Normativa UEJul. 30, 2011
UE: autoridad alimentaria emite informe sobre Hexabromocyclododecanes en alimentos
EFSA was asked by the European Commission to deliver a scientific opinion on hexabromocyclododecanes (HBCDDs) in food. HBCDDs are additive flame retardants primarily used in expanded and extruded polystyrene applied as construction and packing materials, and in textiles.
Technical HBCDD predominantly consists of three stereoisomers (α-, β- and γ-HBCDD). Also δ- and ε-HBCDD may be present but at very low concentrations. HBCDDs are present in the environment and likewise in biota and in food and feed. Data from the analysis of HBCDDs in 1,914 food samples were provided to EFSA by seven European countries, covering the period from 2000 to 2010. The Panel on Contaminants in the Food Chain (CONTAM Panel) selected α-, β- and γ-HBCDD to be of primary interest. Since all toxicity studies were carried out with technical HBCDD, a risk assessment of individual stereoisomers was not possible. Main targets were the liver, thyroid hormone homeostasis and the reproductive, nervous and immune systems. HBCDDs are not genotoxic. The CONTAM Panel identified neurodevelopmental effects on behaviour as the critical endpoint, and derived a benchmark dose lower confidence limit for a benchmark response of 10 % (BMDL10) of 0.79 mg/kg body weight. Due to the limitations and uncertainties in the current data base, the CONTAM Panel concluded that it was inappropriate to use this BMDL to establish a health based guidance value, and instead used a margin of exposure (MOE) approach for the health risk assessment of HBCDDs.
Since elimination characteristics of HBCDDs in animals and humans differ, the Panel used the body burden as starting point for the MOE approach. The CONTAM Panel concluded that current dietary exposure to HBCDDs in the European Union does not raise a health concern. Also additional exposure, particularly of young children, to HBCDDs from house dust is unlikely to raise a health concern.
© European Food Safety Authority, 2011
Following a request from the European Commission, the Panel on Contaminants in the Food Chain (CONTAM Panel) was asked to deliver a scientific opinion on hexabromocyclododecanes (HBCDDs) in food. HBCDDs are stereoisomers of 1,2,5,6,9,10-hexabromocyclododecane. Technical HBCDD predominantly consists of three stereoisomers (α-, β- and γ-HBCDD) present in relative amounts of 9-13 % α-HBCDD, <0.5-12 % β-HBCDD and 72-90 % γ-HBCDD. Also δ- and ε-HBCDD may be present in the technical product, although at very low concentrations. The HBCDD stereoisomers occur as enantiomer pairs.
HBCDDs constitute an important and widely used group of additive flame retardants primarily used in expanded and extruded polystyrene applied as construction and packing materials, and also used in textiles. Concentrations in products are usually in the range between 0.7 % and 3.0 % by weight. As they are mixed into polymers and not chemically bound to the plastic or textiles, HBCDDs might leach from the products into the environment. Technical HBCDD has been on the market since the 1960s but the use in insulation boards started in the 1980s.
HBCDD stereoisomers are susceptible to elimination of HBr and reductive debromination. Abiotic transformation of γ-HBCDD to α-HBCDD has been shown, and it can be concluded that α-HBCDD is the most persistent of the three main HBCDD stereoisomers.
Based on the composition of technical HBCDD and occurrence of the stereoisomers in food and the environment, the CONTAM Panel selected α-, β- and γ-HBCDD to be of primary interest for this opinion.
Following an advice of the CONTAM Panel, a monitoring programme was carried out starting in 2006 and results obtained from the analysis of HBCDDs in 1,914 food samples were provided by seven European countries, covering the period from 2000 to 2010. ‘Fish and other seafood’ was the food group with the highest number of samples followed by ‘Meat and meat products, ‘Milk and dairy products’ and ‘Eggs and egg products’. There were only few occurrence data in the food group ‘Food for infants and small children’. The data were characterised by a high proportion of non-detects. The analytical results were reported as total HBCDD or as α-HBCDD, β-HBCDD and γ HBCDD, whereas the sum of the three individual stereoisomers was calculated for the purpose of risk assessment. Overall, α-HBCDD is the main contributor to the total levels of HBCDDs in all food categories.
For the food groups of ‘Eggs and eggs products’, ‘Milk and dairy products’ and ‘Meat and meat products (including edible offal)’ the lower bound (LB) and upper bound (UB) of the sum of the three individual stereoisomers are 0.14 and 0.54 ng/g fat, 0.03 and 0.67 ng/g fat, 0.14 and 0.79 ng/g fat, respectively. For these food categories the sum of the three stereoisomers is higher than the reported values of total HBCDD. The CONTAM Panel noted that the high proportion of non-detects has an impact on the sum of the three stereoisomers, particularly on the UB estimates.
For the food group of ‘Fish and other seafood’ the CONTAM Panel concluded that the estimated mean LB and UB of the reported total HBCDD were a more realistic estimation of levels of HBCDDs in fish than the sum of individual stereoisomers. The LB and UB of the reported mean for total HBCDD are 0.98 and 1.16 ng/g wet weight.
