Abstract for TER96003

Developmental Toxicity Evaluation of Melatonin Administered by Gavage to Sprague Dawley (CD) Rats on Gestational Days 6 Through 19

CASRN: 73-31-4
Chemical Formula: C13H16N2O2
Molecular Weight: 232.2814
Report Date: March 26, 1998


The following abstract presents results of a study conducted by a contract laboratory for the National Toxicology Program. The findings may not have been peer reviewed and were not evaluated in accordance with the levels of evidence criteria established by NTP in March 2009. For more information, see the Explanation of Levels of Evidence for Developmental Toxicity. The findings and conclusions for this study should not be construed to represent the views of NTP or the U.S. Government.

Melatonin, widely used as a nonprescription sleep aid, is also under investigation for contraceptive, antioxidant, anticancer, and antiaging effects. This study was performed due to the widespread use of MEL by the general population and the lack of pertinent developmental toxicity data.

Dose selection was based on a screening study in which CD rats were treated by gavage with 0, 1, 10, 100, 150, or 200 milligrams MELper kilogram body weight/day on gestational days 6 through 19 (NTP, 1997). In the screening study, prenatal growth, viability, and external morphological development were not affected. Mild maternal toxicity was noted at greater than or equal to 100 mg/kg/day (NTP, 1997).

In this study, female Sprague-Dawley-derived (CD) rats were dosed by gavage with MEL (50, 100, or 200 mg/kg/day) or its vehicle (0.5% aqueous methylcellulose) on gd 6 through 19. The dose volume was 5 ml/kg. Twenty-five timed-mated rats were assigned to each group. Dams were monitored at regular intervals throughout gestation for clinical signs, food and water intake, and body weight. At necropsy on gd 20, the following were recorded: maternal clinical condition; body, liver and gravid uterine weights; pregnancy status; and number of corpora lutea. In the gravid uterus, the numbers of resorbed, dead, or live fetuses were recorded. All live fetuses were weighed, sexed, and examined for external morphological anomalies. Approximately one-half of the fetuses were examined for visceral anomalies, including internal head structures, and the remaining fetuses were examined for skeletal anomalies.

Pregnancy was confirmed in all of the females assigned to this study. No maternal deaths occurred, and clinical signs associated with melatonin exposure were minimal. Twenty-four percent of the high-dose dams were classified as lethargic and/or dazed following the initial dose on gd 6. Aversion to the dose formulation was indicated by a dose-related incidence of rooting behavior among MEL-treated dams. At its peak (gd 15), rooting was observed in 0, 16, 96, and 100% of the dams from the control through high-dose groups, respectively.

Maternal body weight gain was decreased in the high-dose group during the first three days of treatment. This effect was less robust between gd 9 and 12, and was not evident during subsequent measurement periods. Increased relative maternal liver weight in the low and high-dose groups was not clearly related to treatment. Absolute liver and gravid uterine weights were not affected.

Relative maternal food intake (g/kg/day) was significantly decreased at the high dose from gd 6 to 12. In contrast, the low-dose group consumed more food than controls from gd 12 to 18. Maternal relative water intake was not affected.

Melatonin did not affect any of the endpoints related to embryo/fetal growth, viability, or morphological development. Average live litter size in MEL-treated groups was between 98-103% of the control mean, and average fetal body weight per litter in MEL-treated groups was 100-101% of the control mean. Likewise, the incidences of prenatal mortality and fetal morphological anomalies were statistically equivalent among groups.

In summary, no significant embryo/fetal toxicity was noted in CD rats dosed by gavage with MEL (0, 50, 100, or 200 mg/kg/day on gd 6-19). Mild maternal toxicity was noted at 200 mg/kg/day and aversion to dosing at 50 mg/kg/day. Thus, the maternal toxicity no observed adverse effect level was 100 mg/kg/day, and the lowest observed adverse effect level was 200 mg/kg/day. The developmental toxicity NOAEL was 200 mg/kg/day. low dose between gd 12 and 18.