扒哥吃瓜

Introduction

1.听听听听听听听听听听听听听The Scientific Advisory Committee on Nutrition (SACN) last considered maternal diet and nutrition in relation to offspring health, in its reports on 鈥楾he influence of maternal, foetal and child nutrition on the development of chronic disease in later life鈥� (SACN, 2011) and on 鈥楩eeding in the first year of life鈥� (SACN, 2018). In the latter report, the impact of breastfeeding on maternal health was also considered. In 2019, SACN agreed to conduct a risk assessment on nutrition and maternal health focusing on maternal outcomes during pregnancy, childbirth and up to 24 months after delivery; this would include the effects of chemical contaminants and excess nutrients in the diet.

2.听听听听听听听听听听听听听SACN agreed that, where appropriate, other expert Committees would be consulted and asked to complete relevant risk assessments e.g., in the area of food safety advice. This subject was initially discussed during the Committee on the Toxicity of Chemicals in Food, Consumer Products and the Environment (COT) horizon scanning item at their January 2020 meeting with a scoping paper being presented to the听COT听in July 2020. This included background information on a provisional list of chemicals proposed by SACN. It was noted that the provisional list of chemicals was subject to change following discussion by听COT听who would be guiding the toxicological risk assessment process: candidate chemicals or chemical classes can be added or removed as the听COT听considered appropriate. The list was brought back to the听COT听with additional information in September 2020. Following a discussion at the September 2020,听COT听agreed that papers on a number of compounds should be prioritised, among which was the mycotoxin citrinin.

3.听听听听听听听听听听听听听The following statement sets out the advice of the听COT听on whether UK exposures to citrinin would pose a risk to maternal health, i.e. maternal outcomes during pregnancy, childbirth and up to 24 months after delivery.

Background

4.听听听听听听听听听听听听听Citrinin is a mycotoxin produced by several species of fungi of the genera听Aspergillus,听Penicillium听and听Monascus. Its occurrence is generally due to formation after harvest under storage conditions. It occurs mainly in grains but is also found in other products of plant origin e.g. beans, fruits, fruit and vegetable juices, herbs and spices as well as in spoiled dairy products.

5.听听听听听听听听听听听听听Experimental data indicate that citrinin residues may occur in the edible tissues of pigs (Meerpoel et al., 2020a) and in edible tissues and eggs in chickens (Abdelhamid and Dorra, 1990, Meerpoel et al., 2020a) following oral exposure to highly contaminated feed materials. However, citrinin was not detected in edible animal products in the 2014 Total Diet Study (TDS) so the carryover of citrinin from feed into animal products is not considered further in this assessment (FSA, 2014).

6.听听听听听听听听听听听听听Citrinin is also an undesirable contaminant in Monascus fermentation products such as red yeast rice (RYR), also known as red mould rice (RMR). RYR is used in Asian cuisine as a food colourant and flavour enhancer and in supplements claiming to decrease plasma triglyceride and cholesterol levels (Wei et al., 2003). In 2019, the maximum level for citrinin in RYR preparations was reduced from 2000 碌g/kg to 100 碌g/kg in Commission Regulation (EC)听听No听听(补尘别苍诲尘别苍迟:听). The majority of packaging of RYR supplements either states that the product is not suitable for children and/or women who are pregnant or breast feeding, or recommends that these groups should consult a general practitioner (GP) prior to consumption. Due to the presence of warnings on supplement packaging, and the focus of this assessment being on the maternal diet, RYR supplements are not considered further in this assessment.

Previous assessments

European Food Safety Authority 2012 opinion

7.听听听听听听听听听听听听听In 2012, the European Food Safety Authority (EFSA) assessed the risks to public and animal health related to the presence of听citrinin听in food and feed. Based on the available evidence,听EFSA听concluded that the establishment of a health-based guidance value (HBGV) would not be appropriate. While a concern for genotoxicity and carcinogenicity could not be excluded,听EFSA听did not consider the database sufficient to apply a margin of exposure (MOE) approach. Instead, the risk of听citrinin听was characterised and an intake of 0.2 ug/kg bw per day identified as a level of no concern for nephrotoxicity in humans. The available exposure data did not permit听EFSA听to reach a firm conclusion regarding the likelihood of consumers exceeding the level of no concern for nephrotoxicity on a daily basis over a prolonged period. A concern for genotoxicity and carcinogenicity could not be excluded at the level of no concern for nephrotoxicity. The derivation of the HBGV is discussed in more detail from paragraph 38.