The mean dietary exposure to HBCDDs across dietary surveys in European countries was estimated for children from three to ten years old (‘Other children’) ranging from 0.15 to 1.85 ng/kg body weight (b.w.) per day for the minimum LB and maximum UB, respectively. Total dietary exposure for adults is about half the exposure for ‘Other children, with minimum LB and maximum UB of, respectively, 0.09 and 0.99 ng/kg b.w. per day. Dietary exposure to HBCDDs is decreasing with increasing age down to 0.06 and 0.54 ng/kg b.w. per day for the minimum LB and maximum UB, respectively, for ‘Very elderly’ (from 75 years of age and older).
Similar exposure patterns across age classes are found for the dietary intake of high consumers (95th percentile). The minimum LB and maximum UB dietary intake of HBCDDs across dietary surveys in European countries are, respectively, 0.80 and 4.46 ng/kg b.w. per day for ‘Other children’, followed by ‘Adults’ with 0.39 and 2.07 ng/kg b.w. per day, and down to 0.27 and 1.26 ng/kg b.w. per day for the ‘Very elderly’.
For a specific population group consisting of high consumers of fish the total mean dietary UB intake of HBCDDs (maximum UB across European surveys) is 2.76 ng/kg b.w. per day. The total dietary UB intake of consumers of fish liver (once a week) is estimated to be 1.94 ng/kg b.w.
As contamination of food samples of plant origin is generally lower than that of food samples of animal origin, it can be assumed that the dietary exposure of vegetarians to HBCDDs is lower than that for people consuming a mixed diet.
For breast-fed infants with average human milk consumption (800 mL per day) the reported range for total HBCDD in human milk (0.13-31 ng/g fat) results in daily exposures of 0.60-142 ng/kg b.w. For infants with high human milk consumption (1,200 mL per day) this is 0.90-213 ng/kg b.w.
The available toxicokinetics data suggest that orally administered HBCDD is easily absorbed and rapidly distributed in different tissues, with some differences observed between γ- and α stereoisomer. In contrast to γ-HBCDD, α-HBCDD was found to concentrate in adipose tissue.
Debromination and hydroxylation seem to be the major metabolic pathways for HBCDDs, but stereoisomerisation of γ isomer to α- and β-isomers was observed in mice treated with γ-HBCDD. No stereoisomerisation of α-HBCDD was reported.
Calculation of elimination half-lives of HBCDD stereoisomers in female mice, based on concentrations in adipose tissue, vary from 3-4 days for γ-HBCDD, to 17 days for α-HBCDD. The half-life in humans for HBCDDs (reported as sum of α-, β- and γ-HBCDD) was estimated to be 64 days (range 23-219 days). This difference in kinetics affects the extrapolation of animal data to humans.
Toxicological studies have been carried out using different experimental designs with single or repeated administration during gestation, postnatally or in adulthood using technical HBCDD. The composition of these mixtures differs from the HBCDD profile found in wildlife and in foods. Main targets for HBCDD toxicity were the liver, thyroid hormone homeostasis, the reproductive, the nervous and the immune systems.
The activation of constitutive androstane receptor- (CAR) or pregnane-X-receptor (PXR)-dependent gene expression, leading to disruption of thyroid hormone homeostasis, is considered to be associated with neurodevelopmental effects on behaviour and may also be responsible for effects on reproduction.
The available studies indicate that HBCDDs are not genotoxic.
There is limited information from only one long-term toxicity/carcinogenicity study for HBCDDs in B6C3F1 mice, indicating that the incidence of altered foci in the liver of males was increased, as was the incidence of liver carcinoma in females, but without a dose-relationship. The CONTAM Panel noted that the incidence of liver carcinoma was within the range of background levels for this strain of mice. Given the lack of genotoxicity the Panel concluded that carcinogenicity is not a critical effect in the hazard characterisation of HBCDDs.
The two available epidemiological studies did not show any association between the levels of HBCDDs in blood and bone mineral density in an elderly female population, and between levels of HBCDDs in human milk and effects on neonatal thyroid-stimulating hormone (TSH).
Since all toxicity studies were carried out with technical HBCDD, a risk assessment of individual stereoisomers was not possible.
Based on the information from animal experiments the CONTAM Panel identified neurodevelopmental effects on behaviour in mice, observed in a study with single administration of technical HBCDD on postnatal day (PND) 10, as the critical end-point and derived a benchmark dose lower confidence limit for a benchmark response of 10 % (BMDL10) of 0.93 mg/kg b.w. to be used as reference point for the hazard characterisation.
Because elimination kinetics of HBCDDs in rodents and humans differ, external dose levels of HBCDDs associated with toxic effects in animals cannot be simply extrapolated for the risk assessment in humans. Instead, the internal dose or body burden provides a more appropriate dose metric for a direct comparison of effects in animals and humans. Based on the calculated BMDL10 value of 0.93 mg/kg b.w. as derived from a study using a single oral administration, and considering an oral absorption of in rodents of 85 %, a body burden at the BMDL10 of 0.79 mg/kg b.w. was derived.
