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Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information
The bioavailability of orally ingested Cr(III) is so low (1%) that a significant passage into breast milk can be excluded. In addition, there is no potential for accumulation in tissues that could later serve as a source for Cr(III) in breast milk. 
Link to relevant study records
Reference
Endpoint:
toxicity to reproduction
Remarks:
other: effects on sperm parameters and estrous cycle
Type of information:
migrated 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:
other: Meets generally accepted scientific standards, well documented and acceptable for assessment
Reason / purpose:
reference to same study
Principles of method if other than guideline:
At the end of the exposure period (3 months), samples were collected for sperm count and motility from male animals exposed to 0, 2000, 10000 or 50000 ppm. In addition, vaginal cytology evaluations were performed on the last 12 days of the study from female animals.
GLP compliance:
no
Limit test:
no
Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Taconic Laboratory Animals and Services
- Age at study initiation: 6 weeks
- Weight at study initiation: 92 g (male), 93 g (female)
- Housing: 5 per cage
- Acclimation period: 11 - 14 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20.6 - 23.9
- Humidity (%): 35 - 65
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
oral: feed
Vehicle:
other: diet (irradiated NTP-2000 open formula diet)
Details on exposure:
DIET PREPARATION
- Rate of preparation of diet (frequency): four times throughout the study
- Storage temperature of food: room temperature, protected from light (stability of the test substance under these conditions was at least 42 days)
Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
93 days
Frequency of treatment:
continuous
Remarks:
Doses / Concentrations:
2000, 10000 or 50000 ppm
Basis:
nominal in diet
Remarks:
Doses / Concentrations:
160, 805 and 4243 mg/kg bw (males)
Basis:
other: average daily doses
Remarks:
Doses / Concentrations:
162, 780 and 4254 mg/kg bw (females)
Basis:
other: average daily doses
No. of animals per sex per dose:
10
Control animals:
yes, plain diet
Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: No data


DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: weekly


BODY WEIGHT: Yes
- Time schedule for examinations: day 1, weekly throughout the study and at sacrifice


FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No, food consumption was measured by cage covering a 7-day period
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No data
Oestrous cyclicity (parental animals):
Evaluation of vaginal smears, cycle length and the number of cycles
Sperm parameters (parental animals):
testis weight, sperm count in testes, sperm count in epididymides, enumeration of cauda epididymal sperm reserve, sperm motility
Postmortem examinations (parental animals):
SACRIFICE
- Male and female animals: All surviving animals


HISTOPATHOLOGY / ORGAN WEIGHTS
Organ weights of liver, right kidney, heart, lungs, thymus and right testis
Dose descriptor:
NOAEL
Remarks on result:
not determinable
Remarks:
no NOAEL identified Generation not specified (migrated information)
Reproductive effects observed:
not specified

Effects on systemic repeated dose toxicity after oral exposure are described in detail in section 7.5.1.

Reproductive organ weights were not affected.

Sperm parameters of exposed animals were similar of those of control animals. 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 a significant increase in the number of females with regular cycles in the high dose group only.

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

There are two subchronic feeding studies in rats and mice available performed with the source substance Cr(III) picolinate (Rhodes et al., 2005) which also investigated potential effects on reproductive organs, sperm parameters or oestrus cycle. Even at daily doses greatly exceeding the limit dose of 1000 mg/kg/day, none of these parameters were affected. It can therefore be safely predicted that basic Cr(III) acetate will not affect fertility parameters.

The REACh regulation states that testing into the reproductive toxicity of a substance are not required if the substance is of low toxicological activity (no evidence of toxicity seen in any of the tests available), it can be proven from toxicokinetic data that no systemic absorption occurs via relevant routes of exposure and there is no or no significant human exposure.

Most, if not all, prerequisites for a compete waiving of reproductive toxicity testing requirements are met for basic Cr(III) acetate. The acute and repeated-dose toxicity studies reflect the fact that Cr(III) is poorly absorbed from the gastrointestinal tract (1%). No systemic effects were seen in any animal study.


Short description of key information:
Subchronic oral studies in the rat showed no effects on reproductive organs, sperm parameters or oestrus cycle parameters. Cr(III) is poorly absorbed and no systemic effects are expected at all.

Justification for selection of Effect on fertility via oral route:
Hazard assessment is conducted by means of read-across from a structural analogue/surrogate. The selected study is the most adequate and reliable study based on the identified similarities in structure and intrinsic properties between source and target substance and overall assessment of quality, duration and dose descriptor level (refer to the endpoint discussion for further details).