Netherlands Food and Consumer Product Safety Authority (NVWA) 2015 risk assessment

8.听听听听听听听听听听听听听The Netherlands Food and Consumer Product Safety Authority (NVWA) monitors the occurrence of mycotoxins in the Netherlands and advises the Dutch government on food safety risks related to mycotoxins. In 2015, NVWA commissioned the National Institute for Public Health and Environment (RIVM) to undertake a literature search (covering the period 2011 to 2015) to find out whether any new toxicity studies had been published since the听EFSA听opinion that could be used to derive a benchmark dose (BMD) or a HBGV (RIVM, 2017).听The point of departure (POD) selected was 48 渭g/kg bw/day, the听lower 95% confidence bound of the听benchmark dose (lower confidence limit) (BMDL05) in a reproductive toxicology study in rats (Singh et al., 2014).听In their assessment,听RIVM听agreed with听EFSA鈥檚 concern regarding the genotoxicity and/or carcinogenicity of citrinin and found a lack of new evidence published since the听EFSA听opinion. The approach and outcomes are discussed further from paragraph 42.

Toxicology

9.听听听听听听听听听听听听听EFSA听carried out a full assessment of听citrinin听in 2012. Their assessment has been used as a baseline point for the following hazard characterisation. In addition, a literature search covering the period 2012-2024 was carried out, ensuring that relevant data published after the听EFSA听assessment were also considered here. The key studies used in the RIVM risk assessment (2017) were retrieved as part of this literature search. The following sections therefore summarise all relevant toxicological information up to 2024.

Toxicokinetics

10.听听听听听听听听听听听听听The available information on citrinin showed it is eliminated predominantly by renal excretion; approximately 75 % of radiolabelled citrinin (14C-citrinin) given to pregnant Spraque-Dawley rats by subcutaneous administration was recovered in urine (Reddy et al., 1982a). A study by Meerpol et al. (2020b) demonstrated differences in the toxicokinetic properties of citrinin between pigs and chickens, including clearance being much slower in pigs than in chickens (Meerpoel et al., 2020b).

11.听听听听听听听听听听听An in vitro study in Chinese hamster lung fibroblast cells demonstrated that the cytotoxicity of the metabolite dihydrocitrinone was less than that of citrinin (F枚llmann et al., 2014) while the interaction of dihydrocitrinone with albumin from different species in vitro did not differ significantly (Faisal et al., 2019).

12.听听听听听听听听听听听听听12. A study in human volunteers demonstrated that ingested citrinin undergoes conversion to dihydrocitrinone, which is then excreted in the urine along with the remaining parent compound (Degen et al., 2018).

13.听听听听听听听听听听听听听A study by Singh (2012) suggested that听citrinin听can cross the placenta (discussed further in the Developmental and reproductive toxicity section, see paragraph 31).

Experimental toxicity

Genotoxicity

14.听听听听听听听听听听听听听EFSA听concluded that the available data indicated that听citrinin听was not mutagenic in conventional bacterial assays either with or without metabolic activation by S9 fraction (EFSA, 2012). Mutagenicity in the Ames test was reported in a single study when rat hepatocytes were used as the activating system (Sabater-Vilar et al., 1999). In mammalian cells听in vitro,听citrinin听did not induce DNA single-strand breaks, oxidative DNA damage or sister chromatid exchanges but did induce micronuclei, aneuploidy and chromosomal aberrations.

15.听听听听听听听听听听听听听In in vitro assays published since the听EFSA听opinion citrinin induced a dose-dependent increase in micronucleus frequencies, chromosomal aberrations and sister chromatid exchanges (Anninou et al., 2014; F枚llmann et al., 2014; Tsai et al., 2023). Tsai et al. (2023) concluded that citrinin exposure activated cancer and cell cycle-related signalling pathways when human embryonic kidney 293 (HEK293) cells were treated for 3 and 30 days (Tsai et al., 2023).

16.听听听听听听听听听听听听听In vivo, citrinin induced chromosome abnormalities and hypodiploidy in the bone marrow of mice exposed to oral doses of 5-20 mg/kg bw for eight weeks (Jeswal, 1996).

