Oncology 
Pharmaceuticals:  
Reproductive Toxicity 
Testing and Labeling 
Recommendations 
Guidance for Industry 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
May 2019 
Pharmacology/Toxicology 
   
Oncology 
Pharmaceuticals:  
Reproductive Toxicity 
Testing and Labeling 
Recommendations 
Guidance for Industry 
 
 
Additional copies are available from: 
 
Office of Communications, Division of Drug Information 
Center for Drug Evaluation and Research 
Food and Drug Administration 
10001 New Hampshire Ave., Hillandale Bldg., 4th Floor  
Silver Spring, MD  20993-0002  
Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353; Email: druginfo@fda.hhs.gov 
https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
May 2019 
Pharmacology/Toxicology 
 
  Contains Nonbinding Recommendations 
TABLE OF CONTENTS 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  ASSESSMENT OF EMBRYO-FETAL DEVELOPMENTAL TOXICITY ............... 3 
A.  General Recommendations ........................................................................................................... 3 
B.  Genotoxic Pharmaceuticals ........................................................................................................... 4 
C.  Biotechnology-Derived Pharmaceuticals ..................................................................................... 4 
D.  Conjugated Pharmaceuticals ........................................................................................................ 4 
E.  Combination Products ................................................................................................................... 4 
F.  Liposomal Products ....................................................................................................................... 5 
III.  ASSESSMENT OF FERTILITY..................................................................................... 5 
IV.  ASSESSMENT OF PRE- AND POSTNATAL DEVELOPMENTAL EFFECTS ..... 6 
V.  ASSESSMENT OF RISK FOR SPECIFIC POPULATIONS ...................................... 6 
A.  Pharmaceuticals for Use in Males Only ....................................................................................... 6 
B.  Pharmaceuticals for Use in Postmenopausal Women Only ....................................................... 6 
C.  Pharmaceuticals for Use in Pediatric Populations ...................................................................... 6 
VI.  RECOMMENDATIONS ON CONTRACEPTION ...................................................... 7 
A.  Genotoxic Pharmaceuticals ........................................................................................................... 7 
1. Males ................................................................................................................................................ 7 
2. Females ............................................................................................................................................ 8 
B.  Nongenotoxic Pharmaceuticals ..................................................................................................... 8 
1. Males ................................................................................................................................................ 8 
2. Females ............................................................................................................................................ 9 
REFERENCES ............................................................................................................................ 10 
 
  Contains Nonbinding Recommendations 
Oncology Pharmaceuticals: 
Reproductive Toxicity Testing and Labeling Recommendations 
Guidance for Industry1 
 
 
 
This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on 
this topic.  It does not establish any rights for any person and is not binding on FDA or the public.  You 
can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations.  
To discuss an alternative approach, contact the FDA office responsible for this guidance as listed on the 
title page. 
 
 
 
I.  INTRODUCTION 
 
The purpose of this guidance is to assist sponsors in evaluating reproductive toxicity (mainly for 
effects on embryo-fetal development (EFD)) for oncology pharmaceuticals and to provide 
recommendations for product labeling on duration of contraception following cessation of 
therapy to minimize potential risk to a developing embryo or fetus.  This guidance is intended to 
facilitate the development of oncology pharmaceuticals while avoiding unnecessary use of 
animals, in accordance with the 3R (reduce, refine, replace) principles.  The following concepts 
are discussed in this guidance:   
 
  Evaluation of EFD toxicity for various types of pharmaceuticals 
 
  Evaluation of EFD toxicity for pharmaceuticals intended for specific populations 
` 
  Use of available information, such as the results of genotoxicity and general toxicity 
studies, knowledge of target biology, and available data on genetically modified animals 
in assessing the need for a dedicated EFD study 
 
  Labeling recommendations for duration of contraception in male and female patients to 
minimize risk to a developing embryo or fetus (Females and Males of Reproductive 
Potential subsection of labeling)2 
                                                 
1 This guidance has been prepared by the Division of Hematology Oncology Toxicology in the Center for Drug 
Evaluation and Research at the Food and Drug Administration. 
 
