Background: Various extracts of Syzygium guineense Wall. leaves showed scientificallyrncorroborated effects against hypertension, diabetic mellitus, breast and colon cancers, pain,rninflammation, free radicals, snake venom, parasites, different bacterial strains, and fungi. It isrnwidely stated that herbal products are presumed to be safe. However, validating the efficacy andrnassessing the safety of herbal products is mandatory. During pregnancy, an embryo or fetus can bernaffected by exposure to a variety of chemicals. The potential teratogenicity and reproductiverntoxicity of S. guineense leaf extract has not been determined yet. Therefore, the aim of this thesisrnresearch was to investigate the teratogenicity, reproductive toxicity, developmental neurotoxicity,rnand developmental immunotoxicity as well as glandular and hepato-renal toxicity of the ethanolrnextract of S. guineense leaves in rats. rnMethods: For the teratogenicity study, five groups of Wistar albino rats, each consisting of tenrnpregnant rats were used as experimental and control animals. Groups I-III rats were treated withrn250, 500, and 1000 mg/kg body weight of 70% ethanol extract of S. guineense leaves, respectively.rnGroups four and five were control and ad libitum control, respectively. Rats were treated beginningrnfrom day 6 to day 12 of gestation. Embryos and fetuses were respectively retrieved on day 12 andrnday 20 of gestation. The embryos were assessed for developmental anomalies and growthrnretardation. The fetuses were examined for developmental delays, growth retardation, grossrnexternal malformations, as well as skeletal and visceral anomalies. Histopathological alterationsrnof the placenta also were evaluated for any treatment-related anomalies. rnFor the extended one-generation reproductive toxicity study, the parental Wistar rats, rn20/sex/group, were randomly assigned into four groups. Groups one, two, and three received 250, rn500, and 1000 mg/kg body weight of 70% ethanol extract of S. guineense leaf for 10 weeks,rnrespectively: two premating, two mating, three pregnancy, and three lactational weeks. In thernparental rats, the effect of extract administration on the food intake, weight gain, weight andrnhistology of reproductive organs, liver, kidneys, adrenal glands, and thyroid gland were evaluated.rnMoreover, serum level of thyroid hormones and biochemical tests were measured. Sperm analysisrnwas carried out and the length of estrous cycle was measured. Reproductive indices (pre-coitalrninterval, pregnancy duration, mating, fertility, and gestation indices) and pregnancy outcomes alsornwere evaluated. Once the pregnant dams gave birth, the pups were assessed for gross anomalies at birth. The weight of pups was measured on postnatal day zero, four, seven, fourteen, and twentyone.rnrnIn addition, pups anogenital distance was measured on postnatal day four. The presence ofnipple retention was assessed on postnatal day twelve. Moreover, postnatal death of pups wasrnreported on postnatal day 1, 4, 7, 14, and 21. At weaning (postnatal day 21), the pups wererandomly assigned into three cohort groups: to assess reproductive toxicity (set-1), developmentalneurotoxicity (set-2), and developmental immunotoxicity (set-3). All pups assigned into the threecohort groups were orally treated on a daily basis with similar doses used for the parental rats. Set1rnpups,rn20/sex/grouprnwererntreatedrnuprntornpostnatalrndayrn70.rnTorninvestigaternthernextendedrneffectrnofrnthernrntestrnplantrnon thernfirst-generationrnrats,rntherntests conductedrnon thernparentalrnratsrnwerernrepeatedrnon theset-1rnrnpups. In addition, weight at and the day of vaginal opening/preputial separation wererespectively evaluated in female and male set-1 rats. Set-2 pups, 10/sex/group, were treated untilrnpostnatal day 70 and the effect of the test plant extract on the weight and histopathology of thernbrain and spinal cord was investigated. Set-three pups, 10/sex/group, received the treatment untilpostnatal day 60 and the toxic effect of the plant extract on the weight and histopathology of spleen,thymus, and lymph nodes was evaluated. Data were analyzed by one-way analysis of variance andrnchi-square test using SPSS version 24. rnResults: The results of potential teratogenicity assessment indicated that administration of 70%ethanol extract of S. guineense leaf resulted in a significant reduction of food intake and weightgain during pregnancy in high dose treated group. It also reduced the crown-rump length, andaverage morphological score of 12 days old rat embryos. Moreover, the crown-rump length of 20days old rat fetuses was diminished by the treatment of 1000 mg/kg body weight of