Response to Letter From Rainer Otter Regarding Albert O. et al. (2017). Identifying Greener and Safer Plasticizers: A Four-Step Approach

Response to Letter From Rainer Otter Regarding Albert O. et al. (2017). Identifying Greener and... In the letter written by Dr Rainer Otter, an employee of BASF, the company that manufactures cyclohexane-1, 2-dicarboxylic acid, diisononyl ester (brand name: Hexamoll DINCH), a number of allegations are made regarding our manuscript entitled “Identifying Greener and Safer Plasticizers: a Four-Step Approach” (Albert et al., 2017). We will address below each of the five points raised by Otter. LACK OF NEED TO DEMONSTRATE SAFE USE OF SUBSTITUTES Our statement that “…there is no requirement imposed on manufacturers, in any jurisdiction, to ensure that the replacement chemicals do not have the deleterious effect(s) associated with the original chemicals.” is asserted by Otter to be incorrect. This is not the case. The cited statement includes a reference to the “deleterious effects associated with the original chemicals”. To the best of our knowledge, there are no requirements imposed on manufacturers to specifically investigate the endocrine disruptive properties of new plasticizers, in particular with respect to their well-described reproductive endpoints, such as testicular and ovarian histology after fetal/lactational exposure; there is a large consensus on the adverse effects of the phthalates on these endpoints in the peer-reviewed literature. In Canada, requirements for new chemicals vary as certain thresholds of annual production are met. There is a defined set of assays to which every new chemical is subject. Our message is that replacement chemicals do not have to be proven safer than the chemicals they are meant to replace. For these alternatives, there are no criteria to assess perturbations during gestational development under the Canadian Environmental Protection Act (CEPA). Usually, chemicals are assessed in adult animals, following acute exposure and generic endpoints are ascertained. In the case of phthalates, several studies have found that the window of highest susceptibility for deleterious effects extends beyond the types of studies required by CEPA. Similarly, REACH does not require testing of chemicals to establish that a replacement chemical is free of the deleterious effects caused by the chemical they are replacing. CRITERIA FOR DETERMINING THE CHARACTERISTICS OF CHEMICALS AS PLASTICIZERS Otter indicates that the characterization of glass transition temperature and tensile strength of test bars are important but not sufficient to conclude on the suitability of molecules as plasticizers. We agree; we never indicated that these were sufficient characteristics. Indeed, in our manuscript we refer to Erythropel et al. (2012, 2013, 2015), where the characterization of proposed alternatives was extensively justified with the aim of finding responsible and efficient replacements to DEHP. Chemical engineers focused their research on plasticizing properties, biodegradability, and leaching of the new chemicals, not on optimizing each compound for specific applications. Dibenzoate plasticizers have already been used as alternatives to phthalate plasticizers and are as compatible, if not better, than phthalates as plasticizers. They have been used for a “variety of applications worldwide for more than 40 years” (Gravel and McBride, 2010). One limitation is their poor biodegradability due to the ether group found in diethylene glycol dibenzoate, and di(propylene glycol) dibenzoate. 1, 4 butanediol dibenzoate was designed to eliminate this functional group that resulted in limited biodegradation by soil microorganisms. One of our criteria was to identify chemicals that facilitate the processing of polyvinyl chloride (for which phthalates and other plasticizers, including DINCH are used) and have ideal characteristics in terms of plasticizers function. Glass transition temperature is an indicator of when a polymer becomes more amenable to processing. These chemicals facilitate the processing of PVC and form resins of suitable physical characteristics. As with any plasticizer, this will require optimization for specific applications. INCONCLUSIVE HAZARD PROFILE The dosages used in both the in vivo acute toxicity study (step 3) and the in utero and lactational exposure study (step 4) were extensively justified in the article. These choices were based on environmental relevance, peer-reviewed literature and guided by OECD recommendations. The study cited by Otter (Thai et al., 2007) used a single oral dose of 25 mg/kg to adult men. This has no resemblance to the experimental approach we describe. Thai et al. also mention 1, 4 butanediol was “quickly absorbed and cleared” with time to maximal plasma concentration and elimination on the scale of minutes. Although “liquid ecstasy” sounds scary, 1, 4 butanediol is already used routinely as a solvent and in the manufacture of some types of plastics, elastic fibers and polyurethanes. Material Safety Data Sheet documents describe the LD50 for 1, 4 butanediol in rats as 1525 mg/kg (which is well beyond any expected exposure) (Sciencelab.com). THE QUESTIONABLE FAVORABLE PROFILE OF DINCH The effects of DINCH on