2 See 21 CFR 201.57(c)(9)(i) and (iii) and the draft guidance for industry Pregnancy, Lactation, and Reproductive 
Potential:  Labeling for Human Prescription Drug and Biological Products  Content and Format (December 
2014).  When final, this guidance will represent the FDAs current thinking on this topic.  For the most recent 
version of a guidance, check the FDA guidance web page at 
https://www.fda.gov/RegulatoryInformation/Guidances/default.htm. 
 
 
1  Contains Nonbinding Recommendations 
This guidance provides information for development of pharmaceuticals that are intended to treat 
patients with cancer.  The patient population is the same as that described in the scope of the 
International Council for Harmonisation (ICH) guidance for industry S9 Nonclinical Evaluation 
for Anticancer Pharmaceuticals (ICH S9) (March 2010) 3 and further clarified in ICH S9 
Nonclinical Evaluation for Anticancer PharmaceuticalsQuestions and Answers (ICH S9 
Questions and Answers) (June 2018). 4  Although an assessment of EFD toxicity is needed to 
support marketing applications for the treatment of patients with advanced malignancies, fertility 
and pre- and postnatal development (PPND) studies are generally not warranted.5  For 
pharmaceuticals used in certain adjuvant (e.g., breast cancer) or neoadjuvant indications, 
however, an assessment of fertility and PPND may be needed on a case-by-case basis and results 
could be submitted after approval.6  Therefore, this guidance also discusses fertility and PPND 
studies.  For additional information on the timing of study result submission to the Agency, 
consult ICH S9 and ICH S9 Questions and Answers. 
 
This guidance does not address risks of reproductive toxicity from radiopharmaceuticals, cellular 
and gene therapy products, cancer vaccines, biosimilar or interchangeable products, or generic 
drugs.  This guidance does not address margins of safety by systemic exposure or dose.  For 
many oncology pharmaceuticalsespecially small moleculesa safety margin is not identified 
(i.e., embryo-fetal toxicities are observed in animals at exposures or doses that are comparable to 
or below those in patients (National Toxicology Program 2013)).  This guidance does not 
address the potential risks to a developing embryo or fetus during clinical trials because 
pregnancy testing and use of highly effective methods of birth control are usually adequate to 
minimize the risk of unintentional exposure of the embryo or fetus when including women of 
reproductive potential in clinical trials.   
 
This guidance complements ICH S9 and ICH S9 Questions and Answers.  Specific study designs 
for evaluating reproductive toxicity are addressed in the ICH guidances for industry S5(R3) 
Detection of Toxicity to Reproduction for Human Pharmaceuticals (November 2017) and S6(R1) 
Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals (S6(R1)) (May 2012).  
In general, when the weight of evidence (WOE) indicates clear adverse reproductive effects, 
additional reproductive toxicology studies may not be warranted.  This guidance provides 
examples of WOE approaches (see section II. A., General Recommendations) not described in 
ICH S9.  Because of the potential risk of developmental toxicity from oncology pharmaceuticals, 
a consistent approach is needed in the duration of contraception to minimize exposure of a 
developing embryo or fetus to these pharmaceuticals.   
 
                                                 
3 See ICH S9, available at 
https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM085389.pdf.  
 
4 See ICH S9 Questions and Answers, available at 
https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM520942.pdf.  
  
5 See ICH S9. 
 
6 See ICH S9 Questions and Answers, questions 5 through 7. 
 
2  Contains Nonbinding Recommendations 
For this guidance, the term pharmaceuticals refers to small molecules, biotechnology-derived 
products, and related compounds, such as conjugated products.  The term teratogenicity in this 
guidance refers to events leading to a disruption of normal EFD that may lead to malformations.  
For certain classes of pharmaceuticals (e.g., immune oncology), embryo-fetal lethality may arise 
by mechanisms other than direct action on the fetus, such as immune rejection with no overt 
teratogenicity.  For this guidance, the phrase embryo-fetal lethality indicates mortality of the 
embryo or fetus, irrespective of its cause.   
 
