Chromium (III) hydroxide

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.

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.

Link to relevant study records

Reference

Endpoint:

screening for reproductive / developmental toxicity

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

supporting 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:

As with all inorganic salts, the significance for toxicity or environmental assessment is the presence of specific ions that will form when in solution or when in biological systems.In the case of Cr III salts, the counter ion will have an effect on solubility and this is itself dependant on the type of media being used and in particular the pH of that media. It is generally accepted that in the case of metal salts, testing with salts that are soluble in the respective test media will ensure maximum exposure of the metal ions. This will include chlorides and nitrates as being more soluble and will indeed have relevance when dissolved in acid media, such as if ingested.Read-across to other chromium III salts is therefore considered valid as long as the exposure in the test system is greater than wold be expected for the substance under review for registration.

Qualifier:

no guideline followed

Version / remarks:

Standard principles of research, but not following specific guidelines

Principles of method if other than guideline:

Males rats were treated with tolerated doses of Chromium (III) chloride and potassium chromate (VI) at 1000 mg/l in drinking water. A reduced body weight suggested this was the maximum tolerated, but clearly some impact on health. Males were mated and numbers of matings observed. Viability of the foeti were assessed with number of implantations and resorptions. Small numbers of animals in this screening study make statistical analysis uncertain.

GLP compliance:

no

Limit test:

yes

Justification for study design:

Research to compare Cr III and Cr VI at tolerated daily doses.

Specific details on test material used for the study:

Chromium chloride (Trivalent chromium compound: Janssen Chinica, B-2440 Geel, Belgium),

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

Animals were maintained under controlled temperature of 21 f 1°C in 12 h light: 12 h darkness schedule (lights 06.00 - 18.00 h) in cages containing four or five animals. Food and tap water were freely available in the home cage.Male rats were provided access to drinking water containing the test substances for 12 weeks

Route of administration:

oral: drinking water

Details on mating procedure:

Male rats were presented with a female of the same strain, brought into estrus by sequential subcutaneous treatment with 12.5 pg/animal estradiol benzoate

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

Male rats were provided access to drinking water containing the test substances for 12 weeks

Dose / conc.:

1 000 mg/L drinking water

Remarks:

Cr(Cl)3 hydrate

Dose / conc.:

24 mg/kg bw/day (nominal)

Remarks:

Expressed as Cr3+

Dose / conc.:

50 mg/kg bw/day (nominal)

Remarks:

Equivalent Cr(OH)3

No. of animals per sex per dose:

13 Control15 Treated

Control animals:

yes, concurrent no treatment

Positive control:

No

Parental animals: Observations and examinations:

All males were sacrificed after 12 weeks of exposure. Body weight and weights of paired testes, seminal vesicles (stripped of fluid) and preputial glands were recorded.

Sperm parameters (parental animals):

No

Litter observations:

No

Postmortem examinations (parental animals):

Not applicable

Postmortem examinations (offspring):

No

Statistics:

Chi - square test or Student’s “t” test

Reproductive indices:

Fertility

Offspring viability indices:

Not applicable

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

Reduced weight gain / weight loss.Reduced feeding observed.Reduced agression

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Lower weights in treated group, but vigour apparently no affectedReduced agression

Food consumption and compound intake (if feeding study):

no effects observed

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

no effects observed

Behaviour (functional findings):

effects observed, treatment-related

Description (incidence and severity):

Reduced agression

Reproductive function: oestrous cycle:

not examined

Description (incidence and severity):

Females were induced into oestrus cycle

Reproductive function: sperm measures:

not examined

Reproductive performance:

effects observed, treatment-related

Description (incidence and severity):

Reduced ejaculations, but similar number attempted matings. This was considered most likely linked to reduced vigour reflected by clinical signs of reduced activitiy

Dose descriptor:

NOAEL

Effect level:

1 000 mg/L drinking water

Based on:

test mat.

Sex:

male

Basis for effect level:

body weight and weight gain

Key result

Dose descriptor:

NOAEL

Effect level:

ca. 24 mg/kg bw/day (nominal)

Based on:

element

Remarks:

Cr3+

Sex:

male

Basis for effect level:

body weight and weight gain

Clinical signs:

not examined

Key result

Reproductive effects observed:

no

Lowest effective dose / conc.:

1 000 mg/L drinking water

Treatment related:

yes

Relation to other toxic effects:

reproductive effects as a secondary non-specific consequence of other toxic effects

Dose response relationship:

not specified

Relevant for humans:

not specified

The results showed mixed results with some parameters such as viablity of implants possibles 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.

Pre-mating dose of 12 weeks is longer than normally used in guideline methods.

