HOMEODISP- USE OF MCCP AS DISPENSING VEHICLE MAY REVOLUTIONIZE HOMEOPATHIC PRACTICE

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Introduction of HOMEODISP or Microcrystalline Cellulose Powder as a better alternative to sugar of milk and cane sugar in homeopathic dispensing is of course a part of scientific redefining of homeopathic practice. Actually, it is one of the great inventions that happened in homeopathy after the period of Samuel Hahnemann. It may take some time for homeopathic community to recognize it’s revolutionary implications, but it will happen gradually.

One of the wonderful properties of Microcrystalline Cellulose Powder is it’s extraordinarily high adsorption capacity. 1gm of MCCP can adsorb and hold more than 1 ml potentized drug. In the picture shown above, I have taken 20 gms of MCCP in a vial and added 20ml of potentized drug. Still it remains dry, powdery, uncaked and free flowing. This high adsorption capacity is one of the reason why I am saying MCCP is superior to lactose and cane sugar for using as homeopathic dispensing vehicle.

MCCP is chemically inert, and will not interact with water or alcohol contained in potentized drugs. It simply adsorbs the medicines on to the periphery of microcrystals of cellulose. Once put in the mouth, MCCP easily disperses into individual microcrystals and releases the whole medicinal content into buccal cavity, wherefrom it is absorbed into blood stream through the walls of buccal capillaries.

Since our digestive enzymes cannot split cellulose into constituent glucose molecules MCCP passes through the intestinal tract totally undigested. As such, MCCP has no any nutritional or caloric value, unlike lactose and cane sugar which are digested and absorbed into the system as glucose. Obviously, MCCP is more safe to diabetic patients. This factor also makes MCCP an ideal dispensing vehicle.

Potentized homeopathic medicines are currently dispensed as medicated sugar pills or sugar of milk. MCCP is proved to be a better alternative for this purpose.

Sugar pills commonly used for homeopathic dispensing are made of cane sugar or sucrose. Sucrose is the organic compound belonging to the class of ‘carbohydrates’, commonly known as table sugar and sometimes called saccharose. A white, odorless, crystalline powder with a sweet taste, it is best known for its role in food. The molecule is a disaccharide composed of the monosaccharides glucose and fructose with the molecular formula C12H22O11.

Sugar of milk or Lactose is a disaccharide sugar found in milk. It has a formula of C12H22O11. Lactose is a disaccharide derived from the condensation of monosacharides galactose and glucose, which form a β-1→4 glycosidic linkage. Its systematic name is β-D-galactopyranosyl-(1→4)-D-glucose. The glucose can be in either the α-pyranose form or the β-pyranose form, whereas the galactose can only have the β-pyranose form: hence α-lactose and β-lactose refer to anomeric form of the glucopyranose ring alone. Lactose is hydrolysed to glucose and galactose, isomerised in alkaline solution to lactulose, and catalytically hydrogenated to the corresponding polyhydric alcohol, lactitol. Lactose crystals have a characteristic tomahawk shape that can be observed with a light microscope.

Both sucrose and lactose, used in homeopathic pharmacy, could be hydrolyzed into their sub-units by digestive enzymes, and absorbed into blood stream.

HOMEODISP or Ultra-purified Pharmaceutical Grade Microcrystalline Cellulose Powder I.P is a better alternative to cane sugar and lactose for dispensing homeopathic medicines.

Cellulose is an organic compound with the formula (C6H10O5)n, a polysaccharide consisting of a linear chain of several hundred to over ten thousand D-glucose units. Cotton fibers represent the purest natural form of cellulose, containing more than 90% of this polysaccharide. In many ways, cellulose makes the ideal excipient for pharmaceuticals as well as food articles. A naturally occurring polymer, it is composed of glucose units connected by a 1-4 beta glycosidic bond. These linear cellulose chains are bundled together as microfibril spiralled together in the walls of plant cell. Each microfibril exhibits a high degree of three-dimensional internal bonding resulting in a crystalline structure that is insoluble in water and resistant to reagents. There are, however, relatively weak segments of the microfibril with weaker internal bonding. These are called amorphous regions but are more accurately called dislocations since microfibril containing single-phase structure. The crystalline region is isolated to produce microcrystalline cellulose.

Microcrystalline cellulose is a term for refined wood pulp and is used as a texturizer, an anti-caking agent, a fat substitute, an emulsifier, an extender, and a bulking agent in food production.The most common form is used in vitamin supplements or tablets. It is also used in plaque assays for counting viruses.

Microcrystalline Cellulose powder is subjected to an ultra-purification process to make pharmaceutical grade MCCP .IP, which is distributed as HOMEODISP.

Experiments have been conducted in homeopathic dispensing by using cellulose, both as cotton fibers as well as microcystalline cellulose powder (MCCP). Small quantity of pure MCCP were moistened with potentized drugs selected as similimum, and kept until it is dried and advised the patients to keep it under tongue for some time. It acted very promptly, much better than when administered by other conventional means. By keeping under tongue for extended periods, the molecular imprints adsorbed in the microcrystalline cellulose gets gradually released, thereby ensuring appropriate exposure and availability.

Since our digestive enzymes cannot break the cellulose into glucose, MCCP is safer to be administered even to diabetic patients.

HOMEODISP is available in powder as well as tablet forms.

