Sucralose: lack of effects on sperm glycolysis and reproduction in the rat.

Certain chlorine-substituted sugars with chemical similarities to sucralose have been demonstrated previously to diminish or inhibit sperm glycolysis and fertility in the rat ([Ford]). In order to investigate this potential for sucralose, epididymal spermatozoa were recovered from rats exposed in vivo to oral doses of one of three of these substituted sugars: 6-chloroglucose (6-CG, 24mg/kg/day, positive control), sucralose (500mg/kg/day, over 300 times the expected human daily intake), or a 6'-substituted isomer of sucralose, trichloro de-oxy sucrose (TCDS, 100mg/kg/day, a potential trace impurity in commercial sucralose); distilled water served as the negative control. After incubation of the spermatozoa with D-[U-(14)C] glucose, measurements of (14)CO(2) and of ATP content showed no impairment of the glycolytic ability of spermatozoa in any of the groups except for a marked inhibition for those exposed to 6-CG, the positive control. In order to determine whether other parameters of reproduction and fertility could be affected, reproductive endpoints were examined following oral exposure of male and female rats to sucralose. Sucralose was fed in the diet at concentrations of 0, 0.3, 1.0 and 3.0% (approx. 100, 365 and 1150 times the EDI) to groups of 30 male and 30 female rats for 10 weeks prior to mating, and continued through two subsequent generations until weaning of the F(2) pups. Two litters were produced per generation. Food consumption and weight gain in the F(0) and F(1) generations were depressed in all sucralose groups before mating and in all four litters prior to weaning. The decrease in initial average weight for newborn pups probably reflects the increased litter sizes noted for sucralose-treated groups and the reduced food consumption of the dams during gestation and lactation. The latter is a result primarily of the unpalatability of sucralose to rats ([McNeil,]). Caecal enlargement (a common animal response to large doses of indigestible material) occurred in both the F(0) and F(1) parents. Increased kidney weights, possibly associated with increased water intake, were observed primarily among animals receiving 3% sucralose (no renal histopathology has been detected). Decreased thymus weights occurred in F(1) males and in both F(1) and F(2) females at the 3% level. Subsequent studies specifically designed to investigate the potential for adverse immune system effects of sucralose ([McNeil,]) showed no adverse effects. These findings are consistent with investigations by others showing that decreases in thymus weights occur in young rats in response to stressful conditions associated with reductions in weight gain. All reproductive indices (oestrous cycles, mating behaviour, fertility, gestation, maternal and foetal viability, foetal development, parturition, pup maturation and lactation) were comparable between the control and sucralose-treated groups. We conclude from these results that sucralose has no effect on sperm glycolysis or on male or female reproductive performance in the rat.

Sucralose: assessment of teratogenic potential in the rat and the rabbit.

The teratogenic potential of sucralose was examined following gavage administration to pregnant rats and rabbits during organogenesis. Groups of 20 mated rats were dosed on days 6-15 of gestation inclusive at 500, 1000 or 2000mg/kg/day; groups of 16 to 18 inseminated rabbits were dosed on days 6 to 19 of gestation inclusive at 175, 350 or 700mg/kg/day following preliminary studies at higher doses. Concurrent control groups received vehicle alone. Rats were killed on day 21 and rabbits on day 29 of gestation. Foetuses were evaluated at necropsy and after processing for possible soft tissue and skeletal alterations. There was no evidence of teratogenicity for either species. The only observed response to treatment in rats was a slight increase in water intake. Some adult rabbits receiving 700mg/kg/day exhibited marked gastrointestinal disturbance, also seen at higher doses in preliminary studies. Gastrointestinal effects such as these occur non-specifically in response to high doses of poorly absorbed compounds, and in the present study were considered to be responsible for two maternal deaths and four abortions. Full evaluation of rabbit foetuses in the main study (up to 700mg/kg/day) and necropsy of foetuses in a preliminary study with pregnant animals (up to 1000mg/kg/day) showed no evidence of adverse foetal response to sucralose. These teratology studies in both pregnant rodent and non-rodent animal models demonstrate that maternal consumption of high levels of sucralose during the period of organogenesis has no effect on normal foetal development in the rat or rabbit.

Assessment of the toxic and potential teratogenic effects of four glycol ethers and two derivatives using the hydra regeneration assay and rat whole embryo culture.

The widespread use of the glycol ethers as solvents in manufacturing industries presents a vast potential for occupational exposure. In the present study the potential hazards of four glycol ethers and two derivatives were assessed using two in vitro tests, rat whole embryo culture and the hydra regeneration assay. Concentrations used ranged from 0.3 to 1.0 mg/ml in embryo culture and from 0.03 to 80.0 mg/ml in the hydra assay. The embryotoxic potential of the ethylene glycol mono-alkyl ethers was shown to increase with the length of the alkyl chain. This is in contrast to in vivo data but can be explained by the lack of maternal metabolism in the in vitro systems. However, the teratogenic hazard ratings obtained in the hydra assay and the types of malformations observed in embryo culture support in vivo data. Results obtained for diethylene glycol monoethyl ether are in agreement with in vivo data. Results of both assays suggest that ethylene glycol monosalicylate presents a significant potential teratogenic hazard and that ethylene glycol tetra-acetic acid presents toxic and teratogenic potentials. When the effects of maternal toxicity and metabolism are considered, the overall picture presented by the present results is one of general agreement with in vivo data.

[Reproductive and developmental toxicity studies of lactitol (NS-4) (3)--Teratogenicity study in rabbits by oral administration].

Lactitol, a hepatic encephalopathy drug, was administered by oral gavage to pregnant New Zealand White rabbits during organogenesis from day 6 to day 18 of gestation inclusive, at dosages of 0, 0.25, 0.75 or 4.5 g/kg/day. On day 29 of gestation, females were killed to allow examination of their uterine contents. There was a slight reduction in food intake and faecal output among females receiving 4.5 g/kg. One female receiving 4.5 g/kg aborted following a prolonged period of weight loss. No adverse effects on litter parameters were recorded that could be attributed to treatment. Foetal morphogenesis was unaffected by treatment with lactitol. The results show that no-effect dose levels of lactitol are 0.75 g/kg in mother rabbits for general toxicity and for reproductive functions, and 4.5 g/kg for their fetuses.

Effects of female sex hormones in whole embryo culture.

Much work has been done in vivo on the effects of sex steroids on the developing foetus. Many genital anomalies have been reported; defects of other organ systems have been suggested. Synthetic oestrogens are considered to be developmental toxicants in vivo, while natural oestrogens are thought to present little or no risk. A small selection of hormones (17beta-oestradiol, 17alpha-ethynyloestradiol, diethylstilboestrol and progesterone) was tested using the rat whole embryo culture technique to see whether this difference could also be confirmed in vitro. Dysmorphogenic embryotoxic effects were evident with both natural and synthetic oestrogens, but at much higher concentrations than would be expected to circulate in humans after therapeutic use.