In general, FDAs guidance documents do not establish legally enforceable responsibilities.  
Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
as recommendations, unless specific regulatory or statutory requirements are cited.  The use of 
the word should in Agency guidances means that something is suggested or recommended, but 
not required.   
 
 
II.  ASSESSMENT OF EMBRYO-FETAL DEVELOPMENTAL TOXICITY 
 
A.  General Recommendations 
 
In general, EFD toxicity testing should follow the recommendations outlined in ICH S9 and ICH 
S9 Questions and Answers.  A WOE approach showing potential for reproductive toxicity may 
eliminate the need to conduct a dedicated EFD study and could be applied to pharmaceuticals 
discussed in section II.B-F.  For small molecules, EFD studies, when needed, are typically 
conducted in two species; and when the study is positive for teratogenicity or embryo-fetal 
lethality in one species, generally a study in the second species is not warranted.  For 
biotechnology-derived pharmaceuticals, when an EFD study is needed, generally a study in one 
pharmacologically relevant species should be sufficient.  In general, a definitive study is not 
warranted if a dose-range finding study (including non-good laboratory practice) shows clear 
evidence of embryo-fetal lethality or teratogenicity.   
 
A WOE approach may include the following information:   
 
  Reproductive findings in humans, such as when a drug is in a class of pharmaceuticals 
with extensive publicly available information on potential reproductive effects 
 
  Reproductive findings from genetically-modified animals or models employing 
pharmacologic inhibition, as appropriate 
 
  Information from a surrogate molecule, when a surrogate is available and the target 
biology in the animal species is relevant to humans 
 
  Literature-based assessment of target biology in humans or animal species, which can 
describe the following: 
 
  Expression and the role of the molecular target during embryo-fetal development 
 
3  Contains Nonbinding Recommendations 
  Any other relevant information, such as the role of the target in placental 
development, placental transfer, maternal tolerance, etc. 
 
  Use of alternative assays, such as fit-for-purpose in vitro or ex vivo, or nonmammalian in 
vivo assays 
 
The Agency supports the principles of the 3Rs to reduce, refine, and replace animal use in testing 
when feasible.  Sponsors can consult with the Agency if they wish to use other testing methods 
or strategies not described above.  The Agency will consider whether such an alternative method 
or strategy could be used instead of an animal study.   
 
B.  Genotoxic Pharmaceuticals 
 
Pharmaceuticals that target rapidly dividing cells (e.g., crypt cells, bone marrow) in general 
toxicology studies and are genotoxic (e.g., positive in the bacterial mutation (Ames) assay or 
negative in Ames, but positive in two mammalian genotoxicity assays) are presumed to be 
teratogenic and/or lethal to an embryo or fetus.  In this case, FDA does not consider EFD studies 
to be essential.   
 
C.  Biotechnology-Derived Pharmaceuticals 
 
For biotechnology-derived pharmaceuticals, when the WOE is insufficient for EFD hazard 
identification, in general, an EFD study in one pharmacologically relevant species should be 
sufficient.  When no pharmacologically relevant species is available to test the pharmaceutical 
and a relevant surrogate pharmaceutical is not available, in general, an EFD study is not 
warranted.     
 
D.  Conjugated Pharmaceuticals 
 
For conjugated pharmaceuticals containing both a biological and a small-molecule moiety, the 
design of the EFD study depends on several factors, such as binding of the biological moiety to 
the target, the potential for release of the small molecule, the nature of the small molecule (e.g., 
mechanism of action), and knowledge about the source of the toxicities (biological versus the 
small-molecule moiety).  For example, for antibody-drug conjugates (ADCs), when the small 
molecule is a cytotoxic pharmaceutical (genotoxic and targeting rapidly dividing cells), no EFD 
study is warranted (see section II. B., Genotoxic Pharmaceuticals).  If an EFD study with an 
ADC is considered necessary (e.g., insufficient WOE), the sponsor could conduct the study with 
the small molecule alone (or the small-molecule linker) when toxicities of the conjugated 
pharmaceutical are related to the small molecule and the antibody does not bind to the target in 
the animal species.   
 