Carcinogenicity

17.听听听听听听听听听听听听听Fischer 344 rats were fed diet containing citrinin at 0.1 % (correspond to an intake of 1000 mg/kg diet or exposures equivalent to approximately 70 mg/kg bw based on 20 g feed intake) for 80 weeks; the kidney was identified as the main target organ, with reported induction of adenomas (Arai and Hibino, 1983). The first renal tumour was seen at necropsy week 52. Renal adenomas were seen in 35 of the 48 rats that had survived after 40 weeks.

18.听听听听听听听听听听In a series听of in vivo听studies, Kuroda et al. (2013) administered听citrinin听to male Fischer 344 rats by gavage at 20-40 mg/kg bw/day for a maximum of 28 days. The higher dose, which is 2000 times higher than the POD selected by听EFSA, is identified by the authors as 鈥渢he maximal tolerated dose and a nearly carcinogenic dose鈥�. The maximum dose was decreased to 30 mg/kg from day four due to decreases in body weight (bw). Regenerative tubules were observed in the kidney cortex in the high dose group and cell proliferation was significantly increased at both doses. The authors suggested that the increase in cyclin encoding genes (Ccna2, Ccnb1, Ccne1) and transcription factor E2f1 indicated induction of cell cycle progression at all tested doses. Cyclin B1 specifically is ubiquitously expressed in humans and plays a key role in controlling the cell cycle transitions.

Nephrotoxicity

19.听听听听听听听听听听In vitro, the acute cytotoxic effects of both dihydrocitrinone and听citrinin听were significantly decreased in Madin-Darby canine kidney (MDCK) epithelial cell line, in the presence of albumin听(Faisal et al., 2019).

20.听听听听听听听听听听In vivo, the acute lethal dose of听citrinin听ranged from 19-134 mg/kg bw depending on species and route of administration (EFSA, 2012). The main changes in pathology following听citrinin听administration were degeneration and necrosis of the kidneys in all species, indicating nephrotoxicity. Repeat dose studies assessed by听EFSA听(2012) confirmed the nephrotoxicity of听citrinin听and highlighted the differences in susceptibility between species, showing that guinea pigs and dogs were more sensitive than hamsters. Histopathological changes were found at necropsy in the kidneys of all species tested (except hamsters), consistent with the acute signs observed.

21.听 听 听 听 听听In a 90-day study in male Wistar rats by Lee and Pan (2010),听citrinin听was given in the diet in the form of fermented RMR containing different concentrations of听citrinin听(1, 2, 10, 20 and 200 mg/kg).听听At the highest dose tested (stated by听EFSA听to be equivalent to 20 碌g/kg bw/day) no toxicologically significant alterations in body weight gain, daily feed intake, organ weight and serum biochemistry or histopathology of livers and kidneys were observed.

22.听听听听听听听听听听In a repeat听dose study, Jagdale et al. (2020) treated male and female Wistar rats with 25 渭g/kg bw/day or 100 渭g/kg bw/day citrinin by gavage for 28 days. Adverse histopathological changes were reported in the kidney and spleen at the higher dose. No significant histological changes were reported in animals dosed with 25 渭g/kg bw/day.

23.听听听听听听听听听听A 60-day study in rabbits suggested that at low concentrations,听citrinin听(15 mg/kg feed,听equivalent to听0.45 mg/kg bw/day; EHC 240) induced lipid peroxidation and apoptosis in a time-dependent manner in the kidney; this, according to the authors,听appeared to play a major role in the pathogenesis of nephrotoxicity听(Kumar et al., 2014).

Immunotoxicity and Immunomodulation

24.听 听 听 听 听听EFSA听concluded in 2012 that the data on immunotoxicity of听citrinin听were incomplete and often non-specific and therefore did not allow for a conclusive evaluation.

25.听听听听听听听听听听Since the听EFSA听opinion,听in vitro听mammalian cell assays reported to show evidence of immunomodulatory and immunotoxic effects of听citrinin听have been published (Sugiyama et al., 2013: abstract only; Islam et al., 2012; Xu et al., 2022).

26.听听听听听听听听听听When immunoglobulin (Ig) levels were measured in mice treated听in vivo听with听citrinin听(1, 5, or 10 mg/kg bw/day, by gavage) for 14 days, a dose-dependent reduction in IgM was observed in the absence of significant changes in IgA, IgE and IgG (Islam et al., 2012). Changes in the regulation of the different immune cell populations were reported in the spleen, mesenteric lymph nodes and small intestine at 1 mg/kg bw/day.听Ex vivo听exposure of primary splenocytes and mesenteric lymph node cells demonstrated induction of apoptosis in the mice spleen, lymph听nodes and Peyer鈥檚 patches, which authors commented was through alteration of听Bax/Bcl-2听expression.