 Responding to my proposition that MICROCRYSTALLINE CELLULOSE could be a superior substitute to LACTOSE and CANE SUGAR as dispensing vehicles for potentized homeopathic drugs, many friends asked me to provide more details regarding the safety studies of MCCP. Hence I am posting here World Health Organization Report on Microcrystalline Cellulose, prepared by the forty-ninth meeting of the Joint FAO/WHO Expert Committee on Food Additives (JECFA), World Health Organization, Geneva 1998. First draft prepared  by Dr J.B. Greig, Department of Health, Skipton House, 80 London Road, London, SE1 6LW, UK

 

This report contains a detailed overview, evaluation and comments upon hundreds of studies done regarding Biochemical aspects (Absorption, distribution and excretion), Acute toxicity of microcrystalline cellulose in animals, Short-term toxicity studies, Long-term toxicity/carcinogenicity studies, Reproductive toxicity studies, Special studies on embryotoxicity and teratogenicity, Special studies on genotoxicity, Special studies on sensitization, Special studies on skin and eye irritation, Special studies on effects of cellulose fibre on tumour growth,  Toxicity consequent to substance abuse,  Changes in gastrointestinal function and nutrient balance etc with complete references.

“The Committee concluded that the toxicological data from humans  and animals provided no evidence that the ingestion of  microcrystalline cellulose can cause toxic effects in humans when used  in foods according to good manufacturing practice”.

The committee concludes the report with the following statement:

“Persorption of microcrystalline cellulose was reported in various species, which included rats, in early studies. A recent study in which a special fine particle size preparation of microcrystalline  cellulose (median diameter of particles 6 µm) was administered orally to rats (5 g/kg bw per day) for 90 days has failed to confirm the earlier observations. In this study precautions were taken to ensure that, at autopsy, there was no cross-contamination of the tissues with fine particulate matter.

In various parenteral studies of the acute toxicity of microcrystalline cellulose in animals there have been signs consistent with a tissue response to foreign particles. Similarly, microcrystalline cellulose has been associated with the formation of granulomas in human lung when it has been injected intravenously during drug abuse. No such lesions have been described as a consequence of oral ingestion of microcrystalline cellulose by rats or humans.

In 90-day toxicity tests during which microcrystalline cellulose was administered to rats in the diet at concentrations of 2.5 to 50%, increased consumption of food to compensate for the content of this material was observed. Although this may have some effects on mineral absorption there was, in general, no compound-related systemic toxicity. The NOEL exceeded 50 g/kg diet, at which dose level the mean intakes of microcrystalline cellulose by male and female rats were 3.8 and 4.4 g/kg bw per day, respectively.

A two-year feeding study of microcrystalline cellulose in rats was brought to the attention of the Committee. Despite a lack of evidence of toxic effects, the Committee considered that the execution and reporting of the study were not adequate to identify a NOEL.

In vitro and  in vivo genotoxicity studies were negative.

In a three-generation reproductive toxicity study in rats that had been reviewed by an earlier Committee, there were some effects of using 30% microcrystalline cellulose in the diet; these had been considered to be a consequence of the quantity of material reducing the energy density of the diet. However, in recent embryotoxicity and teratogenicity studies in rats there was no evidence of compound-related effects at dietary levels up to 50 g of microcrystalline cellulose per kg diet (equal to 4.6 g/kg bw per day), given on days 6 to 15 of pregnancy.

In some human studies there have been reports of alterations to gastrointestinal function following ingestion of microcrystalline cellulose. The changes do not appear to be related to systemic toxicity”

Microcrystalline cellulose is a purified, partially depolymerzed cellulose prepared by treating alpha-cellulose, obtained as a pulp from fibrous plant material, with mineral acids. The degree of polymerization is typically less than 400. Not more than 10% of the material has a particle size of less than 5 nanometer. Insoluble in water, ethanol, ether and dilute mineral acids. Slightly soluble in sodium hydroxide solution.

Microcrystalline cellulose (C6H10O5)n is refined wood pulp. It is a white, free-flowing powder. Chemically, it is an inert substance, is not degraded during digestion and has no appreciable absorption. In large quantities it provides dietary bulk and may lead to a laxative effect.

Microcrystalline cellulose is a commonly used excipient in the pharmaceutical industry. It has excellent compressibility properties and is used in solid dose forms, such as tablets. Tablets can be formed that are hard, but dissolve quickly. Microcrystalline cellulose is the same as cellulose, except that it meets USP standards.

It is also found in many processed food products, and may be used as an anti-caking agent, stabilizer, texture modifier, or suspending agent among other uses. According to the Select Committee on GRAS Substances, microcrystalline cellulose is generally regarded as safe when used in normal quantities.

The most common form is used in vitamin supplements or tablets. It is also used in plaque assays for counting viruses, as an alternative to carboxymethylcellulose.

A naturally occurring polymer, it is composed of glucose units connected by a 1-4 beta glycosidic bond. These linear cellulose chains are bundled together as microfibril spiralled together in the walls of plant cell. Each microfibril exhibits a high degree of three-dimensional internal bonding resulting in a crystalline structure that is insoluble in water and resistant to reagents. There are, however, relatively weak segments of the microfibril with weaker internal bonding. These are called amorphous regions; some argue that they are more accurately called dislocations, because of the single-phase structure of microfibrils. The crystalline region is isolated to produce microcrystalline cellulose.

Approved within the European Union as a thickener, stabilizer or emulsifiers microcrystalline cellulose was granted the E number E460(i) with basic cellulose given the number E460.

