Subchronic,Reproductive, and Developmental Toxicity of a Fluorotelomer-Based Urethane Polymeric Product

A commercial fluorotelomer-based urethane polymeric dispersion, consisting of polymer, surfactant, and water, was evaluated in subchronic, reproduction, and developmental toxicity studies. The dispersion was administered daily by gavage to rats at dosages of 0, 50, 250, or 1000 mg polymer/kg/day or with 70 mg/kg/day of the sulfonate surfactant. Dose levels of 0, 50, 250, or 1000 mg polymer/kg/day were also used for the reproductive and developmental studies. Nasal olfactory epithelial degeneration and necrosis occurred in all dose groups in the 90-day study. Nasal adhesions were observed only in rats administered surfactant alone. Liver-enzyme alterations at 250 and 1000 mg/kg were considered to be potentially adverse effects. The subchronic no-observed-adverse-effects level (NOAEL) was 50 mg/kg. For the reproduction study, rats were dosed for 10 weeks prior to cohabitation and throughout mating, gestation, and lactation. There were no effects on reproductive function in males or females at any dosage. Thyroid weight was decreased in the 250 and 1000 mg/kg day F₁ groups unaccompanied by microscopic effects. In the developmental toxicity study, female rats were dosed from gestation days 6–20; there was no test-substance-related embryolethality, nor was there any dose-related increase in either fetal malformations. Fetal weight was minimally decreased at 1000 mg/kg/day in the presence of slight maternal toxicity; the NOAEL for developmental parameters was 250 mg/kg/day. The polymeric product was not a specific developmental or reproductive toxin.     

Combined repeated dose and reproductive/developmental toxicity screening test of the nitrophenolic herbicide dinoseb, 2-sec-butyl-4,6-dinitrophenol, in rats

In a combined repeated dose toxicity study with reproduction/developmental toxicity screening test, Crj:CD(SD)IGS rats were dosed with dinoseb, 2-sec-butyl-4,6-dinitrophenol, by gavage at 0 (vehicle), 0.78, 2.33, or 7.0 mg/kg bw/day. Six males per group were dosed for a total of 42 days beginning 14 days before mating. Twelve females per group were dosed for a total of 44-48 days beginning 14 days before mating to day 6 of lactation throughout the mating and gestation period. Recovery groups of six males per group and nonpregnant six females per group were dosed for 42 days followed by a 14-day recovery period. No deaths were observed in males of any dose group or in females of the recovery groups. At 7.0 mg/kg bw/day, eight females died and two animals were moribund during late pregnancy, and a significant decrease in body weight gain was found in both sexes. Hematocrit was significantly higher at 0.78 mg/kg bw/day and above in the main group males at the end of administration period. Reduction in extramedullary hematopoiesis in the spleen was significant at 2.33 mg/kg bw/day in the main group females. Sperm analysis revealed a decrease in sperm motility and an increase in the rates of abnormal sperm, abnormal tail, and abnormal head at 7.0 mg/kg bw/day. A number of dams delivered their pups and of dams with live pups at delivery was significantly lowered in the 7.0 mg/kg bw/day group. Based on these findings, the LOAEL for males and NOAEL for females were 0.78 mg/kg bw/day, and the NOAEL for reproductive/developmental toxicity was considered to be 2.33 mg/kg bw/day.     

Absence of reproductive and developmental toxicity in rats following oral dosing with nelfinavir

The potential for nelfinavir mesylate (VIRACEPT) to produce reproductive toxicity was evaluated in rats administered oral doses of 200, 500, or 1000mg/kg/day. In the fertility and early embryonic development to implantation study, male rats were treated beginning 28 days prior to mating until necropsy and females for 2 weeks prior to mating and through gestation day (GD) 7. In the pre- and postnatal development study, pregnant rats were treated from GD 6 through lactation day (LD) 20. Selected F(1) pups from this study were evaluated in sensory and behavioral tests and were subsequently mated. Pregnant F(1) females were euthanized on GD 20 and their F(2) fetuses were examined. F(1) animals were not directly dosed with the drug. No treatment-related effects were observed on any male reproductive parameters. Administration of nelfinavir did not produce adverse effects on fertility, pregnancy, embryo-fetal development, parturition, or lactation in the F(0) generation. Similarly, no adverse effects of nelfinavir treatment were observed on pre- and postnatal growth, development, reproductive performance and embryo-fetal development in the F(1) offspring. Based on the results of this study, the no-observed-adverse-effect-level (NOAEL) for developmental and reproductive toxicity in rats was considered to be 1000mg/kg/day, the highest dose tested.     