Developmental and reproductive toxicity

27.听听听听听听听听听听EFSA听considered听citrinin听to show reproductive toxicity with teratogenic and embryotoxic effects based on data from听in vitro听and听in vivo听studies (EFSA, 2012).听In vivo听studies also reported maternal toxicity, including nephrotoxicity, at the same dose, indicating that the reproductive, teratogenic and embryotoxic effects of听citrinin听may be secondary to maternal toxicity.

28.听听听听听听听听听听Toxicokinetic investigations in pregnant Charles River CD1 rats provided no conclusive data about the percentage of citrinin that crosses the placenta (Reddy et al., 1982b). Therefore,听EFSA听could not determine the extent to which offspring were exposed based on the available data.

29.听听听听听听听听听听Since the 2012听EFSA听opinion, limited data has been published on the reproductive and developmental effects caused by听citrinin; however, where such effects were observed the doses administered were above听EFSA鈥檚 level of no concern for nephrotoxicity.

30.听听听听听听听听听听A听repeated oral dose toxicity study by听Hayashi et al. (2012) exposed听female BALB/c mice to 0,听1.25 or 7.5听ppm听citrinin听for 70 days听in drinking water. No effects on body weight, food consumption or clinical signs were observed and except for a slight increase in relative ovary weight, no other effects on kidney, liver or ovary were observed. A second experiment was carried out听exposing female BALB/c mice to 0,听15 or 30 ppm听citrinin听for 90 days听in drinking water. A significant decrease in relative liver weight and decreases in water consumption were observed in the lower (15 ppm)听dose听group, while decreases in body weight were observed in the higher treatment group (30 ppm).听Both absolute and relative ovary weights increased, accompanied by large follicles at 鈮� 15 ppm (the authors estimated this was equivalent to 2.25 mg/kg bw/day).

31.听听听听听听听听听听Singh et al. (2012) administered听citrinin听(10 mg/kg feed, equivalent to 1 mg/kg bw/day; EHC 240) to pregnant Wistar rats from gestational day听6-20. A significant increase in the percentage of apoptotic cells in kidneys of dams and foetuses as observed. Toxicity, indicated by the presence of apoptotic cells in the kidneys was inferred by the authors.

32.听听听听听听听听听听In a later one generation study听by the same authors听(Singh et al., 2014) 2014).听male听and female Wistar rats were administered citrinin via the diet (1, 3 and 5 mg/kg听citrinin听in feed, equivalent to 0.1, 0.3 and 0.5 mg/kg bw/day; EHC 240) for 10 weeks prior to mating, during mating and during organogenesis. Clinical signs observed included increased water intake, dullness, rough hair coat and polyuria. Mortality was not observed in the dams. Reproductive effects included reduced foetal bodyweight, reduced crown-rump length and increased number of malformations.

33.听听听听听听听听听听Newly fertilised zebrafish eggs were exposed to concentrations of 0.78-50 渭袦听citrinin听before individuals reached the free-feeding stage, i.e. while the zebrafish were still embryos prior to reaching the juvenile stage of development.听(Csenki et al., 2021).听No mortalities occurred, but exposure to 50 渭M听citrinin听led to pericardial oedema, blood accumulation, incorrect heart looping, and reduced size of cardiac chambers.

Epidemiological studies

34.听听听听听听听听听听The literature search undertaken for the current assessment retrieved epidemiological studies specifically on pregnant women following citrinin exposure. However, no studies specific to the UK were available.

35.听听听听听听听听听听Citrinin and dihydrocitrinone have been reported in urine from different human cohorts from Belgium, Czech Republic, Portugal, Germany, Haiti, Bangladesh, Nigeria, Turkey, and Tunisia (Narv谩ez et al., 2021). Citrinin has also been detected in the breast milk and urine of mothers and the urine of exclusively breastfed infants in two Nigerian communities (Ezekiel et al., 2022).