Microcrystalline cellulose (MCC) is pure partially depolymerized cellulose synthesized from α-cellulose precursor. The MCC can be synthesized by different processes such as reactive extrusion, enzyme mediated, steam explosion and acid hydrolysis. The later process can be done using mineral acids such as H2SO4, HCl and HBr as well as ionic liquids. The role of these reagents is to destroy the amorphous regions remaining the crystalline domains. The degree of polymerization is typically less than 400. The MCC particles with size lower than 5 µm must not be more than 10%. The MCC is a valuable additive in pharmaceutical, food, cosmetic and other industries. Different properties of MCC are measured to qualify its suitability to such utilization, namely particle size, density, compressibility index, angle of repose, powder porosity, hydration swelling capacity, moisture sorption capacity, moisture content, crystallinity index, crystallite size and mechanical properties such as hardness and tensile strength. Thermogravimetric analysis (TGA) and differential thermal analysis (DTA) or differential scanning calorimetry (DSC) are also important to predict the thermal behavior of the MCC upon heat stresses.

Microcrystalline cellulose is a widely used excipient, an inert substance used in many pill and tablet formulations. As an insoluble fiber, microcrystalline cellulose is not absorbed into the blood stream, so it cannot cause toxicity when taken orally. In fact, it is so inert it is often used as a placebo in controlled drug studies. However, some side effects have been noted in animal studies, although usually at much higher dosages than would be normal for a human subject.

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World Health Organization Report on Microcrystalline Cellulose

INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY WORLD HEALTH ORGANIZATION- SAFETY EVALUATION OF CERTAIN FOOD ADDITIVES AND CONTAMINANTS – WHO FOOD ADDITIVES SERIES 40-  Prepared by: The forty-ninth meeting of the Joint FAO/WHO Expert Committee on Food Additives (JECFA).  World Health Organization, Geneva 1998 –  First draft prepared     by Dr J.B. Greig Department of Health, Skipton House, 80 London Road, London, SE1 6LW, UK

EXPLANATION

Microcrystalline cellulose was evaluated at the fifteenth, seventeenth and nineteenth meetings of the Committee (see Annex 1, references 26, 32 and 38). At the nineteenth meeting an ADI “not specified” was allocated. In the light of concern about possible persorption and consequential adverse effects of fine particles, the substance was re-evaluated at the present meeting.

BIOLOGICAL DATA

Biochemical aspects-  Absorption, distribution and excretion

Rats

Four rats were fed 14C-labelled microcrystalline cellulose at 10 or 20% of their diet. No evidence of degradation or digestion was noted. Faecal recoveries of radioactivity ranged from 96-104% and were complete for all labelled material. No radioactivity appeared in the urine (Baker, 1966).

A study was specifically designed to investigate the possibility that persorption of microcrystalline cellulose might induce toxicological effects. Groups of male and female Sprague-Dawley CD rats (20 per group) from Charles River Laboratories were administered, by gavage, suspensions of a special fine particle-size microcrystalline cellulose (median particle size 6 µm). The rats were dosed orally daily for 90 consecutive days at a level of 5000 mg/kg bw per day by means of a 25% suspension in tap water. The animals were killed on study days 91-94 and necropsies were carried out under conditions that reduced the possibility of contamination of tissues with fine particulates. The birefringent microcrystalline cellulose particles were not detected in any organ or tissue, including gut-associated lymphoid tissue, liver, lung, spleen and brain. The size limit for detection of the particles was considered to be < 1 µm (Kotkoskie  et al., 1996; FMC Corporation N.V., 1996

Humans

One human subject received 150 g of microcrystalline cellulose daily in two portions for a 15-day adaptation period. He then received 14C-labelled microcrystalline cellulose (47.6 µCi) in two portions on one day. Supplementation of the diet with unlabelled microcrystalline cellulose continued for 10 days. Twenty-four-hour faecal and urine collections were examined for radioactivity. No radioactivity appeared in the urine or in the expired CO2. All administered radioactivity (98.9 ± 3.0%) was recovered from the faeces within two days (Baker, 1968).

Metabolism of a preparation of 14C-labelled cellulose by four volunteers has been shown to be increased by the consumption, for a period of 3 months, of an additional 7 g/per day of dietary fibre. In six subjects with an ileostomy, the cumulative excretion of 14CO2 was lower than in controls. In two constipated subjects metabolism appeared to be more extensive and occurred over a longer period (Walters  et al., 1989).

Examination of the stools of one male and one female patient given 30 g microcrystalline cellulose as dry flour or gel for 5´ weeks showed the presence of undegraded material of the same birefringence as the original microcrystalline cellulose administered. No significant effects on the human gastrointestinal tract were noted during the administration (Tusing  et al., 1964).

Most (87%) of the radiolabel associated with 131I-labelled alpha-cellulose fibres (retained by a sieve with pores of 1 mm diam) was excreted by 4 male and 4 female volunteers within 5 days of ingestion. Less than 2% of the faecal radiolabel was unbound; urinary excretion of unbound radio-iodine accounted for another 1.9% of the total dose (Carryer  et al., 1982).

Other studies have been carried out to demonstrate the relationship between persorbability and size and consistency of granules. Using quartz sand, the upper limit for persorbability was shown to be 150 µm. Starch granules must be structurally largely intact to possess the property of persorbability. Persorbed starch granules may be eliminated in the urine, pulmonary alveoli, peritoneal cavity, cerebrospinal fluid, via lactating milk and transplacentally (Volkheimer  et al., 1968).

In another study, dyed plant foods (oatmeal, creamed corn) were fed to human subjects, and blood and urine were examined for coloured fibres. Dyed fibres were shown to be present (Schreiber, 1974).

Lycopodium spores and pollen grains have also been shown to be persorbed by humans (Linskens & Jorde, 1974).

Mean intake of dietary microcrystalline cellulose in the USA has been estimated to range from 2.7 g/person per day (children 2 years of age) to 5.1 g/person per day (young adult males). For heavy consumer intake of microcrystalline cellulose (90th percentile) the values are 5.4 to 10.2 g/person per day for the same age groups (CanTox Inc., 1993).