Developmental toxicity evaluation of 1,2,3,4-butanetetracarboxylic acid in Sprague Dawley (CD) rats

1,2,3,4-butanetetracarboxylic acid (BTCA), proposed as a formaldehyde substitute in the treatment of permanent press fabrics, was evaluated for developmental toxicity. Timed-mated CD rats (25 per group) received BTCA 250, 500, or 1000 mg/kg/day or vehicle (deionized/distilled water) by gavage on gestational days (gd) 6 through 19. Maternal feed and water consumption, body weight, and clinical signs were monitored throughout gestation. At termination (gd 20), confirmed-pregnant females (21 to 25 per group) were evaluated for clinical status and gestational outcome; live fetuses were examined for external, visceral, and skeletal malformations. One maternal death, reduced body weight, and reduced weight gain were noted at the high dose; confirmed pregnancy rates were 84 to 100% for each group. There were no treatment-related effects on fetal growth, survival, or morphologic development. The maternal toxicity NOAEL and LOAEL are 500 and 1000 mg/kg/day, respectively. The developmental toxicity NOAEL is > or = 1000 mg/kg/day, and the LOAEL was not established in this study.     

Repeated dose and reproductive/developmental toxicity of perfluorooctadecanoic acid in rats

Male and female rats were given perfluorooctadecanoic acid (PFOdA) by gavage at 40, 200 or 1,000 mg/kg/day, and each female was mated with a male in the same dose group after 14-day administration. Males were dosed for 42 days and females were dosed throughout the gestation period until day 5 of lactation. One female given 1,000 mg/kg/day was euthanized on day 18 of gestation due to a moribund condition; however, no other treatment-related clinical signs of toxicity were observed. Body weights fell at 1,000 mg/kg/day from day 28 through the administration period in males and throughout gestation and lactation in females. Red blood cell count, hemoglobin level and hematocrit were decreased at 200 and 1,000 mg/kg/day in males and activated partial thromboplastin time was prolonged at 1,000 mg/kg/ day in females. Histopathological examination revealed hepatic changes, such as centrilobular hypertrophy and necrosis, in males given 200 and 1,000 mg/kg/day and in females given 1,000 mg/kg/day. Pancreatic zymogen granule was decreased in both sexes at 1,000 mg/kg/day. As for reproductive and developmental toxicity, there were decreases in the number of corpora lutea, implantation, total number of pups born and the number of live pups on postnatal days 0 and 4 at 1,000 mg/kg/day. At this dose, birth weights of pups were decreased and postnatal body weight gain was inhibited. Based on these findings, the NOAEL of PFOdA was considered to be 40 mg/kg/day for repeated dose toxicity and 200 mg/kg/day for reproductive/developmental toxicity.     

The toxicity of behenyl alcohol. I. Genotoxicity and subchronic toxicity in rats and dogs

The genotoxic potential of behenyl alcohol, a saturated long-chain (C22:0) fatty alcohol, was examined in the Ames Salmonella typhimurium reverse mutation assay, the gene mutation, and chromosome aberrations assays in Chinese hamster V79 cells, and the micronucleus assay in NMRI mice. Behenyl alcohol did not increase the number of revertants per plate compared to controls in the S. typhimurium assay, with or without metabolic activation. No significant increases in the number of mutant colonies or in structural chromosome aberrations were observed in Chinese hamster V79 cells. In addition, behenyl alcohol did not increase the frequency of bone marrow polychromatic erythrocyte (PCE) micronuclei in mice in vivo. In two subchronic toxicity studies, CD rats and beagle dogs were administered behenyl alcohol by oral gavage for at least 26 weeks at doses of 0, 10, 100, or 1000 mg behenyl alcohol/kg body weight/day for rats and 0, 20, 200, or 2000 mg behenyl alcohol/kg body weight/day for dogs. Adverse effects were not observed following gross and histopathological evaluations of dosed rats. Compound-related effects in dogs were limited to observations of pale feces, indicative of unabsorbed behenyl alcohol, at doses of 2000 mg/kg body weight/day. There were no histopathological changes observed in dogs dosed with behenyl alcohol. The no-observed-adverse-effect-level (NOAEL) for behenyl alcohol was 1000 mg/kg body weight/day for rats, and 2000 mg/kg body weight/day for dogs, the highest doses used in these studies.     

