Safety of d‐ribose as a novel food

Safety of d‐ribose as a novel food

Following a request from the European Commission, the European food Safety Authority (EFSA) Panel on Dietetic Products, Nutrition and Allergies (NDA) was asked to deliver a scientific opinion on d‐ribose as a novel food (NF) pursuant to Regulation (EU) 2015/2283. The assessment of the safety of this NF, which follows the methodology set out in the EFSA Guidance for the preparation and presentation of an application for authorisation of a NF1according to Regulation (EU) 2015/2283 and in the Commission Implementing Regulation (EU) 2017/2469, is based on the data supplied in the application, the initial assessment by the competent authority of the United Kingdom, the concerns and objections of a scientific nature raised by the other Member States and the responses of the applicant, the information submitted by the applicant following EFSA requests for supplementary information and additional data identified by the Panel.

The NF which is the subject of the application is d‐ribose produced by fermentation using a transketolase‐deficient strain of Bacillus subtilis and marketed as Bioenergy Ribose™.

The information provided on the batch‐to‐batch variability, stability, specifications, production process, and history of the organism used as a source of the NF is sufficient and does not raise safety concerns.

The applicant intends to market the NF as an ingredient in a variety of foods, food supplements and in certain foods for specific groups (total diet replacement for weight control and food for special medical purposes). The maximum proposed use levels range from 0.31 to 5 g/100 g in fortified foods and up to 10 g/day in food supplements.

Based on the proposed uses and maximum use levels and the individual food consumption data from the EFSA Comprehensive Food Consumption Database, the Panel estimated the range of the 95th percentile anticipated intakes of the NF in the European Union (EU) from the consumption of fortified foods only (Table 4). These ranges are: 27–829 mg/kg body weight (bw) per day for infants, 136–553 mg/kg bw per day for toddlers, 102–314 mg/kg bw per day for children, 51–154 mg/kg bw per day for adolescents, 32–106 mg/kg bw per day for adults and 26–93 mg/kg bw per day for the elderly. The expected intake of the NF from food supplements in the target population would be up to 163 mg/kg bw per day for adolescents and 143 mg/kg bw per day for adults.

The Panel acknowledges the limited information available to estimate the intake levels of d‐ribose from the background diet and the extent of its daily endogenous production, and is therefore not in the position to estimate the contribution of these sources to the combined intake of the NF.

Considering the possible scenario of combined intake of the NF from fortified foods and from food supplements, the estimated intake for the 95th percentile of the target population would be 214–317 mg/kg bw per day for adolescents and 175–249 mg/kg bw per day for adults and 169–236 mg/kg bw per day for the elderly.

The Panel considers that consumption of the NF is not nutritionally disadvantageous.

The Panel considers that the microbiological information provided does not raise safety concerns.

The Panel notes that the risk of allergenicity is low.

Based on the genotoxicity tests provided, the Panel concludes that there are no concerns regarding genotoxicity of the NF.

The information on absorption and excretion of d‐ribose in rats is limited. The available data indicate that in humans, d‐ribose is rapidly and nearly completely absorbed when administered at 200 mg/kg bw per hour for 5 h. In humans, at dose levels above 3 g (about 40 mg/kg bw), absorption was faster than metabolism. Application of d‐ribose with meals decreases absorption. In the body, d‐ribose is converted mainly to glucose via the pentose phosphate pathway, rather than nucleic acid precursors, which then is further used in the metabolism/biosynthesis. Part of the ribose and its metabolites is excreted via the urine and the percentage increases with increasing dose.

In a subchronic toxicity study, Wistar rats were administered diets containing the NF at levels of 0.0, 3.6, 7.6 and 15.0 g/kg bw per day in the male groups and 0.0, 4.4, 8.5 and 15.7 g/kg bw per day in the female groups. The most prominent findings in this study are effects on body weight, increases in water intake and urine volume (and dilution of the urine), full and empty caecum weight, liver and other organ weights. Given the high dose levels of d‐ribose used in the study, the type of effects observed in this subchronic study and the high purity of the NF, the Panel considers that the observed effects could be the consequence of nutritional imbalances, but toxicological effects could not be ruled out. Therefore, the Panel derived a No observed adverse effect level (NOAEL) of 3.6 g/kg bw per day based on this study.

In a developmental toxicity study, Wistar rats were mated and the females were administered the NF from gestational day 0–21 at levels of 0.0, 4.25, 7.94 and 9.91 g/kg bw per day for the different groups. The Panel notes that besides maternal toxicity (reduced body weight gain), wavy ribs and delayed ossification were detected in the foetuses in the mi d‐ and high‐dose groups. The foetal skeletal alterations are reported to occur frequently in developmental toxicity studies, often secondary to maternal toxicity. The NOAEL for maternal/foetotoxicity in this study is consequently 4.25 mg/kg bw in the diet, while the NOAEL for teratogenicity is 9.91 mg/kg bw per day, the highest dose tested. Therefore, this study supports the NOAEL from the subchronic study, indicating that metabolic imbalances affect both the maternal organism and the developing embryo.

Several human studies were provided which were not designed to assess the safety of d‐ribose. The administration of single oral doses of 2–87 g d‐ribose consistently report transient decreases of glucose concentrations within 1–3 h. The transient decrease of glucose concentration was not associated with clinical symptoms of hypoglycaemia, except for one case, where a low‐weight female experienced short‐term symptoms of hypoglycaemia after ingesting 10 g of ribose in the fasted state. While in this and in most of the other studies, blood glucose levels did not fall below 2.8 mmol/L, a temporary significant decline of blood glucose to 2.6 mmol/L was observed in one study following a single oral dose of 10 g d‐ribose. The decrease in blood glucose comes along with increases in insulin levels. The glucose‐lowering effect occurs also if meals rich in carbohydrate or fat are ingested before uptake of d‐ribose.

No studies have been provided that investigated intake of d‐ribose in infants, young children and adolescents. Whether young age may be of special concern with regard the glucose‐lowering effects of d‐ribose is not known. However, the Panel considers that children could be particularly vulnerable to glucose‐lowering effects of d‐ribose.

The Panel notes that there is a lack of understanding of the mechanisms responsible for the short‐term decrease in blood glucose reported in the human studies, only limited data on the dose–response relationship between d‐ribose and blood glucose levels, and uncertainty about the risk of symptomatic hypoglycaemia conditions, especially in susceptible persons.

Because the decrease in glucose levels and/or the occurrence of transient symptomatic hypoglycaemia (as reported in one case) is considered adverse, based on the human studies, the lowest observed adverse effect level (LOAEL) would be at intakes of 10 g of d‐ribose. Concerning the human data, taking the above issues into account, the Panel concludes that 5 g per day, equivalent to 70 mg/kg bw per day, would be the NOAEL with respect to hypoglycaemia that can be considered applicable for adults. For children, the Panel acknowledges the lack of human data directly relevant for this population group.

For the animal study, the Panel considered an uncertainty factor of 100 as sufficient given the nature of the NF and the magnitude of the effects observed. Based on the NOAEL of 3,600 mg/kg bw per day derived from the subchronic toxicity study in rats, an acceptable level of intake would be up to 36 mg/kg bw per day. This is half the NOAEL value identified in the human studies for adults with respect to hypoglycaemia. The Panel concludes that 36 mg/kg bw per day would also take into account the potentially increased sensitivity of certain population groups to hypoglycaemia, including children.

The Panel therefore concludes that the NF, d‐ribose, is safe for the general population at intake levels up to 36 mg/kg bw per day.

The Panel considers that the safety of the NF at the intended uses and use levels as proposed by the applicant has not been established.

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Ria Van Hoef