Toxicological studies on the botanical supplement LI12542F6 containing extracts of Sphaeranthus indicus flower heads and Mangifera indica (mango tree) bark.

LI12542F6, a botanical extract composed of Sphaeranthus indicus and Mangifera indica, was evaluated for mutagenicity in bacteria, clastogenicity in mouse bone marrow, acute oral and dermal toxicity in the rat, irritation (dermal, eye) in rabbit, and subacute and subchronic toxicity (28 and 90 days) in the rat. All studies followed standard OECD test protocols, in accordance with the principles of Good Laboratory Practice (GLP). LI12542F6 did not induce mutations in the bacterial assay using Salmonella and Escherichia coli strains, nor did it induce genotoxic effects in erythrocytes from mouse bone marrow. LI12542F6 was found to have oral and dermal LD 50 values greater than the limit dose of 2,000 mg/kg body weight in the rat. In an eye irritation/corrosion test, LI12542F6 caused conjunctival redness, corneal opacity, and chemosis and is classified as Category 2A ("irritating to eyes - reversible eye effect"). Doses in the 28-day and 90-day rat oral toxicity studies were 0, 500, 1,000, and 1,500 and 0, 1,000, 1,500, and 2,000 mg/kg body weight/day, respectively, administered by gavage. Both studies featured a recovery period. Minor effects were random and not treatment related except for local irritation of the forestomach in the 28-day study, evidenced by histopathologic examination, in mid- and high-dose animals. The frequency and severity of these effects were reduced in the recovery group; irritation was not found in the forestomach of rats in the 90-day study. The no observed adverse effect level (NOAEL) was greater than the highest dose tested, that is, >2,000 mg/kg in the 90-day study. This botanical composition will be marketed commercially for muscle health as Myotor™.

Critical review of the current literature on the safety of sucralose.

Sucralose is a non-caloric high intensity sweetener that is approved globally for use in foods and beverages. This review provides an updated summary of the literature addressing the safety of use of sucralose. Studies reviewed include chemical characterization and stability, toxicokinetics in animals and humans, assessment of genotoxicity, and animal and human feeding studies. Endpoints evaluated include effects on growth, development, reproduction, neurotoxicity, immunotoxicity, carcinogenicity and overall health status. Human clinical studies investigated potential effects of repeated consumption in individuals with diabetes. Recent studies on the safety of sucralose focused on carcinogenic potential and the effect of sucralose on the gut microflora are reviewed. Following the discovery of sweet taste receptors in the gut and studies investigating the activation of these receptors by sucralose lead to numerous human clinical studies assessing the effect of sucralose on overall glycemic control. Estimated daily intakes of sucralose in different population subgroups, including recent studies on children with special dietary needs, consistently find that the intakes of sucralose in all members of the population remain well below the acceptable daily intake. Collectively, critical review of the extensive database of research demonstrates that sucralose is safe for its intended use as a non-caloric sugar alternative.

Safety of micronized palmitoylethanolamide (microPEA): lack of toxicity and genotoxic potential.

Palmitoylethanolamide (PEA) is a natural fatty acid amide found in a variety of foods, which was initially identified in egg yolk. MicroPEA of defined particle size (0.5-10 µm) was evaluated for mutagenicity in Salmonella typhimurium, for clastogenicity/aneuploidy in cultured human lymphocytes, and for acute and subchronic rodent toxicity in the rat, following standard OECD test protocols, in accordance with Good Laboratory Practice (GLP). PEA did not induce mutations in the bacterial assay using strains TA1535, TA97a, TA98, TA100, and TA102, with or without metabolic activation, in either the plate incorporation or liquid preincubation methods. Similarly, PEA did not induce genotoxic effects in human cells treated for 3 or 24 h without metabolic activation, or for 3 h with metabolic activation. PEA was found to have an LD50 greater than the limit dose of 2000 mg/kg body weight (bw), using the OECD Acute Oral Up and Down Procedure. Doses for the 90-day rat oral toxicity study were based on results from the preliminary 14-day study, that is, 250, 500, and 1000 mg/kg bw/day. The No Effect Level (NOEL) in both subchronic studies was the highest dose tested.

A reassessment of risk associated with dietary intake of ochratoxin A based on a lifetime exposure model.

Mycotoxins, such as ochratoxin A (OTA), can occur from fungal growth on foods. OTA is considered a possible risk factor for adverse renal effects in humans based on renal tumors in male rats. For risk mitigation, Health Canada proposed maximum limits (MLs) for OTA based largely on a comparative risk assessment conducted by Health Canada (Kuiper-Goodman et al., 2010), in which analytical data of OTA in foods were used to determine the possible impact adopting MLs may have on OTA risks. The EU MLs were used for comparison and resultant risk was determined based on age-sex strata groups. These data were reevaluated here to determine comparative risk on a lifetime basis instead of age strata. Also, as there is scientific disagreement over the mechanism of OTA-induced renal tumors, mechanistic data were revisited. On a lifetime basis, risks associated with dietary exposure were found to be negligible, even without MLs, with dietary exposures to OTA three to four orders of magnitude below the pivotal animal LOAEL and the TD(05). Our review of the mechanistic data supported a threshold-based mechanism as the most plausible. In particular, OTA was negative in genotoxicity assays with the highest specificity and levels of DNA adducts were very low and not typical of genotoxic carcinogens. In conclusion, OTA exposures from Canadian foods do not present a significant cancer risk.

