Novel food information - Meal replacements and formulated liquid diets with added Calcium 3-hydroxy-3-methyl butyrate monohydrate (CaHMB)

Health Canada has notified Abbott Laboratories that it has no objection to the sale of their meal replacements and formulated liquid diets with added calcium 3-hydroxy-3-methyl butyrate monohydrate (CaHMB), manufactured as characterized in the information provided to the Food Directorate. The addition of CaHMB (as a source of HMB) is permitted at up to 1.5 g per serving^{Footnote *}, and in a manner to achieve a daily intake by adults of not more than 6 g^{Footnote *}. The CaHMB, its method of manufacture, and its chemical profile must be as characterized in the information submitted to the Food Directorate.

The safety of CaHMB was assessed according to Division 28 of the Food and Drug Regulations (FDR), because CaHMB is best described as "a substance that does not have a history of safe use as a food." The Food Directorate (FD) has conducted the safety assessments according to its Guidelines for the Safety Assessment of Novel Foods. These guidelines are based upon internationally accepted principles for establishing the safety of novel foods.

Background

The following provides a summary of the notification from Abbott Laboratories and the evaluation by Health Canada, but contains no confidential business information.

1. Introduction

Calcium 3-hydroxy-3-methylbutyrate monohydrate (CaHMB), also known as calcium beta-hydroxy-beta-methylbutyrate or calcium beta-hydroxyisovalerate, has the Chemical Abstracts Services (CAS) Registry Number 135236-72-5. 3-Hydroxy-3-methyl butyrate monohydrate (HMB) is present naturally in a small number of foods at very low levels (in µg quantities). Some examples are avocado, citrus fruit, cauliflower, alfalfa and some fish species.

2. Product Development/Formulation

The CaHMB used by the petitioner is produced synthetically from a proprietary process.

3. Dietary Exposure

The petitioner's exposure report included modelling to calculate the estimated all-user one-day mean and the 90th percentile CaHMB consumption from the dietary intake from all meal replacement products in the US. The estimated all-user mean and 90th percentile intakes of calcium HMB within the total population were estimated to be 2,290 and 4,295 mg/person/day, respectively [2003-2004 and 2005-2006 National Health and Nutrition Examination Surveys (NHANES)]. Within the U.S. population, approximately 2.2% of adults were identified as potential consumers of meal replacement beverages in which CaHMB is proposed for inclusion as a source of HMB.

An exposure assessment was conducted by Health Canada using Canadian Community Health Survey - (CCHS) 2.2 survey data. Foods for Special Dietary Use of relevance were compared to CCHS nutrition survey list of foods, and the CaHMB concentration in grams per 100 g was calculated for each food declared in the survey. One day all users mean exposure, the median, 75th, 90th and 95th percentile intakes were estimated. Health Canada's exposure assessment was able to confirm that the petitioner's estimated intakes are acceptable.

4. Chemical Assessment

Extensive information about the manufacturing processes and controls, as well as analytical results for potential residues of contaminants and impurities in the finished CaHMB were provided by the petitioner. This information could not be compared against published food-grade specifications for CaHMB as such specifications are not currently available. However, Health Canada evaluated the analytical results provided by the petitioner and identified no concerns from a chemical food-safety perspective regarding the use of CaHMB as proposed by the petitioner.

5. Microbiological Assessment

Microbiological specifications were provided by the petitioner. It is unlikely that the addition of CaHMB manufactured as characterized in the information provided to the Food Directorate at the levels proposed to the foods would affect the microbiological safety of the foods to which it is added. It is the continuing responsibility of the manufacturer and the producers of the final foods to ensure that his products are in compliance with Part I, Section 4, of the Food and Drugs Act.

6. Nutrition

CaHMB is proposed as an ingredient for Foods for Special Dietary Use for specific target populations. The petitioner indicates that the intended effect of CaHMB, as a source of HMB in meal replacements and formulated liquid diets, is to help support gain and/or maintenance of lean body mass. The target population is adults with, or at risk for malnutrition and muscle wasting, and elderly individuals with, or at risk of age-related loss of muscle mass and strength. Muscle growth depends on the net balance between protein synthesis and degradation.

HMB is a metabolite of the amino acid leucine. The first step in leucine metabolism is its transamination to alpha-ketoisocaproate (KIC). KIC is then metabolized to HMB by the enzyme KIC-dioxygenase. Approximately 5-10% of leucine is converted to HMB via human metabolism. The remaining 90-95% is metabolized to other substances such as isovaleryl-CoA and HMG-CoA.

The petitioner proposes that inhibition of protein degradation following leucine administration may be related to increases in the metabolites KIC or HMB. The ingestion of HMB directly has been postulated to circumvent the reversible conversion of leucine to KIC thereby reducing protein degradation. There is some evidence to suggest that those consuming CaHMB had increased gains in muscle in response to exercise compared to unsupplemented subjects. No assessment of the purported health benefit was conducted by the Food Directorate.

Health Canada also assessed the impact on calcium intakes from the consumption of CaHMB. As described by the petitioner, in extreme cases, the consumption of CaHMB included in meal replacements could approach 6.0 g per day (4 servings), providing 800 mg of calcium per day. This is not considered to pose a health risk to consumers. Meal replacements are required to contain calcium at 200-400 mg per serving (from all sources). Formulated liquid diets must be formulated as described in Division 24 of the Food and Drug Regulations. Formulated liquid diets are required to have a minimum of 400 mg of calcium (from all sources) per 1000 or 1500 available kilocalories (depending on energy needs) where the recommended intake is more or less than 2500 kcal. Formulated liquid diets should be manufactured in a manner such that CaHMB intakes do not exceed 6.0 g per day. Further, patients being prescribed formulated liquid diets are normally under medical supervision, with their diets closely monitored.

7. Toxicology

The petitioner provided toxicological data to support the safe use of CaHMB. All toxicological studies were conducted according to internationally accepted OECD guidelines for the testing of chemicals and were in compliance with the principles of Good Laboratory Practices according to the FDA/OECD. The studies were sufficient to determine the safety of the product when used as proposed by the petitioner. The toxicology assessment included a short-term oral toxicity study genotoxicity studies, and developmental oral toxicity studies, clinical studies in humans, a safety assessment of impurities associated with CaHMB, and an assessment of ingredients allergenicity.

Conclusion

Health Canada has no objection to the sale by Abbott Laboratories Ltd. in meal replacements and formulated liquid diets with added calcium 3-hydroxy-3-methyl butyrate monohydrate (CaHMB), manufactured as characterized in the information provided to the Food Directorate. The addition of CaHMB is permitted at up to 1.5 g^{Footnote *} CaHMB per serving, and in a manner such that daily intake of CaHMB does not exceed 6 g^{Footnote *} in adults.

Health Canada's non-objection decision with respect to this addition of CaHMB is contingent, in part, on the chemical safety information provided to the Food Directorate. Any change to the manufacturing process for the CaHMB could result in a product with a different chemical profile than what has been reviewed and was considered to be acceptable from a chemical food-safety perspective. In addition, there are no published food-grade specifications for CaHMB which this CaHMB can be considered against. Therefore, any other food manufacturer or distributor who intends to sell foods with added CaHMB must notify the Food Directorate, in accordance with Division 28 of the Food and Drug Regulations. Similarly, the sale of CaHMB manufactured in any manner other than that reviewed by the Food Directorate would also trigger the requirement to notify the Food Directorate as per Division 28.