36.听听听听听听听听听听Three biomonitoring studies were carried out to measure the concentration of听citrinin听and听dihydrocitrinone听in pregnant women, infants听and children in Bangladesh (Ali and Degen, 2020; Kyei et al., 2022, 2023).听Citrinin听was detected in 61 % of the urine samples collected from pregnant women and dietary exposure to听citrinin, based on urinary levels, was estimated to exceed the level of no concern for nephrotoxicity set by听EFSA听(2012) in 16 % of pregnant women. No evidence was found for an association between higher maternal daily intakes of听citrinin, and duration of pregnancy, birth weight, birth length, and head circumference at birth.

Other human studies

37.听听听听听听听听听听EFSA听considered two reports of (accidental) human exposure (Hetherington and Raistrick, 1931; Ambrose and DeEds, 1946); however, both focussed on inhalation of citrinin powder.听EFSA听drew no conclusions from these studies, and the effects were not considered to be relevant to the maternal diet due to the route of exposure.

Health based guidance values

European Food Safety Authority

38.听听听听听听听听听听听听听In 2012,听EFSA听concluded that the establishment of a HBGV for citrinin would not be appropriate, given the available data on genotoxicity and the limitations and uncertainties in the database.

39.听听听听听听听听听听听听听For compounds that are potentially genotoxic or carcinogenic,听EFSA听normally recommends the use of the MOE approach. However,听EFSA听did not consider an MOE approach appropriate for citrinin due to the lack of human dietary exposure data. Instead,听EFSA听decided to characterise the risk of听citrinin听and determine a level of no concern for nephrotoxicity in humans. A level of no concern is not a HBGV but is a concentration below which there is no appreciable concern for nephrotoxic effects. This level does not specifically address other end points.

40.听听听听听听听听听听听听听The level of no concern was based on a no observed adverse effect level (NOAEL) of 20 渭g/kg bw per day determined from a study in rats by Lee and Pan (2010) (detailed in paragraph 21).听EFSA听applied a default uncertainty factor (UF) of 100 for interspecies (10) and interindividual (10) variation to derive a level of no concern of 0.2 渭g/kg bw per day for nephrotoxicity.

41.听听听听听听听听听听听听听EFSA听however noted that a concern for genotoxicity and carcinogenicity could not be excluded at the level of no concern for nephrotoxicity.

National Institute for Public Health and Environment (RIVM)

42.听听听听听听听听听听听听听In 2015, the NVWA commissioned the RIVM to produce a report based on a literature search to determine whether toxicity studies published since the听EFSA听opinion could be used to derive a BMD or a HBGV.

43.听听听听听听听听听听听听听From the studies retrieved, the RIVM selected the developmental toxicity study by Singh et al. (2014) (paragraph 32) and the subchronic toxicity study by Hayashi et al. (2012) (paragraph 30) for BMD analysis.

44.听听听听听听听听听听听听听The lowest BMDL derived was the BMDL05 of 48 渭g/kg bw/day for 鈥榙ecreased crown rump length鈥� from the Singh et al. (2014) study; the study was considered the appropriate POD for risk assessment. The听RIVM noted that effects on the foetuses could be secondary to maternal toxicity. Since information on maternal effects was limited (only maternal body weight was measured), effects on foetuses were considered relevant and the BMDL05 on decreased crown rump length the most appropriate.听This BMDL05 was 2.4 times higher than the NOAEL determined by听EFSA听in 2012.

45.听听听听听听听听听听听听听罢丑别 RIVM concluded that there were no new scientific articles available in the years 2011 to 2015 on the听in vivo听genotoxicity or carcinogenicity of citrinin. A re-evaluation of the study by听Arai and Hibino听(1983) (detailed in paragraph 17) on the听tumorigenicity of citrinin in rats revealed that the study was not suitable for BMD analysis. Therefore, the RIVM agreed with听EFSA鈥檚 conclusion regarding the genotoxicity and/or carcinogenicity of citrinin and did not derive a HBGV. The RIVM further supported听EFSA鈥檚 request for a听well-designed toxicological study in laboratory animals to further explore the carcinogenic potential of citrinin.

The Committee on Toxicity of Chemicals in Food, Consumer products and the Environment

46.听听听听听听听听听听听听听Based on the assessment by听EFSA听in 2012 and new data published between 2012-2024 the听COT听agreed that听citrinin听is nephrotoxic. In addition, and of specific interest to the assessment on maternal toxicity, both听in vitro听and听in vivo听studies indicate that dietary exposure to citrinin may cause reproductive and developmental toxicity, although most of the effects occur at maternally toxic doses.