E.  Combination Products 
 
A combination product should be used in EFD studies when the pharmaceuticals in the 
combination will not be used as monotherapy and the toxicity profile is expected to be different 
in the combination product compared with each pharmaceutical alone (e.g., when the 
4  Contains Nonbinding Recommendations 
combination product may generate a new metabolite or result in a substantially increased level of 
a previously identified metabolite).  In this case, the EFD study of each pharmaceutical alone 
may provide an incomplete EFD assessment.  If the EFD data or WOE assessment is available 
with one (or more) of the pharmaceuticals in the combination product, indicating teratogenicity 
and/or embryo-fetal lethality, in general, an additional EFD of the combination product is not 
warranted.  When pharmaceuticals in a combination will be also used as monotherapy, then an 
EFD assessment or study of each pharmaceutical alone should be conducted.  
 
F.  Liposomal Products 
 
In general, liposomal formulations are produced to change the pharmacokinetic parameters of the 
active pharmaceutical ingredient (API) (e.g., to increase the exposure or change the distribution 
of the API).  No EFD study is warranted when the liposomal product contains a genotoxic 
pharmaceutical targeting rapidly dividing cells (see section II. B., Genotoxic Pharmaceuticals) or 
when the WOE indicates teratogenicity or embryo-fetal lethality.  In addition, if an EFD study 
was previously evaluated with the unencapsulated pharmaceutical and showed teratogenicity 
and/or embryo-fetal lethality, in general, separate EFD studies with the liposomal product are not 
warranted.  However, the sponsor should conduct EFD studies with the liposomal 
pharmaceutical if WOE is insufficient and the API has not previously been shown to cause 
teratogenicity or embryo-fetal lethality, because changes in pharmacokinetic parameters and 
novel components used in a liposome could affect EFD.   
 
 
III.  ASSESSMENT OF FERTILITY 
 
A study of fertility and early embryonic development is not warranted for pharmaceuticals 
intended for the treatment of patients with advanced cancer.  The sponsor should use information 
available from general toxicology studies on the pharmaceuticals effect on reproductive organs 
as the basis of the assessment on impairment of fertility.7  A general toxicology study in sexually 
mature NHPs is not warranted to assess fertility.   
 
When the indication is not for an advanced cancer, stand-alone fertility studies may be warranted 
on a case-by-case basis.8  When the NHP is the only relevant species, the sponsor can assess 
fertility effects in repeat-dose toxicology studies, and a separate fertility study is not warranted.  
A stand-alone fertility study is not warranted if, based on the totality of data (e.g., knowledge of 
the target biology and/or results of general toxicology studies), potential fertility risk is identified 
or if, based on the patient population, a fertility study is not warranted.  For example, if a 
pharmaceutical intended to treat early-stage prostate cancer depletes male hormones, a male 
fertility study is not warranted (because the pharmaceutical is assumed to reduce fertility) and a 
female fertility study also is not warranted (because the pharmaceutical is male specific).   
                                                 
7 See ICH S9. 
 
8 See ICH S9 Questions and Answers, questions 5 through 7. 
 
5  Contains Nonbinding Recommendations 
IV.  ASSESSMENT OF PRE- AND POSTNATAL DEVELOPMENTAL EFFECTS 
 
In general, a PPND study is not warranted for pharmaceuticals intended to treat patients with 
advanced cancer.  A PPND study may be warranted on a case-by-case basis when the cancer is 
not advanced.9  The following examples describe when a PPND study is not needed when 
treating patients with nonadvanced cancer, because the study outcome is expected or the study 
will not provide useful information:   
 
  A PPND usually is not warranted for a teratogenic pharmaceutical.  The pharmaceutical 
is expected to adversely affect the growth and development of the offspring.   
 
  When a pharmaceutical causes embryo-fetal death, the sponsor should consider whether a 
sufficient number of offspring may be available to assess developmental effects.  For a 
pharmaceutical causing high embryo-fetal mortality, in general, a PPND study is not 
warranted.   
 
