

Conclusions:

No adverse fertility or developmental effects observed when male mice were treated at 25 mg/kg/day for 4 weeks prior to meting.

Executive summary:

The test was performed on a bio-available salt of chromium III that is commonly used in dietary supplements. The counter ion, picolinate, is itself under checks for possible reproductive effects, but a negative response in this study means that it is good evidence that neither chromium III or picolinate are hazarous for reproduction.

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

25 mg/kg bw/day

Study duration:

subacute

Species:

rat

Effect on fertility: via inhalation route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEC

30 mg/m³

Study duration:

subchronic

Species:

rat

Quality of whole database:

Expressed as Cr3+ (44 mg/m3 as Cr2O3)

Effects on developmental toxicity

Description of key information

An increase in the average number of total resorbed or dead foeti was observed in the treated group as compared to controls; however, the increase was not statistically significant.

No significant effect of exposure was seen on gross or skeletal malformations or skeletal variations. Foeti sired by exposed males weighed more than those of unexposed males but this finding was considered a statistical anomaly.

Note that both chromium III and oxalic acid salts are found in food. Chromium III is an essential element and oxalic acid is a product of metabolism that is typically excreted.

In view of high concentrations in the diet and in living tissues, the substance is not considered to be toxic for reproduction.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

25 mg/kg bw/day

Study duration:

subacute

Species:

mouse

Additional information

No signs of maternal toxicity were observed.

No decrease in foetal weight or significantly increased incidence of skeletal defects was observed compared to the controls

Justification for classification or non-classification

Extract from Opinion of the Scientific Committee on Food on the Tolerable Upper Intake Level of Trivalent Chromium (expressed in 4 April 2003)

Chromium (III) chloride dissolved in tap water was given to sexually mature male and female Swiss mice (day 50 of age). Males received water with 1000 or 5000 mg/L chromium chloride and females with 2000 or 5000 mg/L ad libitum for 12 weeks. Controls were given tap water, only. Treated animals consumed less water per day than controls did. Chromium chloride reduced fertility and seminal vesicle weights significantly. Body weights were reduced in males but not in females. Testes and ovarian weights were increased whereas uterine weights were significantly reduced. The number of resorptions and dead foetuses was increased in females impregnated by males exposed to the trivalent compound and the number of resorptions in exposed females as well (Elbetieha and Al-Hamood, 1997). Unfortunately, the authors did not report the actual quantitative exposure to chromium chloride but EGVM (2002b) estimated from the given data oral doses for trivalent chromium of approximately 500 or 1250 mg/kg bw/day for females and 250 or 1250 mg/kg bw/day for males.

The fertility of male Sprague Dawley rats exposed to chromium (III) chloride in drinking water at a concentration of 1000 mg/L for 12 weeks, which is equivalent to about 50 mg CrCl3/kg body weight or about 16,5 mg trivalent chromium/kg body weight, was unaffected but significant reductions in the weight of testes and seminal vesicles were observed (Bataineh et al., 1997).

There are no reports of developmental toxicity studies on chromium (III) compounds given orally