47.听听听听听听听听听听Overall, the new data published since the 2012听EFSA听opinion supported previous听findings or added to the existing knowledge base regarding听citrinin.

48.听听听听听听听听听听罢丑别听COT听therefore agrees with听EFSA听that a HBGV cannot currently be set and that it is appropriate to use the level of no concern for nephrotoxicity to characterise the risk of听citrinin听to consumers. Whilst the RIVM BMDL05 specifically covers reproductive effects, it is 2.4 times higher than听EFSA鈥檚 level of no concern听for nephrotoxicity. Therefore,听the level of no concern for nephrotoxicity is adequately protective for maternal, reproductive and developmental toxic effects.

Exposure Assessment

1. It was not possible to conduct an exposure assessment to citrinin during pregnancy, childbirth and up to 24 months after delivery due to the absence of data specific to the maternal diet; exposure was instead determined for women of child-bearing age (16-49 years), using consumption data from the National Diet and Nutrition Survey (NDNS) and occurrence data from the 2014 Total Diet Study (TDS) (Bates et al., 2014, 2016, 2020; Roberts et al., 2018; FSA, 2014).

2. Occurrence data from all food samples analysed for citrinin were below the limit of quantification (LOQ) and the exposures calculated were based on the lower bound (LB) and upper bound (UB) values. In this scenario the LB occurrence value for a given commodity is zero and the actual occurrence may be as low as zero (or as high as the upper bound). Therefore, it is not possible to conclusively determine whether a specific commodity contributes to the overall exposure.

3. Mean total exposure to citrinin for women of child-bearing age was 0-17 ng/kg bw/day, whilst exposure in high consumers (97.5th percentile) was 0-43 ng/kg bw/day. The food groups with the highest UB values were tea, with a mean value of 6.2 ng/kg bw/day and a 97.5th percentile value of 23 ng/kg bw/day; instant coffee, with a mean value of 2.6 and 97.5th percentile value of 17 ng/kg bw/day; and wine, with a mean value of 1.0 ng/kg bw/day, and 97.5th percentile value of 6.5 ng/kg bw/day.

4. Citrinin was not detected in edible animal products in the 2014 TDS and the carryover of citrinin into animal products could therefore not be included in the exposure assessment.

Risk characterisation

53.听听听听听听听听听听听听听Citrinin听is nephrotoxic and has been reported to affect liver function. It has also been associated with reproductive toxicity and teratogenic and embryotoxic effects, usually at doses that caused maternal toxicity. These adverse effects may be secondary to maternal toxicity.

54.听听听听听听听听听听听听听Based on the data available, including data published since the most recent听EFSA听opinion in 2012, the听COT听did not think it appropriate to establish a HBGV but agreed with听EFSA鈥檚 approach of using a level of no concern for nephrotoxicity听in humans of 0.2 渭g/kg bw per day. Whilst the BMDL05 of 48听渭g/kg bw per day听derived by the RIVM was specific to reproductive effects,听EFSA鈥檚 level of no concern was lower and was听considered adequately protective for maternal, reproductive and developmental toxic effects. All other adverse effects reported after听citrinin听exposure occurred at higher doses.

55.听听听听听听听听听听听听听In 2012,听EFSA听did not consider there to be sufficient data to conclude on the immunotoxic effects of听citrinin. While some additional data has been published since听EFSA鈥檚 opinion, the database is still very limited and did not allow the听COT听to draw any conclusions.

56.听听听听听听听听听听听听听The available data did not indicate that听citrinin听caused gene mutations; however,听citrinin听may have a threshold effect on microtubules and/or spindle assembly. The听COT听noted that the renal adenomas detected in rats in the Arai and Hibino (1983) study were uncommon, but the duration of the study did not allow firm conclusions to be drawn. Due to the limitations in the database, the听COT听concluded that a risk of genotoxicity and carcinogenicity cannot be excluded although citrinin shows no evidence of DNA-reactive mutagenicity.

57.听听听听听听听听听听听听听Mean and 97.5th听percentile total estimated exposures for听citrinin听were 0-17 and 0-43 ng/kg bw respectively, below the level of no concern for nephrotoxicity of 0.2 渭g/kg bw per day set by听EFSA.

58.听听听听听听听听听听听听听奥丑颈濒别听EFSA听did not establish a human HBGV, the estimated exposures were over 1000-fold lower than the POD derived by the RIVM from an animal study (48听碌g/kg bw per day) based on reproductive effects. Hence, the estimated exposures here were not of toxicological concern for nephrotoxicity or reproductive and developmental effects.

