2-chloro-N,N-dimethyl-3-oxobutyramide

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

other: Only short information available (tabular data)

Data source

Reference

Reference Type:

publication

Title:

Structure-activity and metabolism studies on organophosphate teratogens and their alleviating agents in developing hen eggs with special emphasis on bidrin

Author:

Roger, J.; Upshall, D.G.; Casida, J.E.

Year:

1969

Bibliographic source:

Biochem. Pharmacol. 18, 373-392

Materials and methods

GLP compliance:

not specified

Limit test:

yes

Test material

Test material information

Constituent 1

Reference substance name:

2-chloro-N,N-dimethyl-3-oxobutyramide

EC Number:

227-372-9

EC Name:

2-chloro-N,N-dimethyl-3-oxobutyramide

Cas Number:

5810-11-7

Molecular formula:

C6H10ClNO2

IUPAC Name:

2-chloro-N,N-dimethyl-3-oxobutanamide

Test animals

Species:

other: fertilized eggs

Strain:

other: White leghorn

Administration / exposure

Route of administration:

other: injection into the yolk sack

Duration of treatment / exposure:

until day 18 - 21

Frequency of treatment:

single treatment on day 4

Duration of test:

until day 18 - 21

Doses / concentrations

Remarks:

Doses / Concentrations:
1 mg/egg
Basis:
nominal conc.

No. of animals per sex per dose:

10 eggs in two replicates

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:

Maternal toxic effects:not examined

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

Bidrin (3-hydroxY-N,N-dimethyl-cis-crotonamide dimethyl phosphate) is teratogenic in hen eggs when injected into the yolk sac at a dosage of 0.03 mg per egg or higher; the cis-crotonamide isomer is the active teratogenic component. The response is dose dependent and the effect is at a maximum with injection on or about day 4 of incubation. Signs include straight legs, micromelia, short spine, wry neck, parrot beak, abnormal feathering, edema and, more rarely. syndactyly and visceral hernia. Many other organophosphates are teratogenic, including the Bidrin metabolites that are not hydrolysis products, but no simple structure-activity relationship is evident. Nicotinic acid, nicotinamide and certain of their precursors, analogs and derivatives are active alleviating agents for Bidrin-induced teratogenesis. The active nicotinic acid analogs are those that may be converted to nicotinic acid or nicotinamide, while the inactive analogs probably are not converted to these products. Treatment with nicotinamide prior to incubation and up to day 10 of incubation greatly alleviates teratogenesis. At equimolar levels, nicotinamide and pyridine nucleotide coenzymes show the same alleviating activity, the only exception to this relationship being the 3-acetylpyridine analog of the coenzyme. It is not known whether the active alleviating agent is a pyridine nucleotide or anyone of several 3-pyridyl compounds. Bidrin is rapidly biodegraded in the egg; successive N-demethylation occurs through the N-hydroxymethyl analogs to yield the unsubstituted amide. Extensive hydrolysis is also involved. Bidrin metabolism between days 4 and 10 of incubation is not affected by nicotinamide; thus, the alleviating agents do not appear to act by altering the metabolism of the teratogenic agents. The metabolism of nicotinic acid is unaffected by the teratogen, Bidrin. Therefore, the alleviating action of nicotinic acid analogs for Bidrin teratogenesis results from mechanisms different from those involving altered rates of metabolism of the teratogen or the alleviating agents.

 

Applicant's summary and conclusion

Conclusions:

No signs of teratogenicity were observed and no effects on survival rate and embryo parameters were found.