One-generation reproductive toxicity study of 2-methylbutane in Sprague-Dawley rats

This study investigated the potential reproductive toxicity of 2-methylbutane in a one-generation reproductive toxicity study using Sprague-Dawley rats. A total of 24 male and female rats per group were given 2-methylbutane by gavage at 0, 100, 300, and 1000 mg/kg/day. Males were dosed for 10 weeks prior to mating and during mating. Females were dosed from 2 weeks before mating to day 21 of lactation. At 1000 mg/kg/day, both genders exhibited an increase in adrenal gland weight, however, a decrease in body weight gain and food intake, an increase in kidney weight, and an increased incidence of histopathological changes of the kidney were also observed in male rats. No treatment-related effects of 2-methylbutane were found in relation to the reproductive capacity of parental animals or the pre- and post-natal development of the F1 generation. There were no treatment-related effects in either gender at ≤ 300 mg/kg/day. Under these experimental conditions, the no-observed-adverse-effect level of 2-methylbutane was 300 mg/kg/day for general toxicity and 1000 mg/kg/day for reproductive capacity and pup development in rats.     

Evaluation of the developmental toxicity of linalool in rats

The developmental toxicity of linalool, a widely used fragrance ingredient, was evaluated in presumed pregnant Sprague-Dawley rats (25/group). Oral dosages of 0, 250, 500, or 1000 mg/kg/day linalool were administered by gavage on gestational days 7 to 17. The presence of spermatozoa and/or a copulatory plug in situ was designated as gestational day 0. Rats were observed for viability, clinical signs, body weights, and feed consumption. Caesarean sectioning and necropsy occurred on gestational day 21. Uteri were examined for number and distribution of implantations, live and dead fetuses, and early and late resorptions. Numbers of corpora lutea were also recorded. Fetuses were weighed and examined for gender, gross external changes, and soft tissue or skeletal alterations. There were no maternal deaths, clinical signs, or gross lesions that were considered related to linalool. During the dosage period, mean relative feed consumption was significantly reduced by 7% and mean body weight gains were reduced by 11% at 1000 mg/kg/day. During the postdosage period, feed consumption values at 1000 mg/kg/day were significantly higher than vehicle control values, which corresponded to the increase in body weight gains during this period. Caesarean section and litter parameters, as well as fetal alterations, were not affected by linalool at any of the three dosages tested. On the basis of these data, the maternal no observed adverse effect level (NOAEL) of linalool is 500 mg/kg/day, whereas the developmental NOAEL is > or = 1000 mg/kg/day. It is concluded that linalool is not a developmental toxicant in rats at maternal doses of up to 1000 mg/kg/day.     

Developmental Toxicity of Dinitroaniline Herbicides in Rats and Rabbits

The potential developmental toxicity of trifluralin was evaluatedin rats and rabbits. Pregnant rats and rabbits were dosed oncedaily by gavage on Gestation Days 6–15 and 6–18,respectively. Doses for rats were 0, 100, 225, 475, or 1000mg/kg; doses for rabbits were 0, 100, 225, or 500 mg/kg. Cesareansections were performed on rats and rabbits on Gestation Days20 and 28, respectively. In rats, maternal toxicity was indicatedin the 475 and 1000 mg/kg treatment groups by depression ofbody weights and food consumption. Fetal viability and morphologywere not adversely affected at any dose level. Developmentaltoxicity was indicated at the 1000-mg/kg dose level by depressionof fetal weight. The NOAEL for maternal toxicity in the ratwas 225 mg/kg the NOAEL for developmental toxicity in the ratwas 475 mg/kg. In rabbits, maternal toxicity was indicated atthe 225 and 500 mg/kg dose levels by abortions and/or deathsin conjunction with anorexia and cachexia. Developmental toxicitywas indicated at the 500 mg/kg dose level by depressed fetalviability and weight. Fetal morphology was not adversely affectedat any dose level. The NOAELs for maternal and developmentaltoxicity in the rabbit were 100 and 225 mg/kg, respectively.Based on these data, trifluralin did not exhibit selective toxicitytoward the developing conceptus.     