The mean intake of dietary microcrystalline cellulose in the United Kingdom has been estimated as 0.65 g/person per day. The highest mean intake, 0.90 g/person per day, was for children aged 10-11 (the youngest group for which data were available). For heavy consumer intake of microcrystalline cellulose (90th percentile) the values ranged from 1.13 g/person per day for adults age 16-24 to 1.83 g/person per day for males age 10-11 (Egan & Heimbach, 1994).

Persorption in animal species:

Rats, pigs and dogs were used to study the persorption of microcrystalline cellulose. The animals were not fed for 12 hours prior to oral administration of the test compound. Rats, dogs and pigs were given 0.5, 140 and 200 g, respectively, of the test compound. Venous blood was taken from the animals 1-2 hours after administration of the test compound, and examined for particles. Persorbed particles were demonstrated in the blood of all three species. The average maximum diameter for persorbed particles was greater in rats than in dogs or pigs (Pahlke & Friedrich, 1974)

Acute toxicity of microcrystalline cellulose in animals

No deaths in 10 rats of each sex administered 5000 mg/kg of Avicel RCN-15.

No deaths in 5 rats of each sex administered 5000 mg/kg of Avicel AC-815.

No deaths in 5 rats of each sex treated with 2000 mg/kg of Avicel RCN-15.

No deaths in 5 rats of each sex treated with 2000 mg/kg of Avicel AC-815.

No deaths in 5 rats of each sex exposed to 5.35 mg/litre of Avicel AC-815.

In the studies summarized in Table 1, there was no evidence of toxicity of microcrystalline cellulose preparations administered either orally or dermally to rats at doses of 5000 or 2000 mg/kg bw, respectively. The observations seen at necropsy in animals treated  intraperitoneally with Cellan 300 at 3160 mg/kg bw are consistent with an irritant reaction caused by the presence of foreign material. An inhalation toxicity study showed only transient effects at a concentration of 5.35 mg/litre.

Groups of five male Sprague-Dawley rats received a single oral dose, by stomach tube, of 10.0, 31.6, 100, 316, 1000 or 3160 mg/kg bw of a suspension of Cellan 300 (refined alpha-cellulose) in either  distilled water or Mazola corn oil. The animals were observed for 7 days following administration. No differences were observed among the groups as regards the average body weight, appearance and behavior  compared to untreated rats. No observable gross pathology was revealed  at autopsy in animals dosed with either suspension. Therefore, the  acute oral LD50 was >3160 mg/kg (Pallotta, 1959).

Similar single doses of refined alpha-cellulose were given i.p. in distilled water suspension to five male rats. During 7 days observation there were no abnormalities in the rats given 316 mg/kg bw or less. At 1000 and 3160 mg/kg bw inactivity, laboured respiration and ataxia were observed 10 min after administration and, at 3160 mg/kg bw, ptosis and sprawling of the limbs were observed. These  animals appeared normal after 24 hours and for the remainder of the  observation period. At sacrifice body weights were higher than normal and gross autopsy revealed adhesions between the liver, diaphragm and peritoneal wall and congestion of the kidneys. Masses resembling   unabsorbed compound were also observed and these were found to a small extent in the mesentery of the animals administered 316 mg/kg bw.

There were no deaths and therefore the acute i.p. LD50 was >3160 mg/kg bw (Pallotta, 1959).

Ten male and ten female Sprague-Dawley rats fasted overnight were  fed Avicel RCN-15 (a mixture of 85% microcrystalline cellulose with 15% guar gum) at a dose level of 5000 mg/kg bw mixed with parmesan cheese. Six of ten males and five of ten females consumed the mixture within 24 hours. After a 14-day period during which all rats gained  weight normally they were killed. There were no gross lesions at necropsy. Under the specified conditions of administration the LD50 was >5000 mg/kg bw (Freeman, 1991a).

An acute inhalation toxicity study using a preparation of Avicel AC-815 (composed of 85% microcrystalline cellulose and 15% calcium  alginate) with mass median aerodynamic diameter of 8.48-8.61 µm (range of measures) was dispersed and delivered at a mean concentration of  5.35 mg/litre in a nose-only inhalation exposure chamber to 5 male and 5 female Crl:CDBR VAF Plus rats for a period of 4 hours. The rats were observed over the 14 days after removal from the chamber. The only signs of toxicity were on removal from the chamber and consisted of  chromodacryorrhea, chromorhinorrhea and, in one male rat, decreased  locomotion; these signs had resolved by the next day. After 14 days no gross lesions were observed at necropsy (Signorin, 1996)

Short-term toxicity studies

Rats

Groups of four male rats were kept on diets containing 0.25, 2.5 or 25% of various edible celluloses for 3 months. No differences were observed among the groups with regard to growth and faecal output. Histopathology of the gastrointestinal tract revealed no treatment-related abnormalities (Frey  et al., 1928).

Three groups of five male rats received 0.5 or 10% microcrystalline cellulose in their diet for 8 weeks. Growth was comparable to controls but the 10% group showed slightly lower body  weights. Haematology, serum chemistry and vitamin B1 levels in blood and faeces showed no differences from controls (Asahi Chemical Industry Co., 1966).

Groups of five male weanling Sprague-Dawley rats received 0, 5, 10 or 20% of acid-washed cellulose in their diet during three consecutive nutrient balance trials over a period of 17 days. Absorption of magnesium and zinc were significantly lower in the animals that were receiving the 10 and 20% cellulose diets. Histopathology of the gastrointestinal tract revealed increased mitotic activity and the presence of increased numbers of neutrophils in crypt epithelial cells, particularly of the duodenum and jejunum (Gordon  et al., 1983).