Effects on developmental toxicity

Description of key information
Cr(III) did not cause developmental effects at doses equivalent to 155 mg/kg bw/day basic Cr(III) acetate monohydrate
Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
migrated 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:
other: Basic data given
Principles of method if other than guideline:
From gestation days 6 - 17, pregnant mice were fed diets containing either 200 mg/kg Cr picolinate, 200 mg/kg CrCl3, 174 mg/kg picolinic acid or the diet only to determine if one of the substances could cause developmental toxicity. Dams were sacrificed on gestation day 17 and their litters were observed for adverse effects.
GLP compliance:
not specified
Limit test:
no
Species:
mouse
Strain:
CD-1
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories, International
- Housing: individually in shoe-box-like cages


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 2
- Humidity (%): 40 - 60
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
oral: feed
Vehicle:
other: diet
Details on exposure:
DIET PREPARATION
- Mixing appropriate amounts with (Type of food): Each of the substances was added to milled rodent chow in sufficient quantities to achieve the appropriate concentration (no further details given).
Analytical verification of doses or concentrations:
not specified
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1/2
- Proof of pregnancy: vaginal plug referred to as day 0 of pregnancy
Duration of treatment / exposure:
gestation days 6 - 17
Frequency of treatment:
daily
Duration of test:
17 days
Remarks:
Doses / Concentrations:
200 mg/kg
Basis:
nominal in diet
No. of animals per sex per dose:
no data
Control animals:
yes, plain diet
Details on study design:
- Dose selection rationale: A pre-test was performed with doses of 50, 100 and 200 mg/kg of Cr picolinate. Significant increases in cervical arch defects were seen with the high dose. As that dosage was obviously not maternally toxic, it was chosen for the main study.
Maternal examinations:
CAGE SIDE OBSERVATIONS: No data


DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily


BODY WEIGHT: Yes


FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No data
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No


POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day # 17
- Organs examined: uterus/determination of body weights
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: No
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
Fetal examinations:
- External examinations: Yes: all per litter
- Soft tissue examinations: No
- Skeletal examinations: Yes: all per litter
- Head examinations: No
Statistics:
test for homogeneity of variance by the Levene statistic, ANOVA folowed by an LSD post-hoc test, Pearson chi-square test, 2 x 2 factorial ANOVA
Dose descriptor:
NOAEL
Effect level:
>= 200 mg/kg bw/day (nominal)
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEL
Effect level:
< 200 mg/kg bw/day (nominal)
Basis for effect level:
other: developmental toxicity
Abnormalities:
not specified
Developmental effects observed:
not specified

In maternal animals, weight gain and food consumption were not affected by treatment. No signs of maternal toxicity were observed in dams in any of the groups.

Fetal weight, number of implantantions and percentage of resorbed or dead fetuses did not differ among treatment groups and no gross malformations were observed in any of the fetuses. However, the mean litter percentage of fetuses displaying bifurcated cervical arches was significantly greater in the Cr picolinate treated group relative to the control group (5.79 vs. 2.09%). The per litter incidence of bifurcated arches in fetuses in the picolinic acid-treated group was double that of the control group (not significant). No other skeletal defects occured in treated animals. The dosage of chromium was greater for the dams given CrCl3 than for those dosed with Cr picolinate (39 vs. 25 mg/Cr/kg). However, CrCl3 treatment did not result in a significant increase in any defects.

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

A developmental toxicity study in mice was conducted with the source substances Cr(III) picolinate and CrCl3. While Cr(III) picolinate caused an increased incidence in bifurcated cervical arches, this effect was not observed with CrCl3, although the administered chromium dose was higher in the CrCl3 group compared to the Cr picolinate group (39 vs. 25 mg Cr/kg bw/day). Picolinic acid alone caused a doubling of the incidence in bifurcated cervical arches when compared to controls, but this trend did not prove to be statistically significant. It therefore appears as if the ligand, picolinate, contributes to the occurrence of the skeletal variation. The absence of these effects in the CrCl3 group suggests that Cr(III) per se is not detrimental to prenatal development. The maternal and developmental NOAEL is ≥ 39 mg Cr/kg bw/day, equivalent to 155 mg/kg bw/day basic Cr(III) acetate monohydrate


Justification for selection of Effect on developmental toxicity: via oral route:
Hazard assessment is conducted by means of read-across from a structural analogue/surrogate.

Justification for classification or non-classification

The available data on reproductive toxicity do not meet the criteria for classification according to Regulation (EC) 1272/2008 or Directive 67/548/EEC, and is therefore conclusive but not sufficient for classification.