Toxicologic evaluations of DHA-rich algal oil in rats: Developmental toxicity study and 3-month dietary toxicity study with an in utero exposure phase

DHA-rich algal oil ONC-T18, tested for subchronic, reproductive, and developmental toxicity in the rat, did not produce any significant toxicologic manifestations. Based on the absence of maternal or developmental toxicity at any dosage level, a dosage level of 2000 mg/kg/day was considered to be the no observed adverse-effect level (NOAEL) for maternal toxicity and embryo/fetal development when DHA-rich algal oil was administered orally by gavage to pregnant Crl:CD(SD) rats during gestation days 6–19. In a dietary combined one-generation/90-day reproductive toxicity study in rats, the NOAEL for F0 male and female and F1 male systemic toxicity was considered to be 50,000 ppm (highest concentration administered) and 25,000 ppm for F1 female systemic toxicity (higher mean body weight, body weight gain, and food consumption). F0 reproductive performance values, estrous cycle length, gestation length, or the process of parturition, and the numbers of former implantation sites and unaccounted-for sites were unaffected by algal oil exposure. Postnatal survival and developmental parameters in the F1 generation were unaffected by algal oil exposure at all dietary concentrations. There were no neurotoxic effects noted at any algal oil exposure level. The results support the safety of DHA-rich algal oil for its proposed use in food.     

A 15-day oral dose toxicity study of aspirin eugenol ester in Wistar rats

The subchronic toxicity of aspirin eugenol ester (AEE) was evaluated after 15-day intragastrically administration in rats at daily doses of 50, 1000, and 2000 mg/kg. AEE at low-dose showed no toxicity to the tested rats. Following repeated exposure to medium- or high-dose of AEE, apparent changes were observed in the levels of blood glucose, AST, ALP, ALT and TB in both male and female rats, and appeared to be dose-independent. There were no significant gender differences in most indexes of subchronic toxicity throughout the experimental period with the exception of food consumption and body weight. The no-observed-adverse-effect level (NOAEL) of AEE was considered to be 50 mg/kg/day under the present study conditions.     

Evaluation of the teratogenic potential of N-[N-[3-(3-hydroxy-4-methoxyphenyl) propyl]-α-aspartyl]-L-phenylalanine 1-methyl ester, monohydrate (advantame) in the rat and rabbit

To assess its teratogenic potential, advantame (N-[N-[3-(3-hydroxy-4-methoxyphenyl) propyl]-α-aspartyl]-L-phenylalanine 1-methyl ester, monohydrate) was administered to mated rats (22/group) in the diet at 0, 5000, 15,000, and 50,000 ppm (providing approximately 465, 1418, and 4828 mg/kg body weight/day), and to mated rabbits (24/group) via oral gavage at 0, 500, 1000, and 2000 mg/kg body weight/day throughout gestation. Shortly before delivery (rats: day 20; rabbits: day 29), animals were killed and subjected to a detailed necropsy. Fetuses were examined for external, visceral, and skeletal alterations. Atypical coloration of the feces and cage liners seen with test diets in both rats and rabbits was attributed to excretion of test material/metabolites in the feces and urine. Advantame had no adverse effect on rat offspring survival or development. The no-observed-adverse-effect level (NOAEL) for both maternal and developmental toxicity in rats was 50,000 ppm, the highest dietary concentration tested. Due to adverse effects associated with reduced food intake and fecal output, approximately 20% of mated rabbits receiving 200 0mg/kg body weight/day and 1 animal at 1000 mg/kg body weight/day had to be terminated before scheduled necropsy. A NOAEL of 500 mg/kg body weight/day was established for maternal toxicity in rabbits. No teratogenic effects were observed in any animals, and based on a slightly increased incidence of fetal deaths at 2000 mg/kg body weight/day, a finding that was considered to be indirectly related to advantame treatment, 1000 mg/kg body weight/day was considered the NOAEL for developmental toxicity.     