Conclusions:

The results presented in this publication suggest that neither trivalent chromium (chromium chloride) or hexavalent chromium compound (potassiumdichromate) had effect on fertility of the male rat.The results showed mixed results with some parameters such as viablity of implants possibles 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.Pre-mating dose of 12 weeks is longer than normally used in guideline methods.

Executive summary:

Males rats were treated with tolerated doses of Chromium (III) chloride and potassium chromate (VI) at 1000 mg/l in drinking water. A reduced body weight suggested this was maximum tolerated. Males were mated and numbers of matings observed. Viability of the foeti were assessed with number of implantations and resorptions. Small numbers of animals in this screening study make statistical analysis uncertain.

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.

Link to relevant study records

Reference

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

Treatment of females gestation days 6 - 17

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:

Study performed on soluble chromium III salt used as a food supplement and cited in reviews on safety of such food supplements.

Qualifier:

no guideline followed

Principles of method if other than guideline:

From gestation days (GD) 6–17, mated CD-1 female mice were fed diets delivering either 25mg Cr/kg/day as Cr(pic)3, 3.3 or 26mg Cr/kg/day as Cr3 propionate, or the diet only to determine if Cr3 could cause developmental toxicity. Dams were sacrificed on GD 17, and their litters were examined for adverse effects

GLP compliance:

no

Species:

mouse

Strain:

CD-1

Details on test animals or test system and environmental conditions:

Male and female CD-1 mice, obtained from Charles River Breeding Laboratories, International (Wilmington, MA) Housed at ca 22C, with 40–60% humidity and a 12-hr photoperiod

Route of administration:

oral: feed

Details on exposure:

Females were given treated diets containing ca 25 mg/kg/day Cr III as either picolinate or as propionate from gestation days 6 - 17

Analytical verification of doses or concentrations:

not specified

Details on mating procedure:

Animals were bred naturally, two females with one male. Observation of a copulation plug was designated GD 0.

Duration of treatment / exposure:

Females were given treated diets containing ca 25 mg/kg/day Cr III as either picolinate or as propionate from gestation days 6 - 17

Frequency of treatment:

Diet

Duration of test:

12 days

Dose / conc.:

25 mg/kg bw/day (nominal)

Remarks:

Expressed as Cr III either dosed as picolinate or propionate

Dose / conc.:

3.3 mg/kg bw/day (nominal)

Remarks:

Expressed as Cr III dosed as propionate

No. of animals per sex per dose:

Up to 30 females per group.

Control animals:

yes, plain diet

Maternal examinations:

Clinical signs, weight, food consumption

Ovaries and uterine content:

Implantations

Fetal examinations:

Foetal weight, viability, skeletal and other defects

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):

no effects observed

Description (incidence and severity):

Food consumption was virtually identical among the treatment groups, and average food consumption was approximately 7g diet/day.

Number of abortions:

no effects observed

Pre- and post-implantation loss:

no effects observed

Total litter losses by resorption:

no effects observed

Description (incidence and severity):

Percentage of resorbed or dead fetuses did not differ among treatment groups

Details on maternal toxic effects:

NoneMaternal weight gain was not affected by the administration of Cr(pic)3 or Cr3 (Table 1). No signs of maternal toxicity were observed for dams in any of the groups

Key result

Dose descriptor:

NOAEL

Effect level:

> 25 mg/kg bw/day (nominal)

Based on:

element

Remarks on result:

not determinable due to absence of adverse toxic effects

Key result

Abnormalities:

no effects observed

Fetal body weight changes:

no effects observed

Description (incidence and severity):

Fetal weight and percentage of resorbed or dead fetuses did not differ among treatment groups
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): no effects observed

Reduction in number of live offspring:

not examined

Changes in sex ratio:

not examined

Changes in litter size and weights:

not specified

Changes in postnatal survival:

not examined

External malformations:

no effects observed

Skeletal malformations:

no effects observed

Description (incidence and severity):

No skeletal defects in fetuses from Cr(pic)3- or Cr3-treated dams differed in incidence from the control value.

Visceral malformations:

not specified

Other effects:

not specified

Key result

Dose descriptor:

NOAEL

Effect level:

> 25 mg/kg bw/day (nominal)

Based on:

element

Sex:

male/female

Remarks on result:

not determinable due to absence of adverse toxic effects

Key result

Abnormalities:

no effects observed

Key result

Developmental effects observed:

no

Conclusions:

No signs of maternal toxicity were observed.No decrease in foetal weight or significantly increased incidence of skeletal defects was observed compared to the controlsAlthough exposure was not up to the maternal tolerated limit and the exposure period was relatively short, there were no adverse effects observed.

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