Registration Dossier

Administrative data

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

Data source

Reference
Reference Type:
publication
Title:
Exposure of pregnant mice to chromium picolinate results in skeletal defects in their offspring.
Author:
Bailey, M.M. et al.
Year:
2006
Bibliographic source:
Birth Defects Research (Part B) 77, 244-249

Materials and methods

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

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): chromium (III) picolinate
- Analytical purity: no data

Test animals

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

Administration / exposure

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
Doses / concentrations
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.

Examinations

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

Results and discussion

Results: maternal animals

Effect levels (maternal animals)

open allclose all
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

Results (fetuses)

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Any other information on results incl. tables

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.

Applicant's summary and conclusion