 
V.  ASSESSMENT OF RISK FOR SPECIFIC POPULATIONS 
 
A.  Pharmaceuticals for Use in Males Only 
 
EFD studies are not warranted for pharmaceuticals indicated for use in males only (e.g., for 
prostate cancer).  Any concern regarding risk to a developing embryo or fetus resulting from 
seminal transfer could be addressed through duration of contraception (see section VI., 
Recommendations on Contraception).  The information on contraception should be 
communicated in the Females and Males of Reproductive Potential subsection of labeling.  A 
PPND study is not warranted for pharmaceuticals intended to treat this patient population.  The 
sponsor should consider a male fertility study in animals when the pharmaceuticals indication is 
not for an advanced cancer (e.g., early-stage prostate cancer) and adequate assessment of fertility 
is not available based on results of general toxicology studies or target biology (see section III, 
Assessment of Fertility).   
 
B.  Pharmaceuticals for Use in Postmenopausal Women Only 
 
Reproductive toxicity studies are not warranted for oncology pharmaceuticals indicated in 
postmenopausal women only.  In general, menopause is defined as the permanent cessation of 
menses of greater than 12 months with no alternative medical cause or may be defined based on 
additional factors, such as serum follicle-stimulating hormone levels and surgical bilateral 
oophorectomy.  The sponsor should discuss with the appropriate FDA clinical review division 
the criteria used to define menopausal status.   
 
C.  Pharmaceuticals for Use in Pediatric Populations 
 
For pharmaceuticals used for advanced cancer, the sponsor should provide an EFD study or 
assessment (as appropriate) when the indication includes patients who have reached puberty; this 
                                                 
9 See ICH S9 Questions and Answers, questions 5 through 7. 
6  Contains Nonbinding Recommendations 
generally includes females and males of reproductive potential, including adolescents (12 to 17 
years of age).  For additional information on EFD studies, see section II, Assessment of Embryo-
Fetal Developmental Toxicity.  If the treatment is curative or substantially increases survival, the 
sponsor should consider the entire battery of reproductive toxicology studies (i.e., fertility, EFD, 
and PPND),10 unless the treatment falls under the categories described in sections II. through V. 
A. of this guidance, in which case the studies may not be warranted.   
 
 
VI.  RECOMMENDATIONS ON CONTRACEPTION 
 
After determining that a risk of pharmaceutical-mediated developmental toxicity exists, the 
applicants proposed labeling should include recommendations on the duration of contraception 
after completion of therapy.  When a recommendation is necessary (see Tables 1 and 2), the 
Females and Males of Reproductive Potential subsection of labeling should include the duration 
of contraception, to minimize EFD risk in female patients receiving the oncology pharmaceutical 
and to female sexual partners of male patients receiving the oncology pharmaceutical.   
 
The scientific underpinning for the following labeling recommendations is based on several 
factors, including the knowledge of gametogenesis and sex-specific differences in this process.  
The rationale is provided in sections VI. A., Genotoxic Pharmaceuticals, and VI. B., 
Nongenotoxic Pharmaceuticals.  The labeling recommendations are based on prevention of 
developmental toxicity, such as malformations and embryo-fetal lethality, not restoration of 
fertility.  Although the following labeling recommendations are for reducing EFD risk associated 
with the parent pharmaceutical, the same approach could be used for metabolites of concern as 
appropriate (e.g., for a genotoxic metabolite).   
 
For conjugated pharmaceuticals containing both a biological and a small-molecule component, 
the applicant should consider both moieties for a labeling recommendation.  For instance, for an 
ADC with a genotoxic payload, teratogenicity or embryo-fetal lethality is expected, and the 
applicant should use the labeling recommendations in Table 1.  If a pharmaceutical consists of 
two biological moieties conjugated to each other and the pharmaceutical is not expected to cause 
malformations or embryo-fetal lethality, the applicant should use the labeling recommendations 
in Table 2.  The applicant should scientifically justify any proposed labeling recommendation.   
 
