This document provides an overview of teratogenicity and developmental toxicity. It discusses the mechanisms by which teratogens act, including folate antagonism and neural crest cell disruption. It outlines principles such as critical periods of susceptibility and covers historical teratogens like thalidomide and accutane. The document also reviews FDA drug categories during pregnancy and OECD testing guidelines for developmental toxicity studies in animals.

1. By – Ananya Upadhyay

2. Introduction
Mechanism of teratogenicity
Principles
Critical Period
Historical Teratogens
FDA category of drugs used in pregnancy
OECD Guidelines
References
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3. Teratogenicity is the ability to cause developmental
abnormalities in foetus.
Developmental toxicity is any morphological or functional
alteration caused by chemical or physical insult that
interfere with normal growth, homeostasis, development,
differentiation and or behaviour.
A teratogen is an agent that can produce a permanent
alteration of structure or function in an organism exposed
during embryonic or fetal life.
Teratology is the study of abnormalities of physiological
development.
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Folate antagonism
Neural crest cell disruption
Endocrine disruption
Oxidative stress
Vascular disruption
5-HT receptors and transporters
Enzyme mediated teratogenesis

5. I. Teratogenic susceptibility is determined by the genotype
of the conceptus.
II. Susceptibility to teratogenic agents depends on the
developmental stage of the embryo or foetus at the time
of exposure.
III. These agents work by specific mechanisms on
developing cells and tissues to initiate pathogenesis.
IV. Perturbations of developmental processes can result in
death, malformation, growth retardation.
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6. Drug can affect the fetus at 3 stages:
I. Pre-implantation: embryonic lethality
II. Implantation to organogenesis: morphological defects
III. Fetal to neonatal stage: functional disorders, growth
retardation, carcinogenesis
NOTE: The sensitivity of embryo to the induction of
morphological defects is increased during the period of
organogenesis.
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7. THALIDOMIDE
It is a sedative-hypnotic drug used in Europe from 1957 to
1961.
It was marketed for morning sickness, nausea and
insomnia.
Malformation: phocomelia, absence of auricle with
deafness, defects of the muscles of the eye and face
malformation of heart, bowel uterus and gallbladder.
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8. ACCUTANE(Isotertinoin)
It is used to treat acne.
Birth defects: facial malformation, heart defects, mental
retardation.
DIETHYLSTILBESTEROL(DES)
From 1940 to 1970, DES was used to help maintain
pregnancy.
Women who were exposed in utero often developed
vaginal neoplasia, vaginal adenosis, and cervical erosion.
Effects were not seen in offspring until they reach
puberty.
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9. ALCOHOL
Heavy drinking during the early pregnancy greatly
increases the risk of cluster of birth defects known as fetal
alcohol syndrome.
Fetal alcohol syndrome:
• This syndrome includes a small skull [microcephaly],
abnormal facial features, and heart defects, often
accompanied by impeded growth and mental retardation.
• Signs and symptoms: poor body weight, poor memory,
learning disabilities, speech and language delay, difficulty
with attention.
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10. Category A
Adequate studies in human demonstrate no risks.
Safest category
Category B
Animal studies indicate no risk, but there are no adequate
studies in human.
Animal studies show adverse effects, but adequate studies
in human have not demonstrated a risk.
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11. Category C
Animal studies indicated adverse effects and there are no
data from human studies.
These drugs may be used when potential benefits
outweigh the potential risk.
Category D
There is evidence of human fetal risk, but the potential
benefits to the mother may be acceptable.
Category X
Studies in animals or humans show adverse reaction
reports or both have demonstrated fetal abnormalities.
Absolutely contraindicated for use during pregnancy.
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12. PARENTAL DEVELOPMENTAL TOXICITY STUDIES
Principle
• The test substance is administered to pregnant animals
atleast from implantation to one day prior to the day of
scheduled kill.
• Shortly before caesarean section, the females are killed, the
uterine contents are examined and the foetuses are evaluated
for soft tissue and skeletal changes.
Preparation for the test
Selection of animal species
• The preferred rodent species is rat.
• The preferred non-rodent species is rabbit. 12