S. guineenseHowever, any of the doses of this plant did not produce significant effect on the number ofimplantations, resorptions, stillbirths, and live births. The external morphological and visceralexaminations of rat fetuses did not reveal any detectable structural malformations in the cranial,rnnasal, and oral cavities as well as visceral organs. The ossification centers of fetal skull, vertebrae,hyoid, forelimb, and hindlimb bones were not significantly varied across all groups. However,although not statistically significant, high dose treated rat fetuses had a reduced number ofossification centers in the sternum, caudal vertebrae, metatarsal, metacarpal, and phalanges. Theweight of the fetuses and the placentae were decreased. Decidual cystic degeneration was the mostprevalent histopathological changes of the placenta of rats treated with 1000 mg/kg body weightof the test plant extract. In the extended one-generation study, the administration of S. guineense extract resulted inrnsignificantly reduced food intake and weight gain of parental rats. Administration of 1000 mg/kgrnbody weight of the extract prolonged the duration of estrous cycle and pre-coital interval of femalernparental rats. The mean number of litters and live births were significantly reduced in the treatedrngroups. Rats treated with higher doses of the plant extract also showed significantly increasedrnserum ALT, AST, ALP, and urea levels. Moreover, the blood glucose level of rats treated withrn1000 mg/kg body weight of the extract was significantly decreased compared to that in the controlrngroups. The serum level of thyroid hormone (T4) was significantly reduced in the rats treated withrn500 and 1000 mg/kg body weight of S. guineense extract. Treatment of the rats with the high dosern(1000 mg/kg body weight) of the plant extract significantly reduced the relative weight of thernuterus and ovaries. No significant effect was observed in the number and morphology ofrnspermatozoa, duration of gestation as well as mating, fertility, and gestation indices. The pupâ€™srnweight, presence of nipple retention on male pups, anogenital distance, and number of postnatalrndeaths during lactation period were not significantly varied between the treatment and controlrngroups. Furthermore, the weight and histopathology of reproductive organs (weight except forrnuterus and ovaries), liver, kidneys, adrenal glands, and thyroid gland were not significantlyrnaffected by treatment with S. guineense extract. rnSimilar to the parental rats, the result biochemical tests measured in the first-generation set-1 ratsrnindicated that serum levels of ALT, AST, and ALP were significantly increased while food intake,rnweight gain, and serum levels of glucose and thyroid hormone were significantly decreased. Inrnaddition, the relative weight of the seminal gland, uterus, and ovaries was reduced by treatmentrnwith S. guineense extract (1000 mg/kg body weight). The relative weight of the other reproductivernorgans, liver, kidneys, adrenal glands, and thyroid gland was not significantly affected. In the firstgenerationrnrnrats, treatment with 1000 mg/kg body weight of S. guineense extract prolonged thernlength of estrous cycle. The weight at and the day of vaginal opening/preputial separation werernnot significantly altered by treatment with the test plant. Similarly, neither the relative organrnweight nor the histopathology of the brain, spinal cord, spleen, thymus, and lymph nodes wasrnaffected by treatment with S. guineense extract. rnConclusion: In conclusion, administration of 70% ethanol leaf extracts of S. guineense resulted inrndecreased food intake and weight gain of pregnant and nonpregnant rats in the high dose treatment group that indicated its toxicity at a high dose. Treatment of rats with the high dose of S. guineensernextract revealed growth and developmental delays as evidenced by reduced crown-rump lengthrnand average morphological score of 12 days old rat embryos and lower crown-rump length of 20rndays old rat fetuses as well as the average number of total and live births. The plant extracts alsornaffected the blood chemistry, the length of estrous cycle, and the weight of reproductive organsrnthat showed its toxicity at a high dose. Therefore, consumption of the plant, especially at a highrndose, may be teratogenic and toxic. Thus, regulation and monitoring of the use of S. guineensernleaves should be considered. Moreover, liberal consumption of S. guineense leaves should be takenrncuriously and cautiously. Further investigation should be conducted by increasing the number ofrntest animals, extending the duration of treatment period, and including additional tests/organs andrnother test animals.