D-mannose

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

disregarded due to major methodological deficiencies

Reliability:

3 (not reliable)

Rationale for reliability incl. deficiencies:

significant methodological deficiencies

Data source

Reference

Reference Type:

publication

Title:

Fuel-mediated teratogenesis: Symmetric growth retardation in the rat fetus at term after a circumscribed exposure to D-mannose during organogenesis

Author:

Buchanan TA and Freinkel N

Year:

1988

Bibliographic source:

Am. J. 0bstet. Gynecol., 158:663-669

Materials and methods

Principles of method if other than guideline:

Ten pregnant animals were infused with the test item for 12 hours during early neurulation (day 9.5 to 10 of development). Foetuses were removed at term and examined for evidence of developmental anomalies and growth retardation.

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

D-mannose

EC Number:

222-392-4

EC Name:

D-mannose

Cas Number:

3458-28-4

Molecular formula:

C6H12O6

IUPAC Name:

D-mannose

Details on test material:

Purity: not reported

Test animals

Species:

rat

Strain:

other: Crl: CD [SD] BR

Administration / exposure

Route of administration:

infusion

Vehicle:

water

Analytical verification of doses or concentrations:

yes

Details on mating procedure:

Female rats were mated with normal males of the same strain. Midnight of the night of mating (confirmed by the presence of sperm in the vaginal smear the following morning) was designated day 0 of intrauterine development. Pregnant females were housed singly with free access to food and water except during infusions.

Duration of treatment / exposure:

days 9.5 and 10

Frequency of treatment:

continuous infusion between days 9.5 and 10

Duration of test:

At day 21.5 of development

No. of animals per sex per dose:

10

Control animals:

other: d-glucose

Results and discussion

Results: maternal animals

Effect levels (maternal animals)

Dose descriptor:

other: developmental toxicity

Effect level:

>= 1.5 - <= 2 other: mg/mL

Based on:

test mat.

Basis for effect level:

other: developmental toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:yes

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

These results indicate that a relatively brief metabolic insult to embryos during early organogenesis may cause lethal developmental anomalies as well as growth retardation and delayed skeletal development that are manifested in the foetus at term.

Executive summary:

Ten pregnant animals were infused with d-mannose for 12 hours during early neurulation (day 9.5 to 10 of development). Ten control animals were infused with equimolar d-glucose during this same time interval.

Mannose infusions produced maternal plasma mananose concentrations in the embryotoxic range; glucose infusions caused only slight and transient hyperglycemia. None of 137 foetuses from the mannose group or 138 foetuses from the glucose group exhibited gross anomalies. However, an excess of resorbed conceptions in the mannose group (21 versus six in the glucose group; p < 0.01) suggested some lethal toxicity from mannose exposure during embryogenesis. Among viable foetuses, the mean body weight of those from the mannose group was significantly reduced compared with those from the glucose group (5.62 + 0.04 versus 5.89 + 0.03 gm, respectively; p < 0.001). Reductions of a similar magnitude were noted in the mean wet weight and protein content of foetal brains, hearts, livers, and kidneys from the mannose group (range, 3.4% to 7.1% below the glucose group), indicating a symmetric pattern of foetal growth retardation. In addition, analysis of foetal ossification sites after Alizarin Red S staining revealed a significant delay of skeletal development in the mannose group. These results indicate that a relatively brief metabolic insult to embryos during early organogenesis may cause lethal developmental anomalies as well as growth retardation and delayed skeletal development that are manifested in the foetus at term.