A mixture of four types of Elceme (in the ratio of 1:1:1:1) was fed to groups of Wistar rats for 30 days at a dietary level of 50%,  and for 90 days at a dietary level of 10% (Elceme is a  microcrystalline cellulose, and the four types are identified by particle size, namely, 1-50 (powder), 1-100 (powder), 1-150 (fibrillar), 90-250 (granulate)). All test animals were observed for food intake and weight gain. For animals in the 10% group, urinalysis,  haematological tests and serum biochemical tests were carried out at weeks 6 and 13 of the test. A complete autopsy including  histopathology was carried out at the end of the study. Animals in the 50% group were subjected to a persorption test, on the last day of the  study, by addition of a cellulose staining dye (Renal, Wine-red) to  the food of the test animals at a level equivalent to 5% of the Elceme. The animals were sacrificed 24 hours after administration of the diet, and a careful histological examination was made of the gastrointestinal tract, spleen, liver, kidney and heart for stained particles.

Animals in the 10% group gained significantly less weight than  those in the control group; the marked decrease commenced in the third or fourth week of the study. Food intake was similar in test and  control groups. Urinalysis, haematological values and biochemical values were similar for test and control group 1. At autopsy some ofthe rats on the test diet had distended stomachs, which often contained considerable amounts of the test diet. The absolute liver and kidney weights and the ratio of the weight of these organs to brain weight was increased in test animals when compared with control animals. No compound-related pathology was reported. Animals in the 50% group showed considerable less weight gain than control animals in spite of a marked increase in food consumption. No persorption of dyed fibres was observed (Ferch, 1973a,b).

Randomly bred rats of both sexes were divided into groups that  received a control diet or the control diet with 330 mg/kg microcrystalline cellulose for a period of 6 months. Six rats in each group were then killed, their organs were examined, and tissues were taken for histopathology. No effects of the treatment were observed (Yartsev  et al., 1989).

Groups of Crl: CD(R) BR/VAF/Plus rats (20/sex per group) were administered 0 (control), 25 000 or 50 000 mg/kg Avicel RCN-15 in the diet for 90 days. A few test animals were noted as having  chromodacryorrhea/ chromorhinorrhea, but this was not considered to be   biologically significant. In some early weeks the rats increased diet consumption, probably to allow for the increased dietary fibre content. Body weight gain was unaffected. During the study and at necropsy there was no evidence of treatment-related changes. Clinical chemistry, haematology and organ weights were unaffected by treatment. Histopathology of 34 organs or tissues, including gastrointestinal tract and gut-associated lymphoid tissue of the ileum, provided no evidence of toxicity of microcrystalline cellulose. The calculated  daily consumption of microcrystalline cellulose was 3769 mg/kg bw per day for males and 4446 mg/kg bw per day for females. The author noted that the NOEL exceeded 50 000 mg/kg diet (Freeman, 1992a).

Groups of Sprague-Dawley CD rats (20 rats/dose per sex) from Charles River Laboratories were administered 0 (control), 25 000 or 50000 mg/kg Avicel CL-611 in the diet for 90 days. (Avicel CL-611 orAvicel(R) Cellulose Gel is composed of 85% microcrystalline cellulose and 15% sodium carboxymethyl cellulose). There were no differences in weight gain of the males; a body weight gain decrement in females was attributed to a decreased caloric intake. No adverse  effects attributable to the treatment were observed. At necropsy organ  weights of the test groups were normal other than changes to adrenals of males receiving 50 000 mg/kg and to absolute brain and kidney weights in females receiving 25 000 mg/kg, but these were not  attributed to the treatment. Histopathology of 36 organs or tissues  from the control and high-dose groups, including gastrointestinal tract and gut-associated lymphoid tissue of the ileum, provided no evidence of toxicity of the microcrystalline cellulose. The mean  nominal consumptions, averaged over weekly periods, of Avicel CL-611  by males and females of the top-dose groups ranged from 2768 to 5577 and 3673 to 6045 mg/kg bw per day, respectively (Freeman, 1994a).

Microcrystalline cellulose (Avicel) was used as a positive control  in a short-term toxicity study (approximately 13 weeks) of Cellulon, a  cellulose fibre. Sprague-Dawley Crl:CB (SD) BR rats, 20 rats/sex per group, received a diet containing 0, 5 or 10% of the appropriate fibre ad libitum. Animals were checked daily, and body weights and food consumption were monitored weekly. Haematology (10 parameters) and clinical chemistry (14 parameters) were performed on blood samples taken from 10 rats/sex per group. All animals were necropsied, and gross observations and the weights of liver, testes with epididymes, adrenals and kidneys were recorded. Histological examination was  carried out on tissue sections from control and high-dose groups.

Food consumption was increased in the groups fed cellulose fibre, although there were no differences in body weight between the fibre-fed and control groups. This effect was attributed to the altered nutritional value of the diet. From the haematology and  clinical chemistry there was only one significant difference of   microcrystalline cellulose group from the control value; this was in  the group of female rats fed 5% microcrystalline cellulose in which there was an elevation of the haematocrit. There was no evidence of a  dose response.

Study of the necropsy results and the histological observations  indicate that there was no evidence of any treatment-related effects of microcrystalline cellulose during the 13-week feeding study in rats  at either 5 or 10% in the diet (Schmitt  et al., 1991).

