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Safety Report
The preceding time line provides the reader with a summarizing overview of the tortuous path a seemingly innocuous starch product has taken to become considered “generally recognized as safe (GRAS)”. The lingering concern is - if it took 40 years for a natural starch product to achieve a somewhat restricted GRAS status, how long will be required for a chemically modified starch product to attain status that will allow it to be used commercially? The initial determination of BCyclodextrin’s safety status in rats by Dr. French in 1957 used data not much more than aneCyclodextrinotal; however, it probably deterred serious consideration of BCyclodextrin for use with food products in the US at least 10 – 15 years. Probably Dr. French’s BCyclodextrin had significant residual levels of toluene, at that time the most commonly used organic solvent to precipitate BCyclodextrin from the reaction mixture of ACyclodextrin, BCyclodextrin, and GCyclodextrin produced by enzymically treating starch. Since the BCyclodextrin/toluene precipitation method was probably the least expensive method at the time for isolating BCyclodextrin, it is likely that Dr. French’s supplier provided material that had not been processed completely to remove all the toluene. It is not surprising, then, that the rats died after a week of eating such material. The fact that 6 years later, Dr. Andersen reported no toxicity when rats were fed a diet of either 1% BCyclodextrin or ACyclodextrin did little to debunk the 1957 report. It’s human nature to believe the negative and to consequently feel righteous in taking the conservative approach based on such information no matter how aneCyclodextrinotal or circumstantial. Studies reported by Japanese investigators (Hayashi – 1971 and Makita – 1975) further provided additional data supporting BCyclodextrin’s safety in rats; Dr. Hayashi’s studies even included IV dosing in rats. It is unlikely that this data was considered in the US; so for the US, BCyclodextrin was still perceived to be unsafe for humans. It is important to note that Japanese manufacturers of BCyclodextrin did not commercially use organic solvents to isolate BCyclodextrin. In 1976 came the final nail in the coffin for the use of BCyclodextrin commercially in the US at least for the next 20 years. Dr. Frank reported toxicity in rats given IV and subcutaneous injections of BCyclodextrin. In 1978 Dr. John Perrin at the University of Florida corroborated the finding of renal toxicity in rats after i.p. dosing. If Dr. Szejtli’s group in Hungary had not undertaken the task in the early 80’s of showing rigorously what the limits of safety for BCyclodextrin were, the US would still not be any closer in 1999 to commercial application of BCyclodextrin. Between 1979 and 1985 Dr. Szejtli’s group at Cyclolab published the results of their rigorous toxicity and safety studies for BCyclodextrin. In the early 1980’s, a Japanese manufacturing company attempted to obtain FDA approval for BCyclodextrin and ACyclodextrin through a US intermediary. Unfortunately the data for ACyclodextrin and BCyclodextrin were switched in the submitted documents and the resultant loss of credibility caused the Japanese manufacturer to withdraw the submission. By the mid 1980’s BCyclodextrin had found its way into a sufficient number of products sold in Japan and Europe that the World Health Organization felt it necessary to establish some guidelines for the use in humans of these natural starch products. It is not clear how the published levels of 0 – 5 mg/kg bw/day were determined, but finally a prestigious organization published a guideline that broke the logjam of officious concern. The problems and concerns of safety surrounding BCyclodextrin brought to the forefront the fact that excipients had no formal process for being determined safe. Heretofore, an excipient simply appeared in various pharmacopoeias as the commercial usage became so great that the quantities ingested by humans could no longer be ignored. In the US, all current excipients had been grandfathered in as GRAS (Generally Recognized as Safe); no truly new excipients had come on the scene in 50 years. Not only was BCyclodextrin new, it created a need for broader definitions of an excipient. In response to this need for standardization of excipients, and, to go further, the global harmonization of the standards for excipients, IPEC (International Pharmaceutical Excipients Council) was created. While IPEC dealt with other excipients than BCyclodextrin, its creation and efforts directed attention to the plight of BCyclodextrin and surely hastened any formal acceptance that has been achieved. In 1992 American Maize Products Co. of the US and Roquette Freres of France joined forces to undertake an approval process for BCyclodextrin using expert scientific testimony to obtain GRAS confirmations from the US FDA. GRAS confirmation is not an approval, but an acknowledgment by the FDA that due scientific diligence has been applied before a non-GRAS material was incorporated into human food products. The fact that two major manufacturers of BCyclodextrin would incur the expense of this CYA approach is testament to the importance these two companies placed on future uses of BCyclodextrin in food products. After a falling out between these two manufacturers, a withdrawal and a resubmission of a request based on a different use, BCyclodextrin finally, officially achieved GRAS status through the GRAS petitioning procedure in November of 1997. This author shudders to think how long it will take a chemically modified Cyclodextrin to achieve an official use status when a truly natural product had to go through all the above to achieve even the tenuous approval it has. |
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