Subchronic oral toxicity and cardiovascular safety pharmacology studies of resveratrol, a naturally occurring polyphenol with cancer preventive activity

To characterize the subchronic oral toxicity of resveratrol, CD rats received daily gavage doses of 0, 200, 400, or 1000 mg resveratrol/kg/day, and beagle dogs received daily capsule doses of 0, 200, 600, or 1200 mg resveratrol/kg/day for 90 days. Resveratrol induced only minimal toxicity, consisting of dose-related reductions in body weight gain in female rats and both sexes of dogs, and a statistically significant increase in bilirubin levels in rats at the 1000 mg/kg/day dose. Clinical observations, hematology, ophthalmology, neurotoxicity evaluations (functional observational batteries), organ weights, and gross pathology provided no biologically significant evidence of resveratrol toxicity in either species. In rats, the high dose of resveratrol reduced the incidence of cardiomyopathy; no other microscopic changes were seen. Histopathologic changes in dogs were limited to minimal inflammatory infiltrates in the kidney and urinary bladder, which were not considered toxicologically significant. A cardiovascular safety pharmacology (telemetry) study in dogs revealed no evidence of resveratrol toxicity. Based on body weight effects, the No Observed Adverse Effect Level (NOAEL) for resveratrol was 200 mg/kg/day in rats and 600 mg/kg/day in dogs. The apparent cardioprotective activity of resveratrol in rats demonstrates that its potentially beneficial activities may extend beyond efficacy in cancer prevention.     

Toxicity study of cefmatilen hydrochloride hydrate (S-1090) (3)--One- and three-month repeated oral dose toxicity studies in rats

One- or three-month repeated oral dose toxicity studies of Cefmatilen hydrochloride hydrate (S-1090) in rats were conducted. Doses were set at 80, 200, 500 and 1250 mg potency/kg/day in the one-month toxicity study, and 100, 300 and 1000 mg potency/kg/day in the three-month toxicity study. Body weights increased favorably and no deaths occurred in all treated groups of both studies. The changes observed in both studies were soft feces, abdominal distention, increased food and water consumption, decreases of urine volume and pH, and a decrease of blood neutrophils in almost all treated groups, reddish-brown feces (due to chelated products of S-1090 and its decomposition products with Fe3+ in the diet) in groups dosed at 300 mg potency/kg or more, and a lower mature granulocyte ratio in the bone marrow in groups dosed at 1000 mg potency/kg or more. In necropsy, cecal enlargement with a large amount of muddy content was observed in all treated groups of both studies. In the three-month toxicity study, elevated drug-metabolizing enzyme activities were noted in the liver of the males in the 1000 mg potency/kg group. These changes were slight except for the cecal enlargement and the rats recovered well with drug withdrawal. Since no toxicologically significant changes were noted in either study, the NOAEL of S-1090 was estimated to be 1250 mg potency/kg/day in the one-month toxicity study and 1000 mg potency/kg/day in the three-month toxicity study.     

Developmental toxicity of di-(C(7)-C(9) alkyl) phthalate and di-(C(9)-C(11) alkyl) phthalate in the rat

Two phthalate esters, di-(C(7)-C(9) alkyl) phthalate (D79P) and di-(C(9)-C(11) alkyl) phthalate (D911P), have been assessed for their potential to cause developmental toxicity in the rat. Groups of 22 timed-mated Sprague-Dawley rats were administered 250, 500, or 1000 mg/kg D79P or D911P daily by oral gavage (5 ml/kg) between gestation days (GD) 1 and 19. Control animals received the vehicle (olive oil) alone. On GD20, the animals were sacrificed and the fetuses examined. Treatment resulted in no signs of maternal toxicity, as assessed by adjusted maternal bodyweight gain throughout gestation and clinical examinations, and no effects upon litter size, fetal survival or bodyweight. Pups of the high dose D79P and intermediate and high dose D911P groups showed increased incidences of supernumerary lumbar ribs. There was a significant increase in dilated renal pelves in pups of the low dose D79P and high dose D911P groups, but only for D911P was there a significant trend. Consequently, the no observed adverse effect level (NOAEL) for maternal toxicity for both D79P and D911P is 1000 mg/kg/day. The NOAEL values for developmental toxicity are 500 mg/kg/day D79P and 250 mg/kg/day D911P.     