13. Housing and feeding conditions
• Mating procedure should be carried out in cages suitable
for this purpose.
• Individual housing of mated rat is preferred.
• Group housing in small numbers is also accepted.
Preparation of animals
• Healthy animals which have been acclimated to laboratory
conditions for at least 5 days and have not been subjected
to previous experimental procedures, should be used.
• Young adult nulliparous female animals should be used at
each dose level.
• The females should be mated with males of same species
and strains.
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14. • Mating of siblings should be avoided.
• For rodents day 0 of gestation is the day on which a
vaginal plug and/or sperm are observed.
• Mated females should be assigned in an unbiased manner
to the control and treatment group.
Procedure
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•Number and Sex of animal
•Each test and control group should contain a
sufficient no. of females to result in approx. 20
female animals with implantation sites at necropsy
•Preparation of dose
•The vehicle should neither be developmentally toxic nor have
effects on reproduction.
•If a vehicle or other addictive is used to facilitate dosing,
consideration should be given to the following characteristics:
effects on absorption, distribution, metabolism, excretion of the
test substance.

15. Dosage
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•Normally, the test substance should
be administered daily from
implantation to the day prior to
scheduled caesarean session.
•At least 3 dose levels and a concurrent
control should be given.
•Intermediate dose level should be
produce minimal observable of either
maternal or developmental toxicity.
•Dose levels should be selected taking into
account any existing toxicity data as well as
additional information on metabolism and
toxicokinetic of the test substance.
•A concurrent control group should be
used.
Animal in the control group should be
handled in an identical manner to test
group animals.
Sham treated control or vehicle
control group is used.

16. Administration of dose
Observation of the dams
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•The test substance or vehicle is usually
administered orally by intubation.
•The test substance should be administered
at approx. the same time each day.
•The dose to each animal should normally
be based on the most recent individual
body weight determination.
•If excess toxicity is noted in the treated
dams, those animals should be humanly
killed.
•Clinical observations should be made
and recorded at least once a day,
preferably at the same time each day.
•Mortality, moribundity, pertinent
behavioural changes, and all signs of
over toxicity are recorded.

17. Post-mortem examination
Examination of uterine contents
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•Females should be killed one day prior to the
expected day of delivery.
•At the time of termination or death during
the study, the dam should be examined
macroscopically for any structural
abnormalities or pathological changes.
•Uteri that appear non-gravid should be further
examined to confirm non-pregnant status.
•Gravid uteri including the cervix should be weighed.
•The uterine contents should be examined for no. of
embryonic or fetal deaths and viable foetus.

18. Results
Maternal toxic response data by dose:
• The no. of animal at the start of the test, the no. of animal
surviving, the no. pregnant, the no. aborting, the no. of
animals delivering early.
• Data from animals that do not survive to the scheduled
kill should be reported.
• Body weight, body weight changes and gravid uterine
weight.
• Food and water consumption
• Necropsy findings, including uterine weight
• NOAEL values for maternal and developmental effects
should be reported.
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19. Developmental endpoints by dose for litters with implants,
including:
• No. of corpora lutea
• No. of implantations, no. and percent of live and dead
foetuses and resorption
• No. and percent of pre and post implantation losses.
Developmental endpoints by dose for litters with implants,
including:
• No. and percent of live offspring.
• Foetal body weight, sex ratio
• External, soft tissue, and skeletal malformation and other
relevant alterations.
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20. Interpretation of results
• A prenatal developmental toxicity study will provide
information on the effects of repeated oral exposure to a
substance during pregnancy.
• The results of the study will allow for the discrimination
between developmental effects occurring in the absence of
general toxicity and those which are only expressed at
levels that are toxic to the maternal animals.
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23. OECD Guidelines: 414
Medical database in studies of drug teratogenicity: Article
COVID-19 vaccination
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