A.  Genotoxic Pharmaceuticals 
 
1.  Males 
 
Genotoxic pharmaceuticals may cause DNA damage in the sperm, potentially resulting in 
adverse effects in the embryo or fetus of a female sexual partner.  Although there are no reports 
of increased malformation in offspring of men treated with oncology pharmaceuticals (Trasler 
and Doersken 1999; Mulvihill 2012), no report has adequately examined effects on children born 
within the first year after cessation of therapy.  In addition, adverse embryo-fetal effects have 
been observed in animals when males treated with genotoxic pharmaceuticals were mated with 
untreated females.  Use of contraception for a period of 3 months after cessation of therapy (see 
                                                 
10 See ICH S9 Questions and Answers, questions 6 and 7. 
7  Contains Nonbinding Recommendations 
Table 1) will minimize the risk of adverse embryo-fetal effects from genotoxic pharmaceuticals.  
The 3 months cover the period of spermatogenesis and the epididymal maturation.   
 
2.  Females 
 
Genotoxic pharmaceuticals may directly affect the embryo or fetus or may cause DNA damage 
in the oocytes.  The duration of folliculogenesis is described as 6 to 12 months (Meirow et al. 
2001; Meirow and Schiff 2005).  Exposure to a genotoxic pharmaceutical in the initial step of 
folliculogenesis results mainly in follicular loss (Kalich-Philosoph et al. 2013).  Although a 
damaged follicle may be further eliminated through the natural process of atresia, adverse 
embryo-fetal effects, including malformations, have been observed in offspring of mice treated 
with the genotoxic pharmaceutical cyclophosphamide at various stages of follicular growth 
(Meirow et al. 2001; Meirow and Schiff 2005).  The 6-month contraception labeling 
recommendation for genotoxic pharmaceuticals after cessation of therapy (see Table 1) covers 
the growth and maturation phase of folliculogenesis and is expected to allow elimination of most 
damaged follicles and oocytes.  Deviations from this labeling recommendation are acceptable 
when justified.  For instance, for a pharmaceutical that is only aneugenic, a contraception period 
of 1 month (with an additional 5 half-lives) is generally acceptable because only dividing oocytes 
are affected by aneugenicity.   
 
 
Table 1.  Genotoxic Pharmaceuticals: Recommendation on the Duration of Contraception 
After Cessation of Therapy 
 
Sex  Recommended Duration of Contraception 
Male  5 x T * + 3 months 
1/2
Female  5 x T * + 6 months 
1/2
* T  = half-life. 
1/2
 
B.  Nongenotoxic Pharmaceuticals 
 
1.  Males 
 
A hypothetical risk of teratogenicity or embryo-fetal lethality exists because of the transfer of a 
pharmaceutical (or its metabolites) through the seminal fluid to a woman.  Although reports 
indicate that there is no increased malformation rate in the offspring of males exposed to 
oncology pharmaceuticals (Trasler and Doersken 1999; Mulvihill 2012), no report has 
adequately examined effects on children born within the first year after cessation of therapy.   
 
Scientific articles indicate that pharmaceuticals administered intravaginally, including 
thalidomide, at clinically relevant concentrations did not cause malformation in the fetus (Hui et 
al. 2014; Breslin et al. 2014; Moffat et al. 2014).  However, an earlier study showed adverse 
embryo-fetal effects when male rabbits were administered thalidomide (Lutwak-Mann 1964).  
8  Contains Nonbinding Recommendations 
Although thalidomide does not accumulate in the semen, many small-molecule pharmaceuticals 
do (Klemmt and Scialli 2005).  Given the data gaps for small-molecule teratogenic 
pharmaceuticals, FDA recommends a contraception period of 5 half-lives.  For teratogenic 
biological products, however, no duration of contraception is necessary because these products 
have not been seen to accumulate in the semen, have limited absorption, and may undergo 
proteolytic degradation caused by the presence of vaginal and cervical enzymes (Scialli et al. 
2015).  See Table 2 for recommendations on the contraception period.   
 
2.  Females 
 
For nongenotoxic pharmaceuticals causing teratogenicity or embryo-fetal lethality, FDA 
recommends a contraception period of 5 half-lives after completion of therapy.  For 
pharmaceuticals that do not cause teratogenicity or embryo-fetal lethality, no duration of 
contraception is necessary (see Table 2).   
 