Oral two-generation reproduction toxicity study with NM-200 synthetic amorphous silica in Wistar rats

Synthetic amorphous silica (SAS) like NM-200 is used in a wide variety of technological applications and consumer products. Although SAS has been widely investigated the available reproductive toxicity studies are old and do not cover all requirements of current OECD Guidelines. As part of a CEFIC-LRI project, NM-200 was tested in a two-generation reproduction toxicity study according to OECD guideline 416. Male and female rats were treated by oral gavage with NM-200 at dose levels of 0, 100, 300 and 1000 mg/kg bw/day for two generations. Body weight and food consumption were measured throughout the study. Reproductive and developmental parameters were measured and at sacrifice (reproductive) organs and tissues were sampled for histopathological analysis. Oral administration of NM-200 up to 1000 mg/kg bw/day had no adverse effects on the reproductive performance of rats or on the growth and development of the offspring into adulthood for two consecutive generations. The NOAEL was 1000 mg/kg body weight per day.     

Toxicity assessment of thiodiglycol

Sulfur mustard (HD) undergoes hydrolysis to form various products such as thiodiglycol (TG) in biological and environmental systems. TG is a precursor in the production of HD and it is also considered as a "Schedule 2" compound (dual-use chemicals with low to moderate commercial use and high-risk precursors). Several toxicological studies on TG were conducted to assess environmental and health effects. The oral LD(50) values were >5000 mg/kg in rats. It was a mild skin and moderate ocular irritant and was not a skin sensitizer in animals. It was not mutagenic in Ames Salmonella, Escherichia coli, mouse lymphoma, and in vivo mouse micronucleus assays, but it induced chromosomal aberrations in Chinese hamster ovarian (CHO) cells. A 90-day oral subchronic toxicity study with neat TG at doses of 0, 50, 500, and 5000 mg/kg/day (5 days/week) in Sprague-Dawley rats results show that there are no treatment-related changes in food consumption, hematology, and clinical chemistry in rats of either sex. The body weights of both sexes were significantly lower than controls at 5000 mg/kg/day. Significant changes were also noted in both sexes in absolute weights of kidneys, kidney to body weight ratios, and kidney to brain weight ratios, in the high-dose group. The no-observed-adverse-effect level (NOAEL) for oral toxicity was 500 mg/kg/day. The developmental toxicity conducted at 0, 430, 1290, and 3870 mg/kg by oral gavage showed maternal toxicity in dams receiving 3870 mg/kg. TG was not a developmental toxicant. The NOAEL for the developmental toxicity in rats was 1290 mg/kg. The provisional oral reference dose (RfD) of 0.4 mg/kg/day was calculated for health risk assessments. The fate of TG in the environment and soil showed biological formation of thiodiglycalic acid with formation of an intermediate ((2-hydroxyethyl)thio)acetic acid. It was slowly biodegraded under anaerobic conditions. It was not toxic to bluegill sunfish at 1000 mg/L and its metabolism and environmental and biochemical effects are summarized.     

Reproductive and developmental toxicity in F1 Sprague-Dawley male rats exposed to di-n-butyl phthalate in utero and during lactation and determination of its NOAEL

Di-n-butyl phthalate (DBP) is one of the commonly used plasticizers in China. DBP can enter the environment and organisms through various routes and then affect reproductive and developmental processes of the organism and its descendants (mainly affecting male offspring). It is known that animals are sensitive to exposure of DBP in utero and during lactation. In the present study, pregnant rats were treated with different doses of DBP (0, 50, 250, and 500 mg/kg body weight/day) by daily gavage from GD1 to PND21. The developmental condition of F1 rats and the reproductive system of mature F1 male rats were monitored. DBP had no obvious effect on pregnant rats; however, it reduced several parameters including birth weight, number of live pups per litter, body weight gain and male anogenital distance. Severe damage to the reproductive system of mature F1 male rats included testicular atrophy, underdeveloped or absent epididymis, undescended testes, obvious decline of epididymal sperm parameters, total sperm heads per g testis, decrease of organ/body weight ratio of epididymis and prostate, and was observed in the group treated with 250 mg/kg BW/day and higher. These results showed that the male reproductive system was the main target organ of DBP exposure. The NOAEL (no observable adverse effect level) for developmental toxicity of DBP was established based on pup body weight and male reproductive lesions at 50 mg/kg BW/day. Accordingly, the RfD for human exposure to DBP through oral intake was recommended as 500 mg/kg BW/day.     