testicular development at PND 8 were based on observations in 4 pups in each of the low and high treatment groups out of 11 and 13 litters, respectively. Experimenters were blinded to the treatment, and these findings were validated by an appropriate statistical analysis. Such effects have previously been observed in the literature after exposure to DEHP. Therefore, there is no scientific rationale substantiating the description of these effects as “unfounded” and “questionable”. Although the implications of hemorrhagic testes may not be fully understood, they are not normal and have been observed following exposure to phthalates in our studies and in others. Vascularization is an important process in early stage testis development and studies have supported the idea that vascular disruption is a key event in male reproductive developmental toxicity (Leung et al., 2016). Furthermore, the presence of hemorrhagic testes implies that something is inherently wrong with the testicular development program; we know that alterations in this program may play a role in testicular dysgenesis syndrome in adulthood and be manifested in other ways (infertility, testicular cancer). To simply disregard this finding as “questionable” would be a disservice to scientific investigation. This is not the first report of toxicity in rodents following exposure to DINCH. Hyperplasia/hypertrophy of thyroid follicles and increases in testicular weight have been reported previously in regulatory documents at 107/128; 325/389; 1102/1311 mg/kg/d in males and females, respectively, in Wistar rats (ECHA, 2016). This same document reports a decrease in AGD/AGI in male pups exposed to DINCH, albeit at a high dose. Other published studies refer to alterations in adipocyte differentiation. Although the toxicity profile of DINCH appears to be less severe than that of DEHP, together these findings suggest DINCH does have biological activity. THE NEED FOR FURTHER STUDIES OF DINCH AS A POTENTIAL ENDOCRINE DISRUPTOR Otter affirms that DINCH is not an endocrine disruptor. There are a limited number of peer-reviewed articles devoid of conflict of interest on DINCH toxicity. The postulate that DINCH should be considered as a safe alternative to DEHP is based on the denial of the observed effects on testicular development in our study and of the growing array of literature raising concern about its endocrine disruptive properties (Boisvert et al., 2016; Campioli et al., 2015; 2017; Nardelli et al., 2015). Although our studies propose alternatives, and as mentioned by Otter, in many ways support the use of DINCH as a chemical having fewer effects than DEHP, there is no consensus in the field about the safety of DINCH. This can be due to a variety of reasons, including different species/strains of species used as models, window and route of exposure, and dose. There are studies suggesting DINCH may have endocrine disrupting properties and it is our responsibility as a scientific community to further explore this possibility, understand its relevance to human health, and generate a consensus as to whether DINCH, or any other alternative, is a viable replacement for plasticizers with well-established deleterious effects on human health. As previously stated, todays’ legislations do not include specific investigations of the well-documented effects of currently used plasticizers on the endocrine and reproductive systems. We therefore stand by our statement that the effects of DINCH need further investigation. Our article was intended to present a framework by which new chemicals should be developed and tested that is applicable to any chemical. Although DINCH, DEHP, DOS, and BDB were used as a “case-study”, the conceptual idea is that identifying responsible replacements prior to their being marketed is good practice and one that should become the norm. REFERENCES Albert O., Nardelli T., Hales B. F., Robaire B. ( 2017). Identifying greener and safer plasticizers: A 4-step approach. Toxicol. Sci . Advanced access published August 2, 2017. doi: 10.1093/toxsci/kfx156. Boisvert A., Jones S., Issop L., Erythropel H. C., Papadopoulos V., Culty M. ( 2016). In vitro functional screening as a means to identify new plasticizers devoid of reproductive toxicity. Environ. Res . 150, 496– 512. http://dx.doi.org/10.1016/j.envres.2016.06.033 Google Scholar CrossRef Search ADS PubMed  Campioli E., Duong T. B., Deschamps F., Papadopoulos V. ( 2015). Cyclohexane-1, 2-dicarboxylic acid diisononyl ester and metabolite effects on rat epididymal stromal vascular fraction differentiation of adipose tissue. Environ. Res . 140, 145– 156. http://dx.doi.org/10.1016/j.envres.2015.03.036 Google Scholar CrossRef Search ADS PubMed  Campioli E., Lee S., Lau M., Marques L., Papadopoulos V. ( 2017). Effect of prenatal DINCH plasticizer exposure on rat offspring testicular function and metabolism. Sci. Rep . 7, 11072. Google Scholar CrossRef Search ADS PubMed  ECHA (European Chemicals Agency). ( 2016). Analysis of the most appropriate risk management option: 1, 2-cyclohexane dicarboxylic acid diisononyl ester. Available at: https://www.echa.europa.eu/documents/10162/fc77bffd-e7ec-4846-b080-11de2564e582. Accessed November 29, 2017. Erythropel H. C., Maric M., Cooper D. G. ( 2