Safety and efficacy of hydroxypropyl methyl cellulose for all ...

The applicant did not introduce new studies regarding the safety of Hydroxypropyl Methyl Cellulose (HPMC), instead referencing prior evaluations conducted by various scientific organizations on cellulose and its derivatives as a collective group. JECFA evaluated cellulose and cellulose derivatives' safety, assigning them a group Acceptable Daily Intake (ADI) of 'not specified.' The most recent thorough assessment of cellulose and its derivatives, including HPMC as food additives, was conducted by the ANS Panel (EFSA ANS Panel). The panel concluded there was no requirement for a numerical ADI. Although the collection of data available on different celluloses is not exhaustive and many studies are outdated, the ANS Panel determined that the physicochemical, structural, biological, and kinetic similarities among modified celluloses support a read-across approach across different cellulose types.

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The primary findings from previous assessments, especially from the ANS Panel's opinion (EFSA ANS Panel), are summarized below.

Currently, there is no data regarding the Absorption, Distribution, Metabolism, and Excretion (ADME) of modified celluloses in the target animal species. However, the lack of significant metabolism observed in rats and humans suggests that, despite increased water solubility, the etherification of cellulose likely hinders microbial cellulases' effects. Therefore, the FEEDAP Panel surmises that these compounds would probably be indigestible in monogastric mammals, poultry, and fish. In ruminants and hindgut animals (like rabbits and horses), the complex microbiota may allow for limited enzymatic attack of these structures.

The etherification of cellulose disrupts hydrogen bonding, rendering the resultant compounds non-ionized and more water-soluble. The EFSA ANS Panel determined that modified celluloses, including ethyl and methyl cellulose, along with hydroxypropyl celluloses, are unlikely to be absorbed intact or fermented within the gastrointestinal tract of animals (rats) or humans; they are excreted mainly unchanged through feces (over 90% of the administered doses), with negligible quantities of metabolites released through urine or expired air (as 14 CO2), indicating no accumulation within the organism.

Fermentation occurs in the hindgut of rabbits, involving a plethora of Bacteroides that limit fiber digestibility. Studies show cellulose digestibility reaching 16% of the administered dose, with cellulose comprising the main component and reporting values of 14% and 18% for fiber (review from the NRC). Additional research presented values ranging from 15% to 25% for rabbits given different plant cellulose sources. In horses, plant structural carbohydrates, including cellulose, undergo digestion primarily in the hindgut. The caecum's microbiota resembles that found in ruminants but contains specific protozoa, resulting in digestibility approximately two-thirds of that noted in ruminants.

The intestinal microbiota of marine and freshwater fish is less abundant than in mammals, containing aerobic and facultative anaerobic bacteria. Conflicting studies have indicated either the complete absence of cellulose degradation in trout or tilapia or limited (13%) activity in trout. In experiments involving purified cellulose (lignin-free and reduced hemicellulose), both trout and carp demonstrated minimal cellulose degradation (Bergot and Breque).

For ruminants, cellulose is initially hydrolyzed by ruminal microorganisms into cellobiose, subsequently fermented to pyruvate, and finally converted into volatile fatty acids. Variations in the forage-to-concentrate ratio within the diet substantially influence rumen microorganisms and, by extension, the fermentation's end products. Also, cellulose's digestibility is contingent upon the rate of hydrolysis and the retention time in the rumen, linked to forage particle size. The intrinsic digestibility of cellulose varies based on the forage's origin and treatment. Natural forages often associate cellulose with lignin, hemicelluloses, and cutin, resulting in a wide digestibility range of 30 to 90%. Cellulose crystallinity reduces the hydrolysis rate but does not alter the extent, with digestion reaching up to 80% (Van Soest).

Cellulose, a linear homopolymer, consists of repeating β-d-glucopyranosyl units connected by (1,4) glycosidic bonds. In its pure form, these straight chains tightly bond through intermolecular hydrogen bonds and van der Waals forces, creating an insoluble fibrous or crystalline substance that exhibits inert properties. The EFSA ANS Panel has recently assessed the ADME of celluloses and concluded that cellulose does not absorb intact within the gastrointestinal tract of animals or humans. Instead, it undergoes fermentation as it traverses the large intestine, resulting in limited short-chain fatty acid production (9% of the administered dose in rats), predominantly acetic and succinic acids, alongside hydrogen, carbon dioxide, and methane emissions.