Thresholds of toxicological concern for endocrine active substances in the aquatic environment.

The threshold of toxicological concern (TTC) concept proposes that an exposure threshold value can be derived for chemicals, below which no significant risk to human health or the environment is expected. This concept goes further than setting acceptable exposure levels for individual chemicals, because it attempts to set a de minimis value for chemicals, including those of unknown toxicity, by taking the chemical's structure or mode of action (MOA) into consideration. This study examines the use of the TTC concern concept for endocrine active substances (EAS) with an estrogenic MOA. A case study formed the basis for a workshop of regulatory, industry and academic scientists held to discuss the use of the TTC in aquatic environmental risk assessment. The feasibility and acceptability, general advantages and disadvantages, and the specific issues that need to be considered when applying the TTC concept for EAS in risk assessment were addressed. Issues surrounding the statistical approaches used to derive TTCs were also discussed. This study presents discussion points and consensus findings of the workshop.

Pulmonary applications and toxicity of engineered nanoparticles.

Because of their unique physicochemical properties, engineered nanoparticles have the potential to significantly impact respiratory research and medicine by means of improving imaging capability and drug delivery, among other applications. These same properties, however, present potential safety concerns, and there is accumulating evidence to suggest that nanoparticles may exert adverse effects on pulmonary structure and function. The respiratory system is susceptible to injury resulting from inhalation of gases, aerosols, and particles, and also from systemic delivery of drugs, chemicals, and other compounds to the lungs via direct cardiac output to the pulmonary arteries. As such, it is a prime target for the possible toxic effects of engineered nanoparticles. The purpose of this article is to provide an overview of the potential usefulness of nanoparticles and nanotechnology in respiratory research and medicine and to highlight important issues and recent data pertaining to nanoparticle-related pulmonary toxicity.

Chromosome aberration test of Pigment Yellow 34 (lead chromate) in Chinese hamster ovary cells.

Lead chromate pigment in the form of the commercial pigment, Pigment Yellow 34, CAS No. 1344-37-2, used in the plastics and coatings industries, did not induce chromosome aberrations in Chinese hamster ovary (CHO) cell line WB(L). Lead chromate pigment is essentially insoluble in water, and in an effort to test the material under realistic conditions, no attempt to solubilize the pigment was made. These results are significant because others have reported lead chromate to cause genotoxicity in various assays, but only under conditions in which its aqueous solubility was artificially enhanced.

Method for calculating ADI-derived guidance values for drug carryover levels in medicated feeds.

There exists the possibility that non-target livestock may receive trace exposure to medications in feed due to residue carryover from previous production runs of medicated feeds at feed mills. We have developed a method by which ADI-Derived Drug Carryover Levels (ADCLs) can be established. It is a practical approach compared to the "zero" levels of residue carryover that may be expected or required by regulatory authorities. The methodology involves application of various safety/uncertainty factors to concentrations of active ingredients (a.i.) already approved for use in medicated feeds for target species. The starting point for each a.i., to be consistent, and to represent the highest possible carryover, is the highest approved concentration for any target animal species, recognizing that this is an approved level based on established ADI and agency review of supporting safety data specific to each a.i. (Hence, these guidance values are characterized to be 'ADI-derived'.) Safety factors are then applied to account for: (a) interspecies extrapolation, (b) differences in the body weights of target and non-target species (i.e., smaller animals receive higher exposures on a body weight basis for a given dietary concentration), (c) a.i. with clear contraindications for use in certain non-target species (i.e., a priori knowledge of non-target species sensitivity), and (d) withdrawal times (i.e., for a.i. that require a washout period prior to slaughter there is potential exposure to non-target species through other feeds not requiring a washout period). The values of the safety/uncertainty factors range from 1 to 3, 1 to 3.17, 1 to 10, and 1 to 10, for each of conditions (a), (b), (c), and (d), respectively. The "proposed safety factor" to apply to the approved concentration in medicated feed is calculated as the product of the values for each of (a) through (d). The final safety factor is the greater of the proposed safety factor or a default minimum safety factor of 30. ADCLs were calculated for several a.i. and compared to limits of quantitation available for detection of carryover residues in animal feeds. This methodology may be used in its present or modified form in any jurisdiction in which mediated feeds are approved. As a start, this approach has been applied to several example products approved and in use in Canada.

An innovative model for regulating supplement products: natural health products in Canada.

On 1 January 2004, Health Canada officially added a new term to the global list of synonyms for dietary supplements: natural health products (NHP). Developed with the intent of providing Canadian consumers with ready access to NHP that are safe, effective, and of high quality, the Natural Health Products Regulations (the NHP regulations) are applicable to the sale, manufacture, packaging, labelling, importation, distribution, and storage of NHP, and are administered by the recently formed Natural Health Products Directorate (NHPD) within Health Canada. This paper provides an overview of the process for regulating supplement products in Canada.