Results of NTP-Sponsored Mouse Cytogenetic Studies on 1,3-Butadiene, Isoprene, and Chloroprene

2011

EFSA Journal

The Panel on Food Contact Materials, Enzymes, Flavourings and Processing Aids of the European Food Safety Authority was requested to consider evaluations of flavouring substances assessed since 2000 by the Joint FAO/WHO Expert Committee on Food Additives (the JECFA), and to decide whether further evaluation is necessary, as laid down in Commission Regulation (EC) No 1565/2000. The present consideration concerns a group of 24 aliphatic, alicyclic and aromatic hydrocarbons evaluated by the JECFA (65th meeting). In the previous version of FGE.78, the Panel concluded that for 13 substances no applicable NOAEL was available for the substance itself or on a structurally related compound and therefore further data were required. Additional data (long term study of toxicity, mutagenicity studies and new tonnage figure) have now become available for beta‐myrcene [FL‐no: 01.008] and the present revision of FGE.78, FGE.78Rev1, includes the evaluation of these data. The substances were evaluated through a stepwise approach (the Procedure) that integrates information on structure‐activity relationships, intake from current uses, toxicological threshold of concern, and available data on metabolism and toxicity. Two substances [FL‐no: 01.011 and 01.013] are genotoxic in vitro and potentially carcinogenic, and are therefore not evaluated using the Procedure. The Panel concluded that the nine substance [FL‐no: 01.002, 01.005, 01.006, 01.010, 01.016, 01.019, 01.020, 01.045 and 01.077] do not give rise to safety concerns at the levels of dietary intake, estimated on the basis of the MSDI approach. For 13 substances [FL‐no: 01.003, 01.004, 01.007, 01.008, 01.009, 01.014, 01.017, 01.018, 01.024, 01.026, 01.029, 01.040 and 01.061] additional toxicity data are requested. For one substance [FL‐no: 01.024] EU production figure is needed to finalise the evaluation. Besides the safety assessment of these substances, the specifications for the materials of commerce have been considered. For two substances [FL‐no: 01.018 and 01.061] the isomeric composition is lacking. For 14 substances [FL‐no: 01.004, 01.007, 01.008, 01.009, 01.017, 01.018, 01.019, 01.020, 01.024, 01.026, 01.029, 01.040, 01.045 and 01.061] further information on the composition of mixture is requested.

Section: Ames Test (Preincubation Method)mentioning

confidence: 99%

Scientific Opinion on Flavouring Group Evaluation 78, Revision 1 (FGE.78Rev1): Consideration of aliphatic and alicyclic and aromatic hydrocarbons evaluated by JECFA (63rd meeting) structurally related to aliphatic and aromatic hydrocarbons evaluated by EF

2011

EFSA Journal

“…Supporting substances are listed in brackets. Negativ e (Tice et al, 1987;Tice, 1988;Shelby, 1990) Unpublished study report and published summary report of a valid multiple endpoint cytogenicity study sponsered by NTP, roughly in accordance with OECD guideline 475 (special dosage regimen used). Positive (Tice et al, 1987;Tice, 1988;Shelby, 1990) Unpublished study report and published summary report of valid cytogenicity study sponsered by NTP.…”

Section: Chromosomal Aberration Assaymentioning

confidence: 99%

Scientific Opinion on Flavouring Group Evaluation 25, Revision 2 (FGE.25Rev2): Aliphatic and aromatic hydrocarbons from chemical group 31