This body burden estimate could in principle be used as the basis to establish a health based guidance value, e.g. a tolerable daily intake. The CONTAM Panel concluded however, that due to the limitations and uncertainties in the current data base on HBCDDs, the derivation of a health based guidance value was not appropriate. Instead, the Panel used a margin of exposure (MOE) approach for the risk characterisation of HBCDDs, by comparing the minimum LB and maximum UB dietary intake for HBCDDs with the estimated human intake associated with the body burden at the BMDL10.
The maximum UB dietary intake for average and high adult consumers results in an MOE of about 3,000 and 1,450, respectively. For high fish consumers the MOE is 1,000 and for regular consumers of fish liver 1,500. For children of the age of 3-10 years with an average and high consumption, the maximum UB dietary intake results in an MOE of 1,600 and 700, respectively.
Usually a MOE of 100, covering uncertainties and variability with respect to kinetic and dynamic differences between animal species and humans (factor 4 × 2.5 = 10) and within the human population (factor 3.2 × 3.2 = 10), is considered sufficient to conclude that there is no health concern. Since the MOE approach is based on a body burden comparison between animals and humans, the potential kinetic differences have been accounted for. Equally, by focusing on the body burden associated with a BMDL10 for neurobehavioural effects in mice induced during a relevant period for brain development, and applying this body burden to the entire life span in humans, individual difference in susceptibility has been covered. Therefore, the calculated MOE should be sufficient to cover inter-species differences in dynamics for the effects observed (factor 2.5).
Considering the uncertainty in the elimination half-life in humans the CONTAM Panel concluded that the MOE should also cover intra-individual differences in kinetics (factor 3.2). This implies that an MOE larger than 8 (2.5 × 3.2) might indicate that there is no health concern.
The calculated MOEs for the various sub-populations, based on the maximum UB dietary intake, are in the range of 700 to 3,000 and thus much larger than a factor of 8. In addition, the CONTAM Panel noted that use of the UB estimates would have resulted in an overestimation of the risk. Therefore it was concluded that current dietary exposure to HBCDD does not raise a health concern.
For breast-fed infants with average or high human milk consumption MOEs ranging from 21 to 5,000 and from 14 to 3,300 have been estimated. The lowest values for these MOEs are about 2.6 and 1.7 fold larger than a factor of 8. Also considering that consumption of human milk occurs only through a restricted period in life, the CONTAM Panel concluded that it is unlikely that exposure via human milk raises a health concern.
The CONTAM Panel was not able to assess the dietary intake of infants (< 1 year) and toddlers (1 3 years) but assumed that dietary intake of contaminants such as HBCDDs of these age groups usually is lower than that of breast-fed infants.
Therefore it concluded that it is also unlikely that dietary exposure to HBCDDs of infants and toddlers will raise a health concern.
Due to the uncertainty regarding the estimated half life of HBCDDs in humans, the CONTAM Panel also considered information on biomarkers of exposure for comparison with the outcome of the MOE approach. It identified information on total HBCDD concentrations in adipose tissue as being most relevant, because they best reflect long-term exposure to HBCDDs. Concentrations in adipose tissue range from <0.5 to 7.5 ng/g fat. When these values are converted into body burden concentrations assuming a fat content of 25 % for the human female adult body, and these body burdens are compared with the body burden at the BMDL10 of 0.79 mg/kg b.w., a margin of 420 to >6,300 can be estimated. A similar range is found using data of HBCDDs in human serum. The CONTAM Panel concluded that this result supports the conclusion that current dietary exposure to HBCDDs in the EU does not raise a health concern.
Dust in homes, classrooms and cars can be an additional source of exposure to HBCDDs for children. Based on a ‘typical’ exposure scenario, ingestion of HBCDDs by young children (1-6 years old) via dust has been estimated to be about 5.9 ng/kg b.w. per day. In the same study a ‘high’ exposure scenario resulted in an estimated daily exposure through dust of 330 ng HBCDDs/kg b.w. The CONTAM Panel noted however that considerably lower intake estimates for HBCDDs from dust has been reported in another study. It therefore concluded that the ‘typical’ exposure scenario provided the most realistic estimate of exposure to HBCDDs from dust. This ‘typical’ exposure scenario results in a MOE of about 500 for exposure to dust only. Combining the UBs of average or high dietary intake of children of this age group with this ‘typical’ dust exposure leads to a total exposure to HBCDDs of about 7.7 and 10.3 ng/kg b.w., respectively. The resulting MOEs are about 390 and 300, respectively. Taking into account the uncertainties in the dust exposure estimates and considering the use of UB dietary intake estimates, the CONTAM Panel concluded that the available information indicates that it is unlikely that additional exposure to HBCDDs from dust raises a health concern.