Consultation publique concernant le projet de l’Anses d’analyse de la meilleure option de gestion des risques du TPP, de l’Homosalate et du BDE47
La stratégie nationale sur les perturbateurs endocriniens adoptée en avril 2014 comporte un volet dédié à l’expertise ; à ce titre l’Anses étudie chaque année des substances qui sont susceptibles d’être perturbatrices endocriniennes, ou qui sont utilisées en substitution de perturbateurs endocriniens, afin de vérifier l’innocuité ou les risques de ces substances, et de proposer les mesures adaptées pour les gérer.
Il a ainsi été demandé à l’Anses de réaliser un projet d’analyse de la meilleure option de gestion des risques pour les trois substances suivantes :
- le Triphenyl phosphate (TPP) (CAS 115-86-6)
- l’Homosalate (CAS 118-56-9)
- le BDE-47 (2,2’,4,4’-tetrabromodiphenyl ether) (CAS 5436-43-1)
Le MTES met à la consultation du public pendant 1 mois ces projets afin de recueillir les observations sur les recommandations de l’Anses. Ces commentaires permettront d’éclairer le gouvernement afin de définir la position des autorités françaises sur les modalités de gestion des risques de ces substances.
Comments regarding the "Analysis of the most appropriate risk management option (RMOA)" for Triphenyl phosphate (EC No. 204-112-2, CAS No. 115-86-6) report published on June 27, 2018., par LANXESS Deutschland GmbH , le 20 juillet 2018 à 15h01
Being the lead registrant for the existing joint submission for the mono-constituent substance Triphenyl phosphate (EC No. 204-112-2, CAS No. 115-86-6) [= TPP] LANXESS Deutschland GmbH is happy to share its thoughts on the "Analysis of the most appropriate risk management option (RMOA)" report published on June 27, 2018.
General comment :
We are surprised regarding the RMOA conducted by Anses on behalf of the French Member State Competent Authority (MSCA) with respect to TPP being a potential endocrine disruptor (ED) and parallel to the ongoing REACH substance evaluation (SEv) currently conducted by MSCA UK on the basis of the same grounds of concern.
Comment on the ’Cover note’ :
Being at the moment the only manufacturer of TPP as such we would like to note that to our understanding TPP, if at all, would only be a potential alternative to decabromodiphenyl ether (decaBDE) for some niches applications that represent far less than 5% of the decaBDE applications relevant for the European Union (EU).
Comment on Chapter 3.2.1 ’Health data’ :
We would like to note that we consider the data base evaluated in the RMOA for the human health assessment of TPP not fully complete as in our view relevant information is missing.
In October 2015 new information regarding TPP was submitted to ECHA in form of an updated REACH registration dossier. This new information comprised of data regarding two new toxicological studies that were requested in ECHA’s decision on a compliance check (decision number CCH-D-0000002044-86-04/F), i.e. a 90-day repeated dose toxicity study (OECD TG 408) in the rat (van Otterdijk, 2015) and a developmental toxicity study (OECD TG 414) in the rabbit (Peter, 2015).
TPP has been included in the community rolling action plan (CoRAP) for a SEv to be conducted by MSCA UK in the year 2017. As agreed with MSCA UK updated information regarding TPP was submitted to ECHA in May 2017. Among other new (literature) data an ‘Assessment on potential Endocrine Activity (toxicity/human health)’ (Tegethoff, 2017) according to the ‘OECD Conceptual Framework for Testing and Assessment of Endocrine Disrupters (as revised in 2012)’ (OECD TG 150) was included into the dossier.
Of this new information to our understanding only the 90-day repeated dose toxicity study in the rat (van Otterdijk, 2015) is considered in the RMOA whereas neither the developmental toxicity study in the rabbit (Peter, 2015) nor the assessment on potential endocrine activity (Tegethoff, 2017) are mentioned or discussed.
We, therefore, refer to the information submitted to ECHA in May 2017 for having the full picture of the available information of that time.
In the following we will provide a brief description of the outcome of the developmental toxicity study and the assessment on potential endocrine activity not mentioned/discussed in the RMOA report :
In the developmental toxicity study following OECD TG 414 TPP was administered by oral gavage to pregnant rabbits from days 6 to 28 of gestation in doses of 32, 80, and 200 mg/kg bw/day (Peter, 2015). Based on the results of this study, both the maternal and developmental No Observed Adverse Effect Level (NOAEL) was determined with 200 mg/kg bw/day, since no adverse effects were observed. No higher doses could be tested in pregnant rabbits based on toxicity in dose range finding studies.