3.2.2. Toxicological Studies

3.2.2.1. Genotoxicity

The data set concerning genotoxicity is incomplete regarding all substances, with several studies not adhering to current standards. However, the unmodified and modified cellulose's chemical structure presents no genotoxicity alerts, with no evidence found in several in vitro and in vivo genotoxicity trials.

Focusing on modified celluloses, methyl cellulose showed negative results in bacterial reverse mutation assays, in vitro chromosomal aberration tests in mammalian cells, and other assays involving yeast and bacteria. In vivo studies on methyl cellulose yielded negative results in chromosomal aberration tests using rat bone marrow and dominant lethal assays in male rats. Carboxymethyl cellulose also returned negative results in bacterial reverse mutation assays and in vitro chromosomal aberration tests, though tested without metabolic activation.

The ANS Panel deemed the read-across from methyl cellulose and carboxymethyl cellulose to other modified celluloses bearing similar simple substituents (including HPMC) reasonable.

Moreover, the FEEDAP Panel acknowledged that methyl and carboxymethyl cellulose have long been utilized as vehicles for non-water-soluble substances in various in vivo genotoxicity studies and are recommended for such purposes by the current OECD test guidelines. Considering the experimental data accumulated, neither microcrystalline cellulose nor modified cellulose, including HPMC, raise any genotoxicity concerns.

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3.2.2.2. Short-term and Subchronic Toxicity

Most conducted studies primarily involved rats, with few performed on rabbits and dogs. Among those adhering to current toxicological testing criteria, the No Observed Adverse Effect Level (NOAEL) values for different modified celluloses typically corresponded to the highest tested levels or alterations in body and organ weights. For microcrystalline cellulose (E 460), identified NOAELs in rats varied from 3,769 to 9,000 mg/kg body weight per day, consistently correlating with the highest tested dosages. In rats, the NOAEL for methyl cellulose (E 461) was judged at a 3% dosage (equivalent to 2,700 mg/kg body weight per day), based on body and organ weight reductions in male rats exposed to the maximal additive level (10%, equating to 9,000 mg/kg body weight per day).

For hydroxypropyl cellulose (E 463), the identified NOAEL corresponded to the highest tested dosage of 6,000 mg/kg body weight per day (given by gavage). Significant studies involving HPMC (E 464) primarily occurred in rats, demonstrating tolerance at dosages of up to 10% (approximately 9,000 mg/km body weight per day). Rabbits could tolerate up to 7,500 mg HPMC/kg body weight per day administered through diet (30-day exposure), while dogs tolerated up to 1,500 mg HPMC/kg body weight per day at comparable maximum dosages. Additional studies concentrated on sodium carboxymethyl cellulose (E 466), particularly in rats showing NOAEL values between 4,500 and 9,000 mg/kg body weight per day (again reflecting the highest tested doses). In these assessments, certain effects (caecum and colonic enlargement, nephrocalcinosis, and epithelial hyperplasia in the urinary bladder) were observed, though not deemed toxicologically concerning: findings within the gastrointestinal tract were attributed to the accumulation of poorly absorbed water-soluble material, and kidney and bladder findings aligned with sodium concentration increases. In a further experiment, rats were dosed daily with 0, 500, 2,500, or 5,000 mg/kg body weight; soft and pale feces appeared in subjects treated with 2,500 mg/kg body weight, attributed to test material, thus assessed without critical toxicological implications. Therefore, the identified NOAEL for this study also registered as the top dose (5,000 mg/kg body weight).

3.2.2.3. Chronic Toxicity and Carcinogenicity

Data on chronic toxicity and carcinogenicity are available for microcrystalline cellulose (E 460), methyl cellulose (E 461), hydroxypropyl cellulose (E 463), HPMC (E 464), and sodium carboxymethyl cellulose (E 466). Some studies were rendered unsuitable due to methodological deficiencies. The sole relevant study assessed high doses of microcrystalline cellulose (E 460) (30%, 15,000 mg/kg body weight) in rats over a 72-week period, finding no effects on survival, feed efficiency, or blood parameters. The only noted indeterminate lesion involved dystrophic calcification within renal tubules. Several methyl cellulose studies (E 461) administered via feed, drinking water, or gavage (in amounts up to 5%, 2,500 mg methyl cellulose/kg body weight per day) over two years showed no adverse effects across examined parameters, with observed tumor incidences remaining consistent relative to controls. The only recognized study on hydroxypropyl cellulose (E 463) via gavage for six months at 0, 1,500, 3,000, or 6,000 mg/kg body weight daily disclosed no adverse effects associated with carcinogenicity, aside from weight loss in high-dosed rats (statistically significant in females). No significant adverse findings emerged, with no carcinogenic effects detected in rats exposed to HPMC (E 464) up to 20% (10,000 mg/kg body weight per day) over one year. Sodium carboxymethyl cellulose (E 466) was analyzed in mice and rats at dosages of 0, 10,000 or 100,000 mg/kg diet, which is equivalent to 0, 1,500, or 15,000 mg/kg body weight daily for mice and 0, 500, or 5,000 mg/kg body weight daily for rats over 104 weeks. Despite increased feed consumption, a treatment-related decline in body weight was recorded towards the study's conclusion. Histological evaluations revealed no intestinal abnormalities or evidence of the additive's passage across the intestinal barrier, with comparable tumor rates across emphasis groups.

