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Toxicological information

Developmental toxicity / teratogenicity

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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: Guideline comparable, published study

Data source

Reference
Reference Type:
publication
Title:
Comparison of the Potential for Developmental Toxicity of Prenatal Exposure to Two Dietary Chromium Supplements, Chromium Picolinate and [Cr3O(O2CCH2CH3)6(H2O)3]+, in Mice
Author:
Bailey MM, Sturdivant J, Jernigan PL, Townsend MB, Bushman J, Ankareddi I, Rasco JF, Hood RD & Vincent JB
Year:
2008
Bibliographic source:
Birth Defects Research (Part B) 83:27–31

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Principles of method if other than guideline:
Method broadly comparable to OECD 414, performed in the mouse using dietary administration
GLP compliance:
no
Remarks:
: published study
Limit test:
no

Test material

Constituent 1
Reference substance name:
Chromium picolinate
IUPAC Name:
Chromium picolinate
Constituent 2
Reference substance name:
Cr3
IUPAC Name:
Cr3
Details on test material:
The study was performed using the water soluble complexes of Cr (III) chromium picolinate and [Cr3O(O2CCH2CH3)6(H2O)3]+ (Cr3)

Chromium(III) picolinate, was synthesised according to the methods of Press et al (1990). Cr3 was synthesised according to the methods of Earnshaw et al (1966). The authenticity of both was established by high resolution electron impact mass spectrometry. Picolinic acid was purchased from Fisher Scientific (Pittsburgh, PA). LM-485 milled rodent diet was purchased from Harlan Teklad (Madison, WI). Either Cr(pic)3 or Cr3 was added to milled rodent chow in sufficient quantities to achieve the appropriate concentration of the test compound. All calculations were based on data from previous studies, which indicated that pregnant CD-1 mice consume an average of 7 g diet/day. Extensive stability studies indicate that chromium test compounds are extremely stable and that no degradation in the diet would be expected. Because the purpose of this study was to determine the effects of pharmaceutical levels of chromium, no special measures were taken to prevent exposure of the mice to small amounts of chromium that may be introduced into the diet through methods of feed preparation or from the cage hardware. The diet purchased, Teklad LM-485 (7012), contained added chromium in the form of chromium potassium sulphate (0.48 mg/kg of diet).

Test animals

Species:
mouse
Strain:
CD-1

Administration / exposure

Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Analytical verification of doses or concentrations:
not specified
Details on mating procedure:
Male and female CD-1 mice, obtained from Charles River Breeding Laboratories, International (Wilmington, MA) were housed in an AAALAC-approved animal facility in rooms maintained at 22721C, with 40–60% humidity and a 12-hr photoperiod. Animals were bred naturally, two females with one male. Observation of a copulation plug was designated GD 0. Mated females were individually housed in shoe-box-type cages with hardwood bedding and were given Harlan-Teklad LM-485 rodent diet and tap water ad libitum.
Duration of treatment / exposure:
Females were exposed from Gestation Day 6-17
Frequency of treatment:
Continuous (dietary)
Duration of test:
Maternal animals were sacrificed on Gestation Day 17.
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
Control
Basis:
other: untreated diet
Remarks:
Doses / Concentrations:
200 mg/kg bw/d chromium picolinate
Basis:
other: based on predicted food consumption
Remarks:
Doses / Concentrations:
15 mg/kg bw/d Cr3
Basis:
other: based on predicted food consumption
Remarks:
Doses / Concentrations:
120 mg/kg bw/d Cr3
Basis:
other: based on predicted food consumption
No. of animals per sex per dose:
Not stated, however the numbers of litters in each group range from 24-29
Control animals:
yes, plain diet

Results and discussion

Results: maternal animals

Effect levels (maternal animals)

open allclose all
Dose descriptor:
NOAEL
Effect level:
26 mg/kg bw/day (nominal)
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEL
Effect level:
26 mg/kg bw/day (nominal)
Basis for effect level:
other: developmental toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Any other information on results incl. tables

No signs of maternal toxicity were observed.

Mean foetal weights, foetal viability and the proportion of resorptions were unaffected by treatment. No gross malformations were observed in any of the foetuses. The number of implantations in the low dose Cr3 group was lower than the other treated groups, however this is not considered to be an effect of treatment in the absence of a dose-response relationship and because implantation occurred prior to exposure. No effects of treatment were observed on the incidence of skeletal anomalies. The authors note that a previous study (Bailey et al, 2006) reported an increased incidence of cervical arch defects in the offspring of mice exposed to chromium picolinate, however the incidence of defects in that study (6.26%) is very similar to the control incidence in this study (5.79% and is therefore not considered to be related to treatment.

Summary of findings

Parameter

Dose group

0

Cr picolinate

Cr3 (low)

Cr3 (high)

Litters

(#)

27

29

26

24

Foetuses

(#)

332

369

275

342

Litter size

(#)

12.30

12.72

10.58

14.25

Foetal weight

(g)

1.02

1.05

1.08

1.02

Implantations

(#)

12.64

13.18

11.00

13.79

Dead/resorbed foetuses

(#)

2.74

3.29

3.48

1.29

Cervical arch defects

(#)

4.65

6.26

5.18

3.98

Cervical arch defects refer to a distal split in the first or second cervical vertebral arch

Applicant's summary and conclusion

Conclusions:
No evidence of foetotoxicity, developmental toxicity or teratogenicity was seen in mice exposed to water-soluble complexes of Cr(III) delivering estimated daily doses of Cr(III) equivalent to 25 mg/kg bw/d (picolinate group), 3.3 mg/kg bw/d (low dose Cr3 group) and 26 mg/kg bw.d (high dose Cr3 group).
Executive summary:

Mated female mice were administered Cr(III) in the diet from Days 6 -17 of gestation. Dams were sacrificed on Day 17 and the uterine contents investigated. Foetuses were assessed for external defects and skeletal findings following double staining. No maternal toxicity was observed. No evidence of teratogenicity, foetotoxicity or developmental toxicity was seen. The results of this study also show that a reported increased incidence of cervical arch defects in a previous study by the same authors was within the background range.

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