The report on the assessment on potential endocrine activity of TPP concludes that following the OECD Conceptual Framework (CF) for Testing and Assessment of Endocrine Disrupters (as revised in 2012) there is no reliable evidence of a specific and biologically relevant endocrine activity of TPP throughout all OECD CF level studies, i.e. in vitro assays and experimental animal studies. Based on a weight of evidence approach of all available toxicity data triphenyl phosphate is not an endocrine disruptor with respect to human health (Tegethoff, 2017).
Unfortunately the web form for the public consultation does not allow for attaching supporting documents. However, LANXESS is happy to provide Anses with the quoted study/assessment reports.
Comment on Chapter 126.96.36.199 ’E-fate and Ecotoxicity of TPP’ :
The RMOA report notes that for "the short term toxicity test, the highest value corresponds to a 84 % inhibition of the nitrogenase activity when exposed to 0.1 mg/L". It should be noted that the information in the present registration dossier for TPP is misleading. In fact when exposed to 0.1 mg TPP/L the nitrogenase activity was reduced to 84 % corresponding to a 16 % inhibition of the nitrogenase activity. Thus inhibition of the nitrogenase activity is not the most sensitive endpoint for the short term toxicity tests. However, we agree with Anses that the available data allow for classification of TPP as Aquatic acute 1, H400.
Further the RMOA is implying that in the registration dossier for TPP "long term data (…) solely based on tests with fish (Oncorhynchus mykiss)" were considered for ecotoxicity assessment. This is not correct, because in the dossier long-term data for invertebrates and algae were presented and have been taken into account for ecotoxicity assessment. However, as the available NOECs for fish were much more critical these were discussed more intensive in the dossier.
We disagree with Anses conclusion that TPP qualifies for being classified as Aquatic chronic 1, H410.
Mayer et al., 1981, reported a NOEC ≥ 0.0014 mg/L for fish, because this was the highest concentration tested in the study. For this reason in the registration dossier the study by Mayer et al. was only considered as a supporting study. As described in the study “growth and survival were not affected in rainbow trout fry exposed to TPP” and regarding eye abnormalities “TPP had no effect at any concentration tested”. If the study by Mayer et al. would have been the only study on this endpoint available the highest concentration tested (0.0014 mg/L) could in principle have been considered as a NOEC. However, there were several other relevant data including the key study by Sitthichaikasem, 1978, that allow for the conclusion that there were no TPP related effects up to the test concentration of 0.037 mg/L.
In the fish study reported by Sitthichaikasem, 1978, based on growth and weight for the sac-frys of rainbow trout, a significant deviation was found at a concentration of 0.055 mg/L in comparison to the control. Based on these data an EC10 of 0.037 mg/L was calculated and taken as equipollent to the NOEC. It should be noted that when repeating the test with fingerlings a NOEC of 0.055 mg/L was observed.
Based on the aforementioned we are of the opinion that the applied NOEC (0.037 mg/L) should be considered as a reliable value that is sufficiently taking any potential hazard for the environment into account. Consequently, a classification as Aquatic chronic 2, H411 is sufficient for TPP.
Comment on Chapter 188.8.131.52 ’Endocrine disruptor characteristic of TPP for the environment’ :
The RMOA report indicates that TPP is listed in the TEDX list of potential endocrine disruptors and was identified in the US EPA EDSP ToxCast program for endocrine disruption bioactivity.
However, to the best of our knowledge at present TEDX only lists two studies (Kojima et al., 2013 and Liu et al., 2013). These studies could be relevant for the assessment whether or not TPP may have endocrine disruption (ED) activity in the environment. Kojima et al. seems to be considered not relevant, at least it was not included in the RMOA. Liu et al. was included in the RMOA but should in our view not be considered relevant as effects mostly occur at concentrations where already acute toxicity is observed.
Furthermore, the RMOA quotes the US EPA EDSP (ToxCast) program on potential endocrine disruptors as further support for an ED concern. ToxCast, however, demonstrated that there was no thyroid receptor activity at all. Only one of eight androgen receptor and 8 of 16 estrogen receptor bioassays revealed bioactivity. The androgen receptor as well as the estrogen receptor activities were only detected at concentrations higher than the EC50 set for TPP. Thus, the ToxCast data clearly do not point to a specific mode of action such as endocrine (disruptive) activity but rather to effects which are based on cytotoxicity.
