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Plant lignan 7-hydromatairesinol, a novel precursor of the mammalian lignan enterolactone was evaluated in a prenatal developmental toxicity study conducted in the Wistar rat. Mated female rats were fed diets containing 0, 0.25, 1, and 4% (w/w) of 7-hydroxymatairesinol in the form of potassium acetate complex (HMRlignan; potassium acetate level approximately 20% w/w within the preparation) for days 0-21 of gestation. Test substance intake was calculated to be 0.14-0.18, 0.46-0.74, and 1.19-2.93 g/kg body weight/day for the low, mid, and high-dose groups, respectively. The rats were sacrificed on day 21 of the gestation period and examined for standard parameters of reproductive performance (fecundity index, gestation index, number of corpora lutea, number of implantations, pre- and post-implantation loss, number of early- and late resorptions, number of live- and dead fetuses, sex-ration and the weight of the reproductive organs). The fetuses were examined for external, visceral, and skeletal alterations. The results from this study showed no effects on reproductive performance or any treatment related findings following external, visceral, and skeletal examination of the fetuses. However, approximately half of the mated dams of the high-dose failed to thrive due to an unexpected large decrease in their food intake, and were sacrificed early. Body weights of the remaining animals of the high-dose group were decreased. Food consumption was decreased in all treatment groups during the first three days of the gestation period as a result of decreased palatability of the feed. In conclusion, the no-observed-effect level (NOEL) for maternal effects was 1%, whereas the NOEL for fetal development following daily oral HMRlignan administration throughout the gestation was equivalent to 4% in the diet.

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The embryotoxicity/teratogenicity of neohesperidin dihydrochalcone (NHDC) was examined in Wistar Crl:(WI)WU BR rats. NHDC was fed at dietary concentrations of 0, 1.25, 2.5 or 5 to groups of 28 mated female rats from day 0 to 21 of gestation. At Cesarean section 25, 22, 23, and 23 rats were found to be pregnant in the control, low-, mid-, and high-dose group, respectively. The NHDC treatment was well tolerated and all animals survived till the end of the study. Body weights (bw) and body weight gains did not differ between controls and NHDC treatment groups. The intake of NHDC was 0.8-0.9, 1.6-1.7, and 3.1-3.4 g/kg bw/day for the low-, mid-, and high-dose group, respectively. Except for cecal enlargement, there were no changes observed at necropsy which could be related to the NHDC treatment. All dams had viable fetuses. The fecundity and gestation index, the number of corpora lutea, implantation sites, live and dead fetuses, early and late resorptions, pre- and post-implantation losses, and sex-ratio were not affected by the treatment. There were no differences for the mean weight of the gravid and empty uterus, ovaries, and placenta between the NHDC treatment groups and the controls. Examination of the fetuses for external, visceral, and skeletal changes did not reveal any fetotoxic, embryotoxic or teratogenic effects of NHDC. In conclusion, no adverse effects were observed at NHDC levels of up to 5% of the diet, the highest dose level tested, at which the rats consumed about 3.3g/kg body weight/day. The observed cecal enlargement is a well-known physiological, adaptive response to the ingestion of high doses of a low-digestible substance and is generally accepted to lack toxicological relevance.

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The embryotoxicity/teratogenicity of alpha-cyclodextrin (alpha-CD) was examined in Wistar Crl:(WI)WU BR rats. alpha-CD was fed at dietary concentrations of 0, 1.5, 5, 10, or 20% to groups of 25 pregnant female rats from day 0 to 21 of gestation. An additional group received a diet with 20% lactose. The additions to the diet of alpha-CD and lactose were made at the expense of pregelatinized potato starch. Body weight as well as food and water intake were recorded during the treatment period. The rats were killed on day 21 and examined for standard parameters of maternal reproductive performance. The fetuses were examined for external abnormalities, body weight and crown rump length. Fetuses were examined for skeletal and visceral abnormalities. Generally, alpha-CD was well tolerated and no deaths occurred in any group. Weight gain and food consumption were similar in all groups during gestation, except for a slightly yet significantly increased food intake in the 20% alpha-CD group from day 6 to 21. Water intake was similar in all alpha-CD groups; in the lactose group, it was significantly higher than in the controls. Maternal reproductive performance was not affected by the alpha-CD treatment. Examination of the fetuses for external, visceral and skeletal changes did not reveal any fetotoxic, embryotoxic, or teratogenic effects of alpha-CD. In conclusion, no adverse effects were observed at alpha-CD intakes of up to 20% of the diet, the highest dose level tested at which the rats consumed about 13 g/kg bw/day.