Groups of Sprague-Dawley (CD) rats (20 rats/dose per sex) from Charles River Laboratories were administered, by gavage, suspensions  of a special, fine particle size, microcrystalline cellulose (median particle size 6 µm). The dose levels were 0 (control), 500, 2500 or  5000 mg/kg per day as a 25% suspension in tap water. Dosing was   performed daily for 90 consecutive days. No treatment-related deaths occurred during the study and the only treatment-related clinical sign (pale faeces) was not attributed to toxicity. There were no toxicologically significant effects in treated animals with respect to body weight, absolute and relative organ weights (5 organs weighed), food consumption, clinical chemistry measurements, haematology measurements or opthalmoscopic examinations. In animals that has received 5000 mg/kg per day there were no treatment-related lesions detected histopathologically (in 36 tissues including gut-associated lymphoid tissue, liver, lung, spleen and brain) nor was there any macroscopic or microscopic finding of microemboli or granulomatous  inflammatory lesions (Kotkoskie  et al., 1996).

Long-term toxicity/carcinogenicity studies

Rats

Three groups of 50 male and 50 female rats received in their die  for 72 weeks either 30% ordinary cellulose or dry microcrystalline cellulose or micro-crystalline cellulose gel. Appearance and behavior was comparable in all groups. No adverse effects were noted. The body weights of males given microcrystalline cellulose gel were higher than  those of the controls. Food efficiency, survival and haematology were comparable in all groups. The liver and kidney weights of males receiving microcrystalline cellulose gel were higher than the controls. Gross and histopathology showed some dystrophic calcification of renal tubules in females on microcrystalline  cellulose but all other organs appeared unremarkable. Tumour incidence  did not differ between the groups (Hazleton Labs, 1963).

The Committtee was aware of a study in which a microcrystalline  cellulose preparation, of which 90% of the particles had a diameter   < 20 µm, was fed to male and female rats at 0 (control), 30, 100 or 200 g/kg diet. The high mortality during the course of the study, the evidence of confounding infection, the limited number of animals for which there was histopathological examination, and the absence of details of the first year of feeding do not provide adequate reassurance as to the ability of this study to detect other than gross effects (Lewerenz  et al., 1981).

Reproductive toxicity studies

Rats 

Groups of eight male and 16 female rats were used to produce P,  F1a, F1b, F2 and F3 generations after having been fed on diets containing 30% microcrystalline cellulose flour or gel or ordinary cellulose as a control. The presence in the diet of such an amount of  non-nutritious material, which contributed no calories, had an adverse effect on reproduction. Fertility and numbers of live pups were  relatively depressed, and lactation performances in all three  generations, as well as survival and the physical condition of the pups, were unsatisfactory throughout the study. The new-born pup appeared smaller, weak and showed evidence of disturbed motor  coordination. Liver weights were increased in the group receiving microcrystalline cellulose gel in all generations but other organ  weights showed no consistent patterns. At autopsy female rats of all generations showed kidney changes comprising pitting, occasional  enlargement and zonation of the cortex. Other organs showed  no consistent changes. No teratological deformities were seen (Hazleton Labs, 1964).

Special studies on embryotoxicity and teratogenicity

Rats  

Seventy-two rats (Sprague-Dawley CD) divided into eight groups were fed a mixture of four types of Elceme in the ratio of 1:1:1:1 in the diet at a level of 0, 2.5, 5 or 10% for 10 days, between days 6 and 15 of pregnancy. Rats of four test groups were killed on day 21 of pregnancy and the following parameters studied: number of fetuses and resorption sites, litter size and average weight of rats, average weight of fetuses and average backbone length. Fetuses were also examined for soft tissue or skeletal defects. The remaining groups were allowed to bear young, which were maintained to weaning (21 days). The following parameters were studied: litter size, weight of  pups at days 7 and 21, and there was a histological study of the offspring. Although there is some suggestion that administration of dietary Elceme resulted in a dose-dependent increase in resorption  sites, as well as a change in sex ratio, and possible defects such as  opaque crystalline lenses, the data has not been presented in a manner  that permits a meaningful interpretation. However, the author concluded that Elceme is non-teratogenic (Ferch, 1973a,b).

Groups of 25 presumed pregnant Crl:CD(R) BR VAF/Plus rats were administered 0 (control), 25 000 or 50 000 mg Avicel RCN-15/kg diet (equal to 2.1 and 4.5 g/kg bw per day, respectively)  ad libitum on   days 6 to 15 of gestation. Animals received basal diet at all other  times. In the group receiving 50 000 mg/kg the food consumption on  days 6 to 15 was significantly higher than that of controls, probably because of the increased fibre content. On day 20 of gestation thedams were killed by carbon dioxide inhalation and the following parameters studied: number and distribution of implantation sites,  early and late resorptions, live and dead fetuses and corpora lutea.  External, visceral and skeletal examinations of the fetuses were also  performed. There was no evidence of any adverse effects of the test  material on either the dams or the fetuses. Due to a protocol error fetal sex was not recorded (Freeman, 1992b).

Groups of 25 presumed pregnant Charles River Sprague-Dawley CD  rats were administered 0 (control), 25 000 or 50 000 mg Avicel  CL-611/kg (equal to 2.2 and 4.6 g/kg bw per day, respectively) diet   ad libitum on days 6 to 15 of gestation. Animals received basal diet at all other times. In the test groups the food consumption on days     to 15 was significantly higher than for controls, probably because of   the increased fibre content. The parameters studied and examinations performed were the same as in the study of Freeman (1992b). There was  no evidence of any effects of the Avicel treatment on the fetuses, and there was no evidence of a change of sex ratio in the pups or of eye defects. Under the conditions of the study, the maternal and fetal  NOEL was > 50 000 mg/kg diet (equal to 4.6 g/kg bw per day) (Freeman,   1994b).

