Reproductive and Developmental Toxicity
OECD 414 Prenatal Developmental Toxicity Study (assessment of skeleton and soft tissues, both rabbit and rat)
Study Purpose and Introduction:
The developmental toxicity testing is designed to detect adverse effects on pregnant female rats and on the development of the conceptuses, consequent to exposure of the female with the test item. The test substance is administered to pregnant animals at least from implantation to one day prior to the day of scheduled kill, which should be is as close as possible to the normal day of delivery. The mating of the male and female animals occurs. The day of mating is regarded as day 0 of pregnancy (vaginal plug and/or sperm in the vaginal smear). The achieved sperm positive females are allocated to dose groups. One control group is used in which the animals receive only the vehicle. Dosing formulations are analyzed for homogeneity and concentration two times during the treatment period. During the study the animals are checked for mortality and clinical signs. Body weight and food consumption of the dams are recorded repeatedly. Blood collection for the determination of thyroid hormones (FT3 (free T3), FT4 (free T4), and TSH), as well as Caesarean section and gross pathology is performed on gestation day 20. Organs of the dams are examined macroscopically. Thyroid glands all sperm positive females are weighed. Thyroid glands, as well as organs with macroscopic findings are fixed for histological or possible histological examination.
The number of implantations, early and late resorptions, live and dead fetuses in each uterine horn and the number of corpora lutea are recorded. Each fetus is weighed and examined for sex and external abnormalities. The ano-genital distance is measured, the placentas are weighed and examined externally. The body of about half of each litter is subjected to visceral examination by means of a dissecting microscope after fixation an appropriate solution. The heads are examined by Wilson’s free-hand razor blade method. After double staining, the skeletons of the other fetuses (not assigned to visceral examination) are examined by means of a dissecting microscope.
Guidelines and literature:
OECD Guidelines for the Testing of Chemicals, Section 4, No. 414, “Prenatal Developmental Toxicity Study” (link: https://www.oecd-ilibrary.org/environment/test-no-414-prenatal-development-toxicity-study_9789264070820-en)
OECD 414 Prenatal Developmental Toxicity Study (assessment of skeleton and soft tissues, both rabbit and rat)
Study Purpose and Introduction:
The developmental toxicity testing is designed to detect adverse effects on pregnant female rats and on the development of the conceptuses, consequent to exposure of the female with the test item. The test substance is administered to pregnant animals at least from implantation to one day prior to the day of scheduled kill, which should be is as close as possible to the normal day of delivery. The mating of the male and female animals occurs. The day of mating is regarded as day 0 of pregnancy (vaginal plug and/or sperm in the vaginal smear). The achieved sperm positive females are allocated to dose groups. One control group is used in which the animals receive only the vehicle. Dosing formulations are analyzed for homogeneity and concentration two times during the treatment period. During the study the animals are checked for mortality and clinical signs. Body weight and food consumption of the dams are recorded repeatedly. Blood collection for the determination of thyroid hormones (FT3 (free T3), FT4 (free T4), and TSH), as well as Caesarean section and gross pathology is performed on gestation day 20. Organs of the dams are examined macroscopically. Thyroid glands all sperm positive females are weighed. Thyroid glands, as well as organs with macroscopic findings are fixed for histological or possible histological examination.
The number of implantations, early and late resorptions, live and dead fetuses in each uterine horn and the number of corpora lutea are recorded. Each fetus is weighed and examined for sex and external abnormalities. The ano-genital distance is measured, the placentas are weighed and examined externally. The body of about half of each litter is subjected to visceral examination by means of a dissecting microscope after fixation an appropriate solution. The heads are examined by Wilson’s free-hand razor blade method. After double staining, the skeletons of the other fetuses (not assigned to visceral examination) are examined by means of a dissecting microscope.
Guidelines and literature:
OECD Guidelines for the Testing of Chemicals, Section 4, No. 414, “Prenatal Developmental Toxicity Study” (link: https://www.oecd-ilibrary.org/environment/test-no-414-prenatal-development-toxicity-study_9789264070820-en)
OECD 426 Developmental Neurotoxicity Study (Peri-and post-natal studies)
Study Purpose and Introduction:
A developmental neurotoxicity study provides information on the effects of repeated exposure to a substance during in utero and early postnatal development. The test item is administered daily, generally orally, to mated females from the time of implantation throughout lactation. At least three dose levels and a concurrent control are used and a total of 20 litters are planned at each dose level. Dams are tested to assess effects in pregnant and lactating females and may also provide comparative information. Offspring are randomly selected from within litters for neurotoxicity evaluation. All dams and all offspring are carefully observed at least once daily with respect to their health condition, including morbidity and mortality. The evaluation consists of observations to detect gross neurologic and behavioural abnormalities, and the evaluation of brain weights and neuropathology during postnatal development and adulthood.
Guidelines and literature:
OECD Guidelines for the Testing of Chemicals, Section 4, No. 426, “Developmental Neurotoxicity Study” (link: https://www.oecd-ilibrary.org/environment/test-no-426-developmental-neurotoxicity-study_9789264067394-en)
OECD 421 Reproduction/Developmental Toxicity Screening Test
Study Purpose and Introduction:
As a screening test, this study provides initial information on possible effects on male and female reproductive performance such as gonadal function, mating behaviour, conception, pregnancy, parturition as well as on development of the F1 offspring from conception to day 13 post-partum associated with administration of repeated maternal and paternal doses.