In summary, chronic toxicity studies based on limited data sets indicated growth retardation associated with certain modified celluloses, primarily at the highest dosing levels. No carcinogenic indications were found across all tested compounds.

3.2.2.4. Reproductive and Developmental Studies

Research covers microcrystalline cellulose (E 460), methyl cellulose (E 461), hydroxypropyl cellulose (E 463), and sodium carboxymethyl cellulose (E 466), evaluated in mice, rats, hamsters, and/or rabbits via oral dosing or gavage. Microcrystalline cellulose studies conducted with rats (dietary exposure) involving mixtures such as guar gum or sodium carboxymethyl cellulose yielded NOAELs for maternal and developmental toxicity at maximum dosages of 4,500 mg/kg body weight (guar gum mixture) and 4,600 mg/kg body weight (sodium carboxymethyl cellulose mixture). Methyl cellulose was tested in mice, rats, hamsters, and rabbits; pregnant mice experienced exposure via gavage (with corn oil as a vehicle) to dosages between 16 to 1,600 mg methyl cellulose per kg body weight for days 6 to 15 of gestation, followed by cesarean sections on day 17. The first study noted maternal toxicity (increased mortality and decreased pregnancy rates) as well as delayed ossification in fetuses at maximum tested levels, suggesting a NOAEL of 345 mg methyl cellulose/kg body weight daily (second highest dosage) in mice. In the second study, higher doses resulted in no maternal sensitivity or fetal abnormalities at exposures up to 700 mg methyl cellulose/kg body weight daily. Two rat studies (n=2), involving pregnant dams dosed via gavage from days 6 to 15 of gestation, found one study (dosage range of 0, 13, 51, 285, or 1,320 mg methyl cellulose/kg body weight daily) showing no maternal toxicity at the highest dosage, yet elevated extra ossification center rates in fetuses from high-dosage dams. Conversely, the other rat assessment noted minimal increase in such alterations within the fetuses from the highest dosage group (1,200 mg methyl cellulose/kg body weight daily). Based on these results, a NOAEL of 285 mg methyl cellulose/kg body weight daily could be designated in rats. No maternal or fetal toxicity was noted in Golden hamsters exposed via gavage to nearly 1,000 mg methyl cellulose/kg body weight daily. An inferior study on rabbits due to poor design was disregarded. The sole relevant developmental toxicity assessment of hydroxypropyl cellulose (E 463) (dissolved in 1% gum arabic solution) involved pregnant rats exposed via gavage across days 7 to 17, with dosages at 0, 200, 1,000 or 5,000 mg/kg body weight, many subjected to cesarean sections on day 20. No treatment-associated adverse effects were seen in either dams or examined fetuses. Some dams were permitted to deliver with no clinical, behavioral, or morphological changes in observed pups; reproductive abilities remained unaffected, with no abnormalities in fetal derived from F1 generations. The highest administered dosage (5,000 mg/kg body weight) may be regarded as the NOAEL of methyl cellulose (E 461) in this context. No mortality or adverse effects arose on implantation or fetal survival in pregnant mice or rats administered with sodium carboxymethyl cellulose up to 1,600 mg/kg body weight per day via gavage.

3.2.2.5. Conclusions Regarding the Toxicological Properties of Celluloses

The FEEDAP Panel concurs with the ANS Panel's approach that, while the available data for various celluloses remains incomplete and many studies are outdated and do not meet contemporary toxicological testing standards, the similarities in the physicochemical, structural, biological, and kinetic aspects of modified celluloses support a read-across strategy within this group. In summary, the available information indicates that celluloses, as a collective group, pose limited toxicological concerns.

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