2011

EFSA Journal

The Panel on Food Contact Materials, Enzymes, Flavourings and Processing Aids of the European Food Safety Authority was requested to evaluate 37 flavouring substances in the Flavouring Group Evaluation 25, Revision 2, using the Procedure in Commission Regulation (EC) No 1565/2000. None of the substances were considered to have genotoxic potential. The substances were evaluated through a stepwise approach (the Procedure) that integrates information on structure-activity relationships, intake from current uses, toxicological threshold of concern, and available data on metabolism and toxicity. The Panel concluded that the ten substances 01.027, 01.028, 01.033, 01.034, 01.038, 01.039, 01.046, 01.054 and 01.057] do not give rise to safety concerns at their levels of dietary intake, estimated on the basis of the MSDI approach. For the remaining 27 candidate substances 01.022, 01.023, 01.030, 01.031, 01.032, 01.035, 01.036, 01.037, 01.042, 01.043, 01.044, 01.047, 01.050, 01.051, 01.052, 01.053, 01.055, 01.056, 01.058, 01.059, 01.060, 01.064, 01.066, 01.067, 01.070 and 10.078] no appropriate NOAEL was available and additional data are required. Besides the safety assessment of these flavouring substances, the specifications for the materials of commerce have also been considered. For five substances, the composition of the stereoisomeric mixture has to be specified further. The 37 candidate substances are aliphatic and aromatic hydrocarbons, which have been divided into eight subgroups: I) acyclic alkanes, II) acyclic alkenes, III) cyclohexene hydrocarbons, IVa) benzene hydrocarbons, IVb) napthalene hydrocarbons, IVc) diphenylmethane, V) bi-and tricyclic, nonaromatic hydrocarbons and VI) macrocyclic, non-aromatic hydrocarbons.Several of the 37 flavouring substances possess chiral centres and/or can exist as geometrical isomers. For five of the flavouring substances [FL-no: 01.021, 01.027, 01.032, 01.035 and 01.078] the stereoisomeric composition/composition of mixture has not been specified sufficiently.Thirty-one of the 37 candidate substances belongs to structural class I, two belongs to structural class II and four to structural class III according to the decision tree approach presented by Cramer et al. (1978).Thirty-three out of the 37 candidate substances have been reported to occur naturally in a wide range of food items.In its evaluation, the Panel as a default used the "Maximised Survey-derived Daily Intake" (MSDI) approach to estimate the per capita intakes of the flavouring substances in Europe. However, when the Panel examined the information provided by the European Flavouring Industry on the use levels in various foods, it appeared obvious that the MSDI approach in a number of cases would grossly underestimate the intake by regular consumers of products flavoured at the use level reported by the Industry, especially in those cases where the annual production values were reported to be small. In consequence, the Panel had reservations about the data on use and use levels provided and the intake...

“…1 (Heck et al, 1989) Abstracted by JECFA at their 63 rd meeting (JECFA, 2006a 6 An Ames test with cedrene washed (unspecified cedrene) was also submitted, but an adequate identification of the substance studied was not possible. Therefore the study is not further discussed Negative (Tice et al, 1987;Tice, 1988;Shelby, 1990) Unpublished study report and published summary report of a valid multiple endpoint cytogenicity study sponsered by NTP, roughly in accordance with OECD guideline 475 (special dosage regimen used). Positive (Tice et al, 1987;Tice, 1988;Shelby, 1990) Unpublished study report and published summary report of valid cytogenicity study sponsered by NTP.…”

Section: Sister Chromatid Exchange Testmentioning

confidence: 99%

Scientific Opinion on Flavouring Group Evaluation 78, Revision 2 (FGE.78Rev2): Consideration of aliphatic and alicyclic and aromatic hydrocarbons evaluated by JECFA (63rd meeting) structurally related to aliphatic hydrocarbons evaluated by EFSA in FGE.25Rev3

2015

EFS2

] is in the process of being deleted from the Union List. This revision is owing to additional genotoxicity data on β-caryophyllene .007] and 90-day studies in rats on β-caryophyllene .007] and myrcene [FLno: 01.008]. The substances were evaluated through a stepwise approach that integrates information on structureactivity relationships, intake from current uses, toxicological threshold of concern, and available data on metabolism and toxicity. The specifications for the materials of commerce are adequate for all substances. The Panel concluded that the 21 aromatic, aliphatic and alicyclic hydrocarbons 01.024, 01.026, 01.029, 01.040, 01.045 .029] based upon the respective MSDI for these substances and the NOAEL for ß-caryophyllene, range between 7400 and 1.1x10 7 . The Panel agrees that this provides sufficient safety margins and that these flavouring substances can be evaluated at step B4 in the Procedure as being of no safety concern.For four substances 01.018, 01.040 and 01.061] adequate margins of safety compared to the estimated levels of intake were estimated based upon a NOAEL from a 90-day study in rats, for the representative substance myrcene . The NOAEL of 44 mg/kg bw per day provides a margin of safety of 9100 for myrcene. The margins of safety for 01.040 and 01.061] based upon the respective MSDI for these substances and the NOAEL for myrcene are 4.8x10 5 , 4.4x10 6 and 1.1x10 7 , respectively. The Panel agrees that this provides sufficient safety margins and that these flavouring substances can be evaluated at step B4 in the Procedure as being of no safety concern. .026] and the mTAMDI have been considered. The mTAMDI figures calculated were above the threshold of concern for all four substances and more reliable exposure data are needed. On the basis of such additional data these flavouring substances should be reconsidered using the Procedure. For the remaining 17 substances evaluated through the Procedure use levels are needed to calculate the mTAMDIs in order to identify those flavouring substances that need more refined exposure assessment to finalise the evaluation.In order to determine whether the conclusion for the 21 JECFA evaluated substances can be applied to the materials of commerce, it is necessary to consider the available specifications.Adequate specifications including complete purity criteria and identity are available for all 21 JECFA evaluated substances.Thus, for the 21 substances 4