Guidelines and literature:
OECD Guidelines for the Testing of Chemicals, Section 4, No. 421, “Reproduction/Developmental Toxicity Screening Test” (link: https://www.oecd-ilibrary.org/environment/test-no-421-reproduction-developmental-toxicity-screening-test_9789264264380-en)
ICH S5 (R3) detection of reproductive and developmental toxicity for human pharmaceuticals
– Fertility and Early Embryonic Development (FEED) Study
– Embryo-Fetal Developmental (EFD) toxicity study
– Pre- and Postnatal Developmental (PPND) toxicity study
Guidelines and literature:
ICH S5 (R3) Guideline on detection of reproductive and developmental toxicity for human pharmaceuticals – Scientific guideline https://www.ema.europa.eu/en/ich-s5-r3-guideline-detection-reproductive-developmental-toxicity-human-pharmaceuticals-scientific-guideline
Fertility and reproduction studies:
OECD 421 Reproduction/Developmental Toxicity Screening Test
Study Purpose and Introduction:
As a screening test, this study provides initial information on possible effects on male and female reproductive performance such as gonadal function, mating behaviour, conception, pregnancy, parturition as well as on development of the F1 offspring from conception to day 13 post-partum associated with administration of repeated maternal and paternal doses.
Guidelines and literature:
OECD Guidelines for the Testing of Chemicals, Section 4, No. 421, “Reproduction/Developmental Toxicity Screening Test” (link: https://www.oecd-ilibrary.org/environment/test-no-421-reproduction-developmental-toxicity-screening-test_9789264264380-en)
OECD 421 Reproduction/Developmental Toxicity Screening Test
Study Purpose and Introduction:
As a screening test, this study provides initial information on possible effects on male and female reproductive performance such as gonadal function, mating behaviour, conception, pregnancy, parturition as well as on development of the F1 offspring from conception to day 13 post-partum associated with administration of repeated maternal and paternal doses.
Guidelines and literature:
OECD Guidelines for the Testing of Chemicals, Section 4, No. 421, “Reproduction/Developmental Toxicity Screening Test” (link: https://www.oecd-ilibrary.org/environment/test-no-421-reproduction-developmental-toxicity-screening-test_9789264264380-en)
OECD 422 Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test
Study Purpose and Introduction:
The study uses the rat, which is the preferred rodent species for toxicity and reproduction toxicity testing. As a screening test, it provides initial information on the possible health hazards likely to arise from repeated exposure over a relatively limited period of time; and on the possible effects on male and female reproductive performance, such as gonadal function, mating behaviour, conception, pregnancy, parturition as well as on development of the F1 offspring from before conception to day 13 post-partum associated with administration of repeated parental doses.
Guidelines and literature:
OECD Guidelines for the Testing of Chemicals, Section 4, No. 422, “Reproduction/Developmental Toxicity Screening Test” (link: https://www.oecd-ilibrary.org/environment/test-no-422-combined-repeated-dose-toxicity-study-with-the-reproduction-developmental-toxicity-screening-test_9789264242715-en)
OECD 443 Extended One-Generation Reproductive Toxicity Study
Study Purpose and Introduction:
The aim of the one-generation reproduction toxicity study is to provide an evaluation of the pre- and postnatal effects of a test item on development as well as a thorough evaluation of systemic toxicity in male and female animals, in pregnant and lactating females and young and adult offspring. The effect of the test item is assessed on the male and female reproductive performance, such as gonadal function, estrous cycle, mating behavior, conception, parturition, gestation, lactation and weaning (P generation) and on the offspring viability, neonatal health and mortality, growth and development of the offspring (F1 generation; Cohort 1A and 1B without producing F2) to adulthood following oral administration.
Guidelines and literature:
OECD Guidelines for the Testing of Chemicals, Section 4, No. 443, “Extended One-Generation Reproductive Toxicity Study” (link: https://www.oecd-ilibrary.org/environment/test-no-443-extended-one-generation-reproductive-toxicity-study_9789264185371-en)
OECD 416 Two-Generation Reproduction Toxicity
Study Purpose and Introduction:
This study for two-generation reproduction testing is designed to provide general information concerning the effects of a test item on the integrity and performance of the male and female reproductive systems, and on the growth and development of the offspring. The test item is administered daily in graduated doses to several groups of males and females. Males and females of the Parent generation are dosed during growth, during their mating, during the resulting pregnancies, and through the weaning of their first generation offspring. The administration of the substance is continued to first generation offspring during their growth into adulthood, mating and production of a second generation. The rat is the preferred species for testing. At least three dose levels and a concurrent control are used. It is recommended that the test substance is administered orally (by diet, drinking water or gavage).
Guidelines and literature:
OECD Guidelines for the Testing of Chemicals, Section 4, No. 416, “Two-Generation Reproduction Toxicity” (link: https://www.oecd-ilibrary.org/environment/test-no-416-two-generation-reproduction-toxicity_9789264070868-en)