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In a standard embryotoxicity/teratogenicity study, alpha-cyclodextrin (alpha-CD) was administered to groups of sixteen, artificially inseminated New Zealand White rabbits at dietary concentrations of 0, 5, 10, or 20%. An additional group received a diet containing 20% lactose. Treatment started on day 0 of gestation and ended on day 29 when the animals were killed. Except for the occurrence of transient diarrhoea in one rabbit of the 20% alpha-CD group for a few days, the treatment was well tolerated. A reduced food intake in the 20% alpha-CD group during the first week of treatment resulted in a reduced weight gain from day 0 to 12 of the study. However, the difference to the controls was not significant and at termination of the study body weights were similar in all groups. Even at the highest dose level, which corresponds to an intake of 5.9-7.5 g/kg bw/day, no signs of maternal toxicity were observed. Maternal reproductive performance was not affected by the treatment. Uterine weight, placental weight, fetal weight, number of fetuses, sex ratio, number of implanation sites, resorptions, and corpora lutea did not differ among the groups. Visceral and skeletal examinations of the fetuses did not reveal any malformations, anomalies or variations that could be attributed to treatment. It was concluded that dietary alpha-CD is generally well tolerated by pregnant rabbits, has no adverse effect on maternal reproductive performance and is not embryotoxic, fetotoxic, or teratogenic at dietary concentrations of up to 20%, the highest dose level tested.

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This paper contains a review of the history, natural occurrence, human consumption, metabolism, manufacture, and the results of eight standardized animal safety studies using trehalose. Trehalose (alpha,alpha-trehalose) is a naturally occurring sugar containing two D-glucose units in an alpha,alpha-1,1 linkage. Trehalose functions in many organisms as an energy source or a protectant against the effects of freezing or dehydration. It also possesses physical and/or chemical properties that are different than other sugars, which may make trehalose an attractive ingredient in food, health and beauty and pharmaceutical products. Data are presented supporting safe human consumption of trehalose in doses up to 50 g, and the physiologic ability of humans to digest it. No consistent treatment-related, dose-dependent adverse effects were observed in any of the eight safety studies performed at doses up to 10% of the diets. On the basis of these toxicity studies, human studies in which doses of trehalose were administered to various populations, and consumption of trehalose in commercial products in Japan, it is concluded that trehalose is safe for use as an ingredient in consumer products when used in accordance with current Good Manufacturing Practices.

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Phytosterol esters (PE) are intended for use as a novel food ingredient with plasma cholesterol lowering activity which works by inhibiting the absorption of cholesterol from the gut. Although PE are naturally present in the normal diet, the levels are insufficiently large to ensure lowering of plasma cholesterol levels. Therefore PE may be added to spreads to achieve the desired cholesterol lowering activity. As part of an extensive programme of safety evaluation studies a two-generation reproduction study has been conducted in Wistar rats, in which the possible effect of PE on male and female reproductive performance and on the growth and development of the offspring was studied. Rats were fed diets containing PE at levels of 0, 1.6, 3.2 and 8.1% (w/w) PE over two successive generations, and a wide range of reproductive and developmental parameters, including sexual maturation parameters and oestrous cycle length, were determined. Macroscopic and microscopic examinations were conducted including a histological examination of selected organs from F1- and F2-weanlings and from F0- and F1-parental animals. Daily clinical observations did not reveal any unusual findings. In both generations, no effects of PE were observed on pup mortality (calculated on litter basis), precoital time, mating index, male and female fertility index, female fecundity index, gestation index, duration of gestation, number of females with stillborn pups, post-implantation loss and pup development. Furthermore, PE had no effect on sexual maturation parameters (preputial separation and vaginal opening) and oestrous cycle length. In addition, there were no dose-related effects on selected organs following histological examination. In conclusion, dietary administration of up to 8.1% PE (equivalent to a dose of 2.5 to 9.1 g PE/kg body weight/day, dependent on the period of the study) during two generations had no effect on reproduction of parental F0- and F1-generation Wistar rats, nor on the development of the F1- and F2-pups, nor on the sexual maturation of the F1-weanlings. Therefore, a nominal dietary PE concentration of 8.1% (equivalent to a dose of 2.5-9.1 g PE/kg body weight/day or 1.54-5.62 g phytosterol/kg body weight/day dependent on the period of the study) was considered to be the no-observed-adverse-effect level following daily oral administration of PE for two successive generations.