Special studies on genotoxicity

Various microcrystalline cellulose preparations have been tested for genotoxicity in several different assay systems. The results of which were negative, are summarized in Table 2.

In the reverse mutation assays the microcrystalline cellulose formulations produced a heavy precipitate on the plate at the highest concentration. Solubility also affected the forward mutation assays and it was not possible to include concentrations of the test material that were cytotoxic. In the  in vivo mammalian micronucleus assays it is improbable that there was appreciable persorption of the test materials, and, therefore, there was little exposure of the bone marrow cells. In the test in which Avicel RCN-15 was used it was administered admixed with the diet of male and female ICR mice. Only mice that had consumed all the diet within 10 hours were retained in the study and were killed after 24, 48 or 72 hours. Because one group of control mice had 0 micronuclei per 1000 polychromatic erythrocytes, the comparison with the test group was statistically significant. This was not considered to be a valid observation. There is no evidence that microcrystalline cellulose is genotoxic.

Special studies on sensitization

  Avicel RCN-15 was determined to be non-sensitizing when topically  applied to ten male and ten female Hartley guinea-pigs (Freeman,  1991e).

Avicel AC-815 was determined to be non-sensitizing when topicall    applied to ten male Hartley guinea-pigs (Freeman, 1996c).

Special studies on skin and eye irritation

Avicel RCN-15 was judged to be minimally irritating after  instillation into the eyes of four male and two female New Zealand White rabbits (Freeman, 1991c).

Avicel AC-815 was judged to be minimally irritating after   instillation into the eyes of four male and two female New Zealand  White rabbits (Freeman, 1996a).

Avicel RCN-15 was judged to be non-irritating after a 4-hour occlusive contact with the skin of three male and three female New Zealand White rabbits (Freeman, 1991d).

Avicel AC-815 was judged to be non-irritating after a 4-hour occlusive contact with the skin of three male and three female New Zealand White rabbits (Freeman, 1996b).

Special studies on effects of cellulose fibre on tumour growth 

The effect of artifical diets containing varied concentrations of either wheat bran or pure cellulose fibre on the induction of mammary  tumours by  N-nitrosomethylurea (i.v., 40 mg/kg) was studied in female F344 rats. The wheat bran diet appeared to possess anti-promotion properties that pure cellulose lacked. The concentrations of serum estrogens, urinary estrogens and faecal estrogens did not vary in a consistent, statistically significant manner (Cohen  et al., 1996).

The effect of a high-fibre diet containing 45 000 mg/kg Avicel PH- 105 on the development of colon tumours was investigated in male Wistar rats that were injected with 1,2-dimethylhydrazine dihydrochloride (25 mg/kg, s.c., once weekly for 16 weeks). The test and control diets were administered for 2 weeks prior to the first injection of the carcinogen. There was a reduction in the number of animals bearing colon tumours and a statistically significant reduction in the number of colon tumours/rat in the high-fibre dietary group. However, for small bowel tumours and tumours of the ear canal there was no significant difference between the dietary groups Freeman et al., 1978).

A later study by the same authors demonstrated that there was no significant effect of increasing the level of cellulose in the diet to 9000 mg/kg (Freeman  et al., 1980).

Observations in humans

Toxicity consequent to substance abuse 

Intravenous abuse of drugs available in tablet form has led to the detection of excipients, e.g., talc, magnesium stearate or microcrystalline cellulose, in the tissues of a series of 33 fatality cases of intravenous drug addicts. Microcrystalline cellulose (21  cases) and talc (31 cases) were detected most frequently and, in some cases, were associated with granulomatous lesions (Kringsholm & Christoffersen, 1987).

Changes in gastrointestinal function and nutrient balance

A number of clinical studies using refined cellulose as roughage  in the human diet for the treatment of constipation showed no  deleterious effects. Groups of 18 children received regular amounts of   edible cellulose instead of normal cereal for three months. The only  effect noted was an increase in bowel movements but no diarrhoea or other gastrointestinal disturbances were seen (Frey  et al., 1928).

Eight male and eight female volunteers supplemented their normal diet with 30 g microcrystalline cellulose per day as either dry powder or gel (15% aqueous) for 6 weeks followed by 2 weeks without supplementation. No adverse findings were reported regarding acceptance or body weight but most subjects complained of fullness and mild constipation. Haematology was normal in all subjects. Biochemical blood values showed no differences between treatment and control periods, nor was there evidence of liver or kidney function disturbance. Urinalysis produced normal findings. The faecal flora remained unchanged. The cellulose content of faeces increase five to eight times during the test period. Microscopy revealed the presence of microcrystalline cellulose (Hazleton Labs, 1962).

In another study, eight healthy males received 30 g microcrystalline cellulose daily as supplement to their diet for 15 days. D-xylose absorption varied between pretest, test and post-test periods, being lower during microcrystalline cellulose ingestion. The absorption of 131I-triolein was unaffected by microcrystalline  cellulose ingestion. No change was noted in the faecal flora nor was there any significant effect on blood chemistry during ingestion of microcrystalline cellulose. Examination of urine, blood and faecal levels of vitamin B1 during microcrystalline cellulose ingestion showed no difference from control periods (Asahi Chemical Industry Co., 1966).

