Certain Phthalate esters have been shown to produce reproductive toxicity in male rodents with an age dependent sensitivity in effects with foetal animals being more sensitive than neonates which are in turn more sensitive than pubertal and adult animals. While the testicular effects of phthalates in rats have been known for more than 30 years, recent attention has been focused on the ability of these agents to produce effects on reproductive development in male offspring after in utero exposure. These esters and in particular di-butyl, di-(2-ethylhexyl) and butyl benzyl phthalates have been shown to produce a syndrome of reproductive abnormalities characterized by malformations of the epididymis, vas deferens, seminal vesicles, prostate, external genitalia (hypospadias), cryptorchidism and testicular injury together with permanent changes (feminization) in the retention of nipples/areolae (sexually dimorphic structures in rodents) and demasculinization of the growth of the perineum resulting in a reduced anogenital distance (AGD). Critical to the induction of these effects is a marked reduction in foetal testicular testosterone production at the critical window for the development of the reproductive tract normally under androgen control. A second Leydig cell product, insl3, is also significantly down regulated and is likely responsible for the cryptorchidism commonly seen in these phthalate-treated animals. The testosterone decrease is mediated by changes in gene expression of a number of enzymes and transport proteins involved in normal testosterone biosynthesis and transport in the foetal Leydig cell. Alterations in the foetal seminiferous cords are also noted after in utero phthalate treatment with the induction of multinucleate gonocytes that contribute to lowered spermatocyte numbers in postnatal animals. The phthalate syndrome of effects on reproductive development has parallels with the reported human testicular dysgenesis syndrome, although no cause and effect relationship exists after exposure of humans to phthalate esters. However humans are exposed to and produce the critical phthalate metabolites that have been detected in blood of the general population, in children and also human amniotic fluid.

Changes in puberty timing have implications for the treatment of individual children, for the risk of later adult disease, and for chemical testing and risk assessment for the population. Children with early puberty are at a risk for accelerated skeletal maturation and short adult height, early sexual debut, potential sexual abuse, and psychosocial difficulties. Altered puberty timing is also of concern for the development of reproductive tract cancers later in life. For example, an early age of menarche is a risk factor for breast cancer. A low age at male puberty is associated with an increased risk for testicular cancer according to several, but not all, epidemiologic studies. Girls and, possibly, boys who exhibit premature adrenarche are at a higher risk for developing features of metabolic syndrome, including obesity, type 2 diabetes, and cardiovascular disease later in adulthood. Altered timing of puberty also has implications for behavioral disorders. For example, an early maturation is associated with a greater incidence of conduct and behavior disorders during adolescence. Finally, altered puberty timing is considered an adverse effect in reproductive toxicity risk assessment for chemicals. Recent US legislation has mandated improved chemical testing approaches for protecting children's health and screening for endocrinedisrupting agents, which has led to changes in the US Environmental Protection Agency's risk assessment and toxicity testing guidelines to include puberty-related assessments and to the validation of pubertal male and female rat assays for endocrine screening.

Di(n-butyl) phthalate (DBP) is a commercially important plasticizer and ubiquitous environmental contaminant. Since previous, limited dose-response studies with DBP that reported alterations in male reproductive development and function failed to establish a NOAEL (no-observed-adverse-effect level), an extensive dose-response study was conducted. Pregnant CD rats were given DBP by gavage at 0, 0.5, 5, 50, or 100 mg/kg/day (n = 19-20) or 500 mg/kg/day (n = 11) from gestation day 12 to 21. In male offspring, anogenital distance was decreased at 500 mg DBP/kg/day. Retained areolas or nipples were present in 31 and 90% of male pups at 100 and 500 mg/kg/day, respectively. Preputial separation was not delayed by DBP treatment in males with normal external genitalia, but cleft penis (hypospadias) was observed in 5/58 rats (4/11 litters) at 500 mg/kg/day. Absent or partially developed epididymis (23/58 rats in 9/11 litters), vas deferens (16/58 animals in 9/11 litters), seminal vesicles (4/58 rats in 4/11 litters), and ventral prostate (1/58 animals) occurred at 500 mg/kg/day. In 110-day-old F(1) males, the weights of the testis, epididymis, dorsolateral and ventral prostates, seminal vesicles, and levator ani-bulbocavernosus muscle were decreased at 500 mg/kg/day. At 500 mg/kg/day, widespread seminiferous tubule degeneration was seen in 25/58 rats (in 9/11 litters), focal interstitial cell hyperplasia in 14/58 rats (in 5/11 litters), and interstitial cell adenoma in 1/58 rats (in 1/11 litters). For this 10-day prenatal (embryonic and fetal) exposure to DBP, the NOAEL and LOAEL (lowest-observed-adverse-effect level) were 50 and 100 mg/kg/day, respectively. This is currently the lowest NOAEL described for the toxicity of DBP.

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