 
Table 2.  Nongenotoxic Pharmaceuticals: Recommendation on the Duration of 
Contraception After Cessation of Therapy* 
 
Teratogenicity or Embryo-Fetal  No Teratogenicity and  
Sex 
Lethality  No Embryo-Fetal Lethality 
Small molecules:  
5 x T ** 
1/2
Male    Not necessary 
Biologics:  
Not necessary 
Female  5 x T **  Not necessary 
1/2  
* This table can also be used for pharmaceuticals that are only aneugenic in the battery of genotoxicity studies and 
when aneugenicity occurs only at high multiples of clinical exposures. 
** T  = half-life.  For pharmaceuticals with short half-lives (5 x T of less than 1 week), FDA recommends a 
1/2 1/2 
minimum contraception period of 1 week. 
9  Contains Nonbinding Recommendations 
REFERENCES 
 
Breslin, WJ, KG Hilbish, TJ Page, and DE Coutant, 2014, Assessment of Fetal Exposure Risk 
Following Seminal Excretion of a Therapeutic IgG4 (T-IgG4) Monoclonal Antibody 
Using a Rabbit Model, Reprod Toxicol, 48:124131. 
 
Hui, JY, M Hoffmann, and G Kumar, 2014, Embryo-Fetal Exposure and Developmetal Outcome 
of Thalidomide Following Oral and Intravaginal Administration to Pregnant Rabbits, 
Reprod Toxicol, 48:115123. 
 
Kalich-Philosoph, L, H Roness, A Carmely, M Fishel-Bartal, and H Ligumsky, 2013, 
Cyclophosphamide Triggers Follicle Activation  
and Burnout; AS101 Prevents Follicle Loss and Preserves Fertility, Sci Transl Med, 
5:111. 
 
Klemmt, L and AR Scialli, 2005, The Transport of Chemicals in Semen, Birth Defects Res Dev 
Reprod Toxicol, 74:119131. 
 
Lutwak-Mann, C, 1964, Observations on Progeny of Thalidomide-Treated Male Rabbits, Br 
Med J, 1:10901091. 
 
Meirow, D, M Epstein, H Lewis, D Nugent, and RG Gosden, 2001, Administration of 
Cyclophosphamide at Different Stages of Follicular Maturation in Mice:  Effects on 
Reproductive Performance and Fetal Malformations, Hum Reprod, 16:632637. 
 
Meirow, D and E Schiff, 2005, Appraisal of Chemotherapy Effects on Reproductive Outcome 
According to Animal Studies and Clinical Data, J Natl Cancer Inst Monogr, 34:2125. 
 
Moffat, GJ, R Davies, G Kwon, MW Retter, GJ Chellman, S Kanapuram, M Moore, M Loomis, 
W Wang, and ITG Pyrah, 2014, Investigation of Maternal and Fetal Exposure to an IgG2 
Monoclonal Antibody Following Biweekly Intravaginal Administration to Cynomolgus 
Monkeys Throughout Pregnancy, Reprod Toxicol, 48:132137. 
 
Mulvihill, JJ, 2012, Preconception Exposure to Mutagens:  Medical and Other Exposures to 
Radiation and Chemicals, J Community Genet, 3:205211. 
 
National Toxicology Program, 2013, NTP Monograph:  Developmental Effects and Pregnancy 
Outcomes Associated With Cancer Chemotherapy Use During Pregnancy, NTP Monogr, 
2:1214. 
 
Scialli, AR, G Bailey, BK Beyer, IB Bgh, WJ Breslin, CL Chen, AM DeLise, JY Hui, GJ 
Moffat, J Stewart, and KE Thompson, 2015, Potential Seminal Transport of 
Pharmaceuticals to the Conceptus, Reprod Toxicol, 58:213221. 
 
Trasler, JM and T Doersken, 1999, Teratogen Update:  Paternal Exposures  Reproductive 
Risks, Teratology, 60:161172. 
10