Twelve men consumed diets containing fibres from various sources for periods of 4 weeks. There was no significant difference between alues of serum cholesterol, triglyceride and free fatty acid levels measured after consumption of the basal diet, compared with the values measured after consumption of a diet containing cellulose fibres (90% cellulose, 10% hemicellulose; James River Corp., Berlin, New Hampshire, USA). There were no significant differences in plasma VLDL and HDL cholesterol or in the ratio of HDL/VLDL+LDL cholesterol. However, the increase in plasma LDL cholesterol after the cellulose diet was significant (Behall  et al., 1984).

A similar study in a group of four men and six women could detect no effect of a diet containing added alpha-cellulose (15 g daily) on serum total cholesterol, triglycerides, HDL cholesterol and the ratio of HDL to total cholesterol. The cellulose was well tolerated (Hillman et al., 1985).

A double-blind cross-over trial of the effects of guar gum andmicrocrystalline cellulose on metabolic control and serum lipids in 22 Type 2 diabetic patients has been carried out. The fibre preparations were given at 15 g/day for a 2-week period and then at 5 g/day for the remaining 10-week period of each treatment phase. There was no effect of the microcrystalline cellulose diet on fasting blood glucose level, glycosylated haemoglobin, serum HDL-cholesterol, serum triglycerides, serum zinc or ferritin, or urinary magnesium excretion (Niemi   et al., 1988).

The effect of various dietary fibres, including microcrystalline cellulose (40 g), on the uptake of vitamin A (approximately sixty times the daily requirement) from a test meal was investigated in 11 female subjects aged 19 to 22. All the dietary fibres significantly increased the absorption of the vitamin A over a period of 9 hours (Kasper  et al., 1979).

A study of apparent mineral balance in a group of eleven men revealed that there was no significant effect of cellulose, added to the diet at 7.5 g per 1000 kcal for 4 weeks, on the mineral balance of calcium, magnesium, manganese, iron, copper or zinc. However, in this report the source of the cellulose fibre was not specified (Behall et al., 1987).

The addition of nutritional grade cellulose (21 g) to the daily diet of healthy adolescent girls resulted in reduction of the serum calcium, phosphorus and iron concentrations. The authors suggested that high-fibre diets may not be advisable (Godara  et al., 1981).

A study of only three men on a low-fibre diet claimed changes in mineral balance consequent on the consumption of additional cellulose fibre, 10 g of Whatman No. 3 filter paper daily, in the diet (Ismail-Beigi  et al., 1977).

Microcrystalline cellulose (5 g) did not appear to inhibit the uptake of iron in women who were neither pregnant nor lactating (Gillooly  et al., 1984).

A group of twenty women, aged 27-48, who were given 20 g packs of alpha-cellulose to be consumed daily for three months, were included in a study of the effect of indole-3-carbinol on estrogen metabolite ratios. Because the control group and the group fed indole-3-carbinol received capsules, the cellulose group could not be blinded; in addition, an unspecified number of subjects in this group dropped out as they found that the cellulose suspension was unpalatable. However, the authors suggest that the estrogen metabolite ratio in the high- fibre group was not different from that in the control group (Bradlow et al., 1994).

COMMENTS

Persorption of microcrystalline cellulose was reported in various species, which included rats, in early studies. A recent study in which a special fine particle size preparation of microcrystalline  cellulose (median diameter of particles 6 µm) was administered orally to rats (5 g/kg bw per day) for 90 days has failed to confirm the earlier observations. In this study precautions were taken to ensure that, at autopsy, there was no cross-contamination of the tissues with fine particulate matter.

In various parenteral studies of the acute toxicity of microcrystalline cellulose in animals there have been signs consistent with a tissue response to foreign particles. Similarly, microcrystalline cellulose has been associated with the formation of granulomas in human lung when it has been injected intravenously during drug abuse. No such lesions have been described as a consequence of oral ingestion of microcrystalline cellulose by rats or humans.

In 90-day toxicity tests during which microcrystalline cellulose was administered to rats in the diet at concentrations of 2.5 to 50%, increased consumption of food to compensate for the content of this material was observed. Although this may have some effects on mineral absorption there was, in general, no compound-related systemic toxicity. The NOEL exceeded 50 g/kg diet, at which dose level the mean intakes of microcrystalline cellulose by male and female rats were 3.8 and 4.4 g/kg bw per day, respectively.

A two-year feeding study of microcrystalline cellulose in rats was brought to the attention of the Committee. Despite a lack of evidence of toxic effects, the Committee considered that the execution and reporting of the study were not adequate to identify a NOEL.

In vitro and  in vivo genotoxicity studies were negative.

In a three-generation reproductive toxicity study in rats that had been reviewed by an earlier Committee, there were some effects of using 30% microcrystalline cellulose in the diet; these had been considered to be a consequence of the quantity of material reducing the energy density of the diet. However, in recent embryotoxicity and teratogenicity studies in rats there was no evidence of compound-related effects at dietary levels up to 50 g of microcrystalline cellulose per kg diet (equal to 4.6 g/kg bw per day), given on days 6 to 15 of pregnancy.

In some human studies there have been reports of alterations to gastrointestinal function following ingestion of microcrystalline cellulose. The changes do not appear to be related to systemic toxicity.

EVALUATION

The Committee concluded that the toxicological data from humans  and animals provided no evidence that the ingestion of  microcrystalline cellulose can cause toxic effects in humans when used  in foods according to good manufacturing practice.

It is recognized that small particles of other materials may be   persorbed and that the extent of persorption is greater with sub-micrometre particles. Despite the absence of any demonstrated persorption of microcrystalline cellulose in the recent study in rats, the Committee, as a precautionary measure, revised the specifications   for microcrystalline cellulose at the present meeting to limit the content of particles less than 5 µm in diameter. The Committee  retained the ADI “not specified” for microcrystalline cellulose  conforming to these specifications.

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