Uncertainties

59.听听听听听听听听听听听听听The following uncertainties and limitations in the assessment were identified:

• The current assessment is based on consumption data from the听National Diet and Nutrition Survey听for women of maternal/childbearing age (16-49) and therefore may not be representative of maternal diet. In addition, the inclusion of the upper bound values for wine, beer, alcopops and cocktails in the assessment may lead to an overestimation of exposure when considering pregnant women because the NHS recommends that those who are pregnant or planning to become pregnant should not drink alcohol.
• Whilst there are suggestions that听citrinin听can cross the placenta (Singh, 2012), there is limited evidence to support this, and hence there remains uncertainty whether, and to what extent,听citrinin听can affect the foetus.
• RYR as a food additive and/or as a supplement was not considered in this assessment because consumption data was not available and an exposure assessment could not be carried out. However, the majority of packaging of RYR supplements in the UK state that the product was either not suitable for women who are pregnant or breast feeding, or, it was recommended these groups should consult a general practitioner (GP) prior to consumption. Higher exposure to citrinin may occur in communities which use RYR as an additive. This may lead to underestimation of exposure for certain population groups.
• Different ethnic groups and their specific dietary behaviours have not been characterized, hence there could be an over- or underestimation of exposure.
• Possible additive/synergistic effects with other mycotoxins have not been considered in this assessment. This could lead to underestimation of the toxicological effects where multiple mycotoxin exposures occur.
• Due to the limitations in the database a risk of genotoxicity and carcinogenicity cannot be excluded. A well-designed toxicological study would be required to further explore the genotoxic and carcinogenic potential of听citrinin.
• 听The transfer of听citrinin听from feed to animal products was not considered further in this assessment because听citrinin听was not detected in animal products in the TDS. This could lead to an underestimation of exposure, should newer TDS data report transfer of citrinin into animal products.
• It should be noted that the TDS data used to calculate exposure were from 2014. Changes in population exposure to citrinin may have occurred since then. Dietary patterns may also have changed; for example, widespread adoption of vegan/vegetarian diets and increased consumption of plant-based drinks may not be fully represented in the data.

Conclusions

60.听听听听听听听听听听听听听Based on the data available the听COT听concluded that a HBGV could not be established and agreed with听EFSA鈥檚 approach, using a level of no concern of听0.2 渭g/kg bw per day听for nephrotoxicity. The听COT听further considered this level to be adequately protective for maternal, reproductive and developmental effects. The RIVM set a BMDL05听of 48 渭g/kg bw per day as a POD听for reproductive effects, which was higher than the POD used to derive the level of no concern for nephrotoxicity, adding further confidence.

61.听听听听听听听听听听听听听听Estimated exposures for听citrinin听were not of toxicological concern for nephrotoxicity or reproductive and developmental effects. In addition,听citrinin听was not detected above the LOQ in any of the food groups considered, further confirming that dietary exposure to听citrinin听is low and supporting the conclusion that levels of听citrinin听in the diet are not of concern to UK consumers.

62.听听听听听听听听听听听听听However, due to limitations in the database a genotoxic and/or carcinogenic risk cannot be excluded. There is a need for further research to explore the potential genotoxic and carcinogenic effects of听citrinin.

厂迟补迟别尘别苍迟听COT/2025/04

List of Abbreviations and Technical terms

Abbreviation / Term	Definition
BMD	Benchmark dose
BMDL	Benchmark dose (lower confidence limit)
BMDL05	the听lower 95% confidence bound of the BMDL
bw	Body weight
COT	Committee on the Toxicity of Chemicals in Food, Consumer Products and the Environment
EFSA	European Food Standards Agency
FSA	Food Standards Agency
GP	General Practitioner
HBGV	Health based guidance value
Ig	Immunoglobulin
LB	Lower bound
LOQ	Limit of quantification
MOE	Margin of exposure
NOAEL	No observed adverse effect level
NVWA	Netherlands Food and Consumer Product Safety Authority
POD	Point of departure
ppm	Parts per million
RIVM	National Institute for Public Health and Environment
RMR	Red mould rice
RYR	Red yeast rice
SACN	Scientific Advisory Committee on Nutrition
SCE	Sister chromatid exchange
TDS	Total Diet Study
UB	Upper bound
UF	Uncertainty factor

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