Toxicity evaluation of a beta-galactosidase preparation produced by Penicillium multicolor

Tilactase is a beta-galactosidase enzyme preparation having lactase activity produced from the fungus Penicillium multicolor. The safety of tilactase was investigated in rats, dogs, and rabbits. Adult and juvenile rats administered 0, 500, 1000, or 4000 mg/kg bw/day of the enzyme preparation by gavage for 35 days, and dogs administered 0, 200, 500, or 1000 mg/kg bw/day in capsules for 30 days, exhibited no significant dose-related changes in body weights, feed consumption, organ weights, urinalysis, hematological profiles, clinical chemistry, or histopathological profiles. Rats receiving the same doses for 6 months also exhibited no dose-related effects, except for a small increase in the weight of the large intestine, an effect considered to be a physiological reaction to passage of a large amount of a non-absorbable substance. The no-observable-adverse-effect level (NOAEL) was 4000 mg/kg bw/day for rats and 1000 mg/kg bw/day for dogs. In three separate studies to examine reproductive and developmental toxicity, rats received 0, 250, 1000 or 4000 mg/kg bw/day by gavage up to the 7th day of pregnancy, during days 7-17 of pregnancy, and from day 17 of pregnancy to 21 days after delivery. There were no treatment-related effects on the dams, gestation period, numbers of implantations, parturition rates, sex ratios, or survival of offspring in any of the studies. No treatment-related external, internal, or skeletal abnormalities were observed in fetuses from any of the three studies. The NOAEL was 4000 mg/kg bw/day. In addition to the three rat studies, rabbits received 0, 250, 500, or 1000 mg/kg bw/day by gavage from the 6th to 18th day of pregnancy. No treatment-related changes were observed in the dams, or fertility indices; nor were there any treatment-related fetal abnormalities. The NOAEL was 1000 mg/kg bw/day. When viable P. multicolor spores were injected into the tail veins of mice, no deaths occured, no fungal cells were observed in various organs, and histopathology showed only focal necrosis in the liver of some of the animals, including the controls. Similar effects were observed when spores were administered to mice in a single dose by gavage. The particular strain of P. multicolor used to prepare tilactase is not pathogenic.     

Oral developmental toxicity study of methylsulfonylmethane in rats.

Methylsulfonylmethane (MSM) is a metabolite of dimethyl sulfoxide, and occurs naturally at low levels in many foods. MSM has received wide attention as a dietary supplement to promote joint health. The objective of these studies was to determine the developmental toxicity potential of MSM when administered orally to pregnant rats during the period of major organogenesis and histogenesis. In a preliminary dose-finding study, distilled MSM microprill (i.e., microspherical pellets of MSM) was administered by oral gavage at dose levels of 0 (vehicle control), 50, 250, 500, and 1000 mg/kg/day to 8-9 sperm-positive female Sprague-Dawley rats/group/day on gestation days 6-20. No evidence of maternal or fetal toxicity was observed. For the definitive developmental study, four groups of 24-25 timed-bred primiparous female rats were administered 0, 50, 500, or 1000 mg MSM/kg/day via gavage on gestation days 6-20. Maternal feed consumption, body weight, body weight gain, uterus weight and corrected body weight/body weight gain were unaffected by treatment. No evidence of maternal toxicity, and no significant differences in litter viability, litter size, or litter body weight were detected. Fetal evaluations failed to show any biologically significant increase in the incidence of anomalies in the MSM treated groups, and no malformations were seen in any of the fetuses. No evidence of fetal mortality, alterations to growth, or structural alterations were observed in the fetuses of dams administered 50-1000 mg/kg/day. Therefore, under the conditions of this study, the no-observed-adverse-effect level (NOAEL) for maternal and developmental toxicity was 1000 mg/kg/day.