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Plant stanol esters are intended for use as an ingredient in food to reduce the absorption of cholesterol from the gastrointestinal tract. Consumption of plant stanol esters has a demonstrated diet-derived public health benefit, as shown by numerous clinical studies. Plant stanol esters are ring-saturated analogs of common dietary sterols that are transesterified with fatty acids from vegetable oils such as canola oil. The reproductive and developmental toxicity of plant stanol esters was investigated in male and female Wistar rats during F0 and F1 generations using dietary concentrations of 1.75, 4.38, and 8.76% stanol esters (equivalent to 1, 2.5, and 5% total stanols). No adverse treatment-related effects were noted on reproductive performance of male or female rats in any dose group. Increased food consumption was observed in high-dose F0 generation males throughout the entire premating period and in F1 males at specific time periods during the premating period. This increase in food consumption was also observed in F0 generation females (mid- and high-dose groups) and F1 generation females (low-, mid-, and high-dose groups) at specific time periods throughout the 10-week premating period. At different intervals throughout the gestation and lactation periods, increased food consumption was observed in F0 generation females of the mid- and high-dose groups, while increased food consumption was noted in F1 generation females of the mid- and high-dose groups during gestation, but not during lactation. Such increases in food consumption are expected as a result of the animals' attempt to compensate for the reduced caloric value of the test diet compared to controls. No adverse developmental effects were noted in F1 or F2 pups of the low- and mid-dose groups based on evaluation of the following parameters: litter size, pup mortality, pups weights, and sex ratio. However, a treatment-related effect on body weight and body weight change was observed in both F1 and F2 male and female pups of the high-dose group, particularly during the latter stages of lactation (postnatal days 14 and 21) in F1 pups, and during the majority of the lactation period (postnatal days 4-21). Lower body weight in the high-dose pups is attributed to a reduction in the caloric value of the test diet compared to control. The pups, unlike adult animals, are particularly sensitive to reductions in caloric value of feed since they are in a rapid growth phase of their development. It is likely that they could not increase their food consumption enough to adequately meet their caloric and nutritional needs. In conclusion, dietary concentrations of up to 4.38% plant stanol esters (equivalent to 2.5% total stanols in the diet) are not associated with adverse effects on reproduction, pup mortality, pup body weight, or pup body weight change.

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In a standard developmental toxicity study, a mixture of vegetable oil-derived stanol fatty acid esters was administered in the diet to groups of 28 mated female HsdCpb:WU Wistar rats at concentrations that provided 0, 1, 2.5, and 5% total stanols (equivalent to 0, 1.75, 4.38, and 8.76% plant stanol esters). Test diets were adjusted with rapeseed oil to maintain an equivalent caloric content of fatty acids at each of the treatment levels. The treatment period extended from day 0 to 21 of gestation. No compound-related toxicity or clinical effects were seen in any of the treated groups. No statistically significant differences were seen in body weights or body weight gain in the low- or mid-dose groups, although slight but statistically significant decreases in mean body weight relative to controls were seen at gestation days 7 and 14 in the high-dose group. The decreases in body weight in the high-dose group may be attributable to the virtual lack of absorption of the dietary stanols. Body weight gains were equivalent to controls throughout the study except for a statistically significant decrease seen only in the 0- to 7-day gestation period in the high-dose group. No significant effects were seen on food consumption in terms of g/rat/day, but a slight, statistically significant increase was seen in the mid-dose group during gestation days 7-14. A significant increase was seen in the high-dose group during the 7- to 21-day period of gestation. Reproductive performance was not affected by the treatment. There were no statistically significant differences in uterine weight, placental weight, fetal weight, number of fetuses, number of implantation sites, number of corpora lutea, and early/late resorptions between the treated and control groups. In addition, there was no biologically meaningful effect on fetal sex ratio. Visceral and skeletal examinations did not show any significant increases in the incidence of malformations, anomalies, or variations that were considered to be treatment related. Dietary plant (8.76% plant stanol esters) stanol esters at concentrations up to 5% total stanols were concluded to have no adverse effects on reproduction or development.

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The embryotoxicity/teratogenicity of gamma-cyclodextrin (gamma-CD) was examined in Wistar Crl:(WI)WU BR rats. gamma-CD was fed at dietary concentrations of 0, 1.5, 5, 10, and 20% to groups of 25 pregnant female rats from day 0 to 21 of gestation. A comparison group received a diet with 20% lactose. The additions to the diet of gamma-CD and lactose were made at the expense of pregelatinized potato starch. Body weight and food and water intake were recorded during the treatment period. The rats were killed on day 21 and examined for standard parameters of reproductive performance. The fetuses were examined for signs of toxic and teratogenic effects. Generally, gamma-CD was well tolerated and no deaths occurred in any group. Weight gain and food consumption were similar in all groups during gestation, except for a slightly reduced food intake in the 20% gamma-CD group from day 0 to 16. Water intake was similar in all gamma-CD groups; in the lactose group, it was significantly higher than in the control group. Reproductive performance was not affected by the gamma-CD treatment. Examination of the fetuses for external, visceral, and skeletal alterations did not reveal any fetotoxic, embryotoxic, or teratogenic effects of gamma-CD. In conclusion, no adverse effects were observed at gamma-CD intakes of up to about 20% of the diet (approximately 11 g/kg body wt/day).

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In a standard embryotoxicity/teratogenicity study, gamma-cyclodextrin (gamma-CD) was administered to groups of 16, artificially inseminated New Zealand White rabbits at dietary concentrations of 0, 5, 10, or 20%. A comparison group received a diet containing 20% lactose. Treatment started on day 0 of gestation and ended on day 29 when the animals were killed. Except for the occurrence of transient diarrhea in 2 and 3 rabbits of the 10 and 20% gamma-CD groups, respectively, in the first few days, the treatment was well tolerated. A reduced food intake in the 20% gamma-CD group during the first week of treatment resulted in a reduced weight gain during this period. However, after week 1 there were no differences in weight gains between the groups, and at termination of the study body weights were similar in all groups. Even at the highest dose level, which corresponds to an intake of 5-7 g/kg body wt/day, no signs of maternal toxicity were observed. Reproductive performance was not affected by the treatment. Uterine weight, placental weight, fetal weight, number of fetuses, sex ratio, number of implantation sites, resorptions, and corpora lutea did not differ among the groups. Visceral and skeletal examinations of the fetuses did not reveal any malformations, anomalies, or variations that could be attributed to treatment. It was concluded that dietary gamma-CD is well tolerated by pregnant rabbits, has no adverse effect on reproductive performance, and is not embryotoxic, fetotoxic, or teratogenic at dietary concentrations of up to 20%.

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The embryotoxicity/teratogenicity of the natural sweetener isomaltulose (Palatinose) was studied in Wistar rats. Groups of 24 mated females were fed diets containing isomaltulose at levels of 0, 2.5, 5 and 10% from day 0 to day 21 of pregnancy. The dams were killed on day 21 of pregnancy. No maternal toxicity occurred and no effects on reproductive performance, nor on embryonic or foetal development, including visceral and skeletal examination, were seen in any of the groups fed isomaltulose. The dietary level of 10% isomaltulose was equivalent to about 7 g/kg body weight/day.

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The embryotoxicity/teratogenicity of erythritol, a low-calorie polyol sugar substitute, was examined in Wistar Crl:(WI) WU BR rats. Erythritol was fed at dietary concentrations of 0, 2.5, 5, and 10% to groups of 32 female rats from Day 0 to 21 of gestation. The treatment was generally well tolerated and no mortality occurred in any group. Weight gain during gestation, food consumption, and food efficiency were similar in all groups except for a significantly reduced weight gain in the 10% erythritol group in Week 2 of gestation. Reproductive performance was not affected by the treatment but the fertility index was generally rather low (69% in both control and high-dose group). Examination of the fetuses for external, visceral, and skeletal alterations did not reveal any fetotoxic, embryotoxic, or teratogenic effects. The slightly lower maternal body weight in the high-dose group was interpreted as a trivial result of the consumption of a low-calorie test substance in high amounts. In conclusion, no adverse effects were observed at erythritol doses of up to about 6.6 g/kg body wt/day, i.e., the highest dose tested.

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Erythritol was fed at dietary concentrations of 0, 2.5, 5, or 10% to Crl:(WI) WU BR rats of both sexes through two successive generations (F0 and F1). Twenty-four rats of each sex were mated in each group. For each generation one litter was reared until the pups were 21 days old. In the 10% erythritol group, food consumption among F0-males and -females was initially significantly reduced until the animals adapted to the erythritol diet during the first week of the study. Thereafter, food intake was higher than in controls. A consistently increased food intake also was seen in F1-males and-females of this dose group. This effect was considered to result from the caloric dilution of the food by erythritol, which has a low physiological energy value. The lower body weight and weight gain of the F0-animals of the 10% erythritol group were attributed to the initially reduced food consumption and occurrence of transient diarrhea until the animals had adapted to the erythritol intake. In the F1-animals of the 10% erythritol group, which were adapted to the treatment from weaning, the rate of body weight gain did not differ from controls. The F1-males and -females of this dose group did, however, have a reduced body weight from weaning, which was attributed to a reduced energy intake among the corresponding F0-dams during Weeks 2 and 3 of lactation. This effect was not seen in the F2-generation. It is concluded that under the conditions of this experiment, the intake of erythritol had no adverse effect on fertility and reproductive performance of parent rats or on the development of their progeny. Gross necropsy and microscopic examination of the parenteral reproductive organs also did not reveal treatment-related changes.

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The sugar replacer isomalt was fed to Wistar rats of both sexes throughout three successive generations at concentrations of 0, 2.5, 5 and 10% in the diet. A group of rats fed a diet containing 10% sucrose served as an additional control group. The initial mating was of 100 rats of each sex in each group. For subsequent matings 20 rats of each sex from each group were used. For each generation two litters were reared until they were at least 3 wk old. Feeding isomalt to rats for three successive generations did not induce any adverse effects on fertility, reproductive performance or development compared with control animals fed diets containing maize starch and sucrose instead of isomalt. The second litter of third-generation rats was given detailed gross and microscopic examinations 4 wk after weaning. A marked treatment-related change was an increase in the relative weight of the caecum (filled and empty), 4 wk after weaning in the second litter of third-generation rats fed 10% isomalt. There was also an increase in the relative weight of the filled caecum in males of the 5% isomalt group. These findings were not accompanied by diarrhoea or histological changes in the caecum. The results of the present study did not demonstrate any deleterious effects on the reproduction, maternal performance or development of rats fed isomalt at dietary levels of up to 10% over three successive generations.

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The embryotoxicity/teratogenicity of the sugar replacer isomalt was studied in Wistar rats and New Zealand White rabbits. Groups of 22-23 female rats were given diets containing isomalt at concentrations of 2.5, 5 or 10%, from day 0 to day 21 of pregnancy. The possible adverse effects of restricted feeding were studied in an additional group (food intake less than 80% of the control values). Groups of 36-37 female rabbits were given diets containing isomalt at concentrations of 2.5, 5 or 10%, from day 0 to day 29 of pregnancy. The female rats and rabbits were killed on days 21 and 29 of pregnancy, respectively. In both species no maternal toxicity occurred and no effects on reproductive performance nor on embryonic or foetal development were seen in any of the groups fed isomalt. The feeding of restricted amounts of stock diet to pregnant rats resulted in decreased maternal weight gain and lower uterus weights. Furthermore, this group had an increased number of resorptions and small foetuses, decreased foetus and placental weights and retarded bone development.

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The sugar replacer isomalt, a 1:1 mixture of the disaccharides glucopyranosylsorbitol and glucopyranosylmannitol, was incorporated in the diet of rats. Female Bay FB:30 rats were adapted to isomalt by feeding them a diet containing a gradually increasing amount of isomalt for several days, prior to mating. Subsequently, they were mated. Isomalt was fed continuously in concentrations of 2.5, 5 and 10% up to day 20 of pregnancy. In addition, one group of female Wistar rats was mated and fed 10% isomalt incorporated in the diet from day 0 up to day 20 of pregnancy, without previous adaptation to isomalt. Finally, one group of untreated female Wistar rats served as controls. Half of the number of females in each group was selected for caesarian section on day 20 of pregnancy. The other half was allowed to litter and rear their pups for 2 weeks (Wistar rats) or 3 weeks (Bay FB:30 rats). In the females of the Bay FB:30 rats, a decreased body-weight gain and food consumption were observed in the 5 and 10% isomalt group. Minor retardation in the development of the foetuses was observed in the 10% isomalt group only with the Bay FB:30 rats and was therefore considered to be related to maternal toxicity. In addition, a dose-related increase in the incidence of wavy ribs occurred in foetuses of the Bay FB:30 rats. However, none of the observed effects were persistent in neonates. Isomalt appeared to have slight toxic effects in the dams of the Bay FB:30 strain but no toxicity in the offspring. In Wistar rats no toxicity and no effects on maternal performance or on embryonic, foetal or neonatal development were seen. Isomalt, when fed at dietary levels up to 10%, did not induce structural or functional teratogenic effects in rats of either the Wistar or the Bay FB:30 strain.

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The influence of various parameters and growth conditions in the "overnight culture" of Salmonella typhimurium strains on mutagenicity test results was investigated. A number of factors were first suspected to be of some importance for the quantitative outcome of the mutagenicity test. None of them, however, was found to influence the results to such a marked extent as to be a major source of variability. Only the brand of nutrient broth used for the propagation of the bacteria proved finally to have a certain effect on the number of (spontaneous and induced) revertant colonies, although no precise and quantitative statements can be made with regard to a possible standardization of this experimental segment in the Salmonella mutagenicity test. The occurrence of such unpredictable but noticeable influences is, however, evidence for the importance of an intralaboratory optimization and standardization of all parts of the test procedure.

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