Table 6 of the RMOA lists several published studies which have been identified in a literature research on potential ED properties of TPP. Unfortunately, only a listing of (potential) effects without any (detailed) discussion on the findings is provided. Data reliability, consistency, and plausibility were not discussed. There is no discussion e.g. on the conclusiveness of the data in light of findings mostly at cytotoxicity or acute toxicity concentrations (e.g. Liu et al., 2013). The listing of studies is followed by a short summary of findings which support the ED concern while there is no discussion of inconsistencies and other issues critical for the conclusion on potential ED properties of TPP. The RMOA concludes that "there is significant evidence that TPP can interfere with endocrine system and impaired reproduction by impacting egg production and hatchability in zebrafish and could be considered as being an ED for environment."
At least to LANXESS it is not comprehensible how such a concluding statement was derived in light of the listed data not being discussed in the RMOA. The listed data are to our understanding of exploratory nature (e.g. did not follow validated guideline study protocols) and so far neither a respective reliability assessment nor a comprehensive data evaluation is available.
Table 7 lists studies regarding (potential) “neurotoxic, metabolic and heart development effects of TPP”. With only four studies listed this dataset is very limited and information regarding reliability assessment and/or comprehensive data evaluation are not presented. Therefore, we welcome that Anses decided not to draw any conclusions on the basis of such a limited database.
Comment on Chapter 184.108.40.206 ’Environmental concentrations’ :
Environmental concentrations of TPP based on only one study are reported. The RMOA notes that the reported concentrations are close to concentrations at which adverse effects were observed in different ecotoxicological tests and, furthermore, that this is “indicating that the observed effects may occur in the environment”. We wish to understand why only one publication with monitoring data was considered in the RMOA as there should be plenty of monitoring data available among the published literature. It is not evident to us whether or not data of a single study are representative for EU surface waters. Therefore, in our view more and representative monitoring data should be included and conclusions on potential effects in the environment should only be drawn based on data which is representative for EU surface water concentrations.
Comment on Chapter ’3.3 General conclusion’ :
We concur with Anses to await the studies running at the US National Toxicology Program (NTP) including a ’Modified One-Generation Study in the rat’ before any further action is initiated. This study will give relevant additional information of potential toxicity of TPP. In addition, the outcome of the ongoing SEv conducted by MSCA UK will give further input for the discussion.
Mayer FL, Adams WJ, Finley MT, Michael PR, Mehrle PM, Saeger VW 1981 : Phosphate Ester Hydraulic Fluids : An Aquatic Environmental Assessment of Pydrauls 50E and 115E. (publication), Aquatic Toxicology and Hazard Assessment, Fourth Conference. ASTM STP 737, D.R. Branson and K.L. Dickson, Eds. : 103-123.
Peter B 2015 : Prenatal Developmental Toxicity Study of Triphenyl Phosphate in Rabbits by Oral Gavage (study report), Testing laboratory : WIL Research Europe BV, 5231 DD’s Hertogenbosch, The Netherlands, Report no : Projekt 505944. Owner company ; LANXESS Deutschland GmbH, Germany, Report date : Jun 15, 2015.
Sitthichaikasem S 1978 : Some toxicological effects of phosphate esterson Rainbow Trout and Bluegill. (Ph.D. dissertation), Ph.D. dissertation, Iowa State University, Ames, Iowa. Testing laboratory : Dept. of Animal Ecology, Iowa State University.
Tegethoff K 2017 : Triphenyl phosphate (EC No. 204-112-2, CAS No. 115-86-6) - Assessment of potential endocrine activity (toxicity/human health) (review of available data on a potential endocrine activity with respect to human health), Testing laboratory : Bayer AG, DD-ED-Product Stewardship Industrial Chemicals & Operations, 42096 Wuppertal, Germany, Owner company ; LANXESS Deutschland GmbH, Germany, Report date : May 2, 2017.
van Otterdijk FM 2015 : 90-Day oral toxicity study with triphenyl phosphate by dietary administration in the rat (study report), Testing laboratory : WIL Research Europe B.V., 5231 DD’s-Hertogenbosch, The Netherlands, Report no : Project 505940. Owner company ; LANXESS Deutschland GmbH, Germany, Report date : Apr 30, 2015.