Safety profile of HPMC (E464)

There are data for microcrystalline cellulose (E 460), methyl cellulose (E 461), hydroxypropyl cellulose (E 463) and sodium carboxymethyl cellulose (E 466), which were tested in mice, rats, hamsters and/or rabbits with oral dosing or via gavage. As regards microcrystalline cellulose (E 460) studies have been conducted in rats (dietary exposure) with a mixture including guar gum or sodium carboxymethylcellulose (E 466) (15% in either case). The NOAEL for both maternal and developmental toxicity were the highest experimental dosages, i.e. 4,500 mg/kg bw (for mixture with guar gum) and 4,600 mg/kg bw (for mixture with sodium carboxymethyl cellulose). Methyl cellulose (E 461) was examined in mice, rats, hamsters and rabbits. In two different studies, pregnant mice were exposed via gavage (vehicle corn oil) to a dose range of 16-1,600 mg methyl cellulose (E 461)/kg bw per day from day 6 to 15 of gestation, followed by a caesarean section at day 17 of gestation. In the first study, maternal toxicity (increase in mortality and reduced pregnancy rate in the survivors) as well as retarded ossification in fetuses were noticed at the highest tested level, pointing to a NOAEL of 345 mg methyl cellulose (E 461) mg/kg bw per day (the last but one highest dosage) in mice. In the second study, no maternal toxicity and fetal abnormalities were observed in mice exposed up to 700 mg methyl cellulose (E 461) mg/kg bw per day. Rat studies (n = 2) were performed in pregnant dams exposed via gavage (vehicle corn oil) to a dose range of 16-1,320 mg methyl cellulose (E 461) mg/kg bw per day from day 6 to 15 of gestation followed by a caesarean section at day 20. In the first study (0, 13, 51, 285 or 1,320 mg methyl cellulose (E 461)/kg bw per day) the highest tested dosage resulted in no maternal toxicity but also in increased incidence of extra centres of ossification in vertebrae of fetuses from high dose dams; in a second rat study, the incidence of such alteration slightly increased in fetuses from the highest dosed group (1,200 mg methyl cellulose (E 461)/kg bw per day). Based on the above results, a NOAEL of 285 mg methyl cellulose (E 461) mg/kg bw per day could be identified in rats. No maternal or fetal toxicity was detected in Golden hamsters exposed via gavage (vehicle corn oil) up to 1,000 mg methyl cellulose (E 461) mg/kg bw per day from day 6 to 10 of gestation followed by a caesarean section at day 20. The study on rabbits was discarded due to poor experimental design. The only relevant developmental toxicity study with hydroxypropyl cellulose (E 463) (dissolved in 1% gum arabic solution) was performed in pregnant rats exposed via gavage from day 7 to 17 of gestation to 0, 200, 1,000 or 5,000 mg/kg bw test item and some of them subjected to caesarean sections at day 20. No treatment-related adverse effects were detected in dams or in the examined fetuses. A number of dams were allowed to deliver and no clinical, behavioural or morphological changes were observed in the examined pups. Their reproductive ability was seemingly not affected and no abnormalities were found in the F1-derived fetuses. The in utero exposure to the highest dose (5,000 mg/kg bw per day) may be considered as the NOAEL of methyl cellulose (E 461) for this study. No mortality, and no adverse effects were observed on implantation or on fetal survival in pregnant mice or rats dosed via gavage with up to 1,600 mg sodium carboxymethyl cellulose (E 466)/kg bw per day.

For hydroxypropyl cellulose (E 463), the identified NOAEL corresponded to the highest dose 6,000 mg hydroxypropyl cellulose/kg bw per day (by gavage). The most relevant feeding studies with HPMC (E 464) were performed in rats which tolerated up to 10%, corresponding to 9,000 mg test item/kg bw per day. Rabbits tolerated up to 7,500 mg HPMC/kg bw per day administered via the diet (30 day exposure) and dogs up to 1,500 mg HPMC/kg bw per day, in either case being the highest tested dosages. More studies were conducted using sodium carboxy methylcellulose (E 466). The most relevant ones were conducted in rats, with NOAEL values ranging from 4,500 to 9,000 mg test item/kg bw per day (in all cases the highest dose tested). In these studies, some effects (caecum and colonic enlargement, urothelial hyperplasia, nephrocalcinosis, diffuse epithelial hyperplasia in the urinary bladder) were observed, however, not considered of toxicological concern: the findings in the gastrointestinal tract were considered to be a consequence of the accumulation of poorly absorbed water-soluble material and the findings in kidneys and urinary bladder were attributed to the up to fourfold higher concentration of sodium in the test diet compared with the basal diet. In one further study, rats were daily exposed (gavage) to doses equivalent to 0, 500, 2,500 or 5,000 mg/kg bw per day. Animals treated with ≥ 2,500 mg/kg bw per day had soft and pale faeces, which was attributed to the presence of test material and not considered of toxicological relevance. In the absence of any other adverse effects, also for this study, the identified NOAEL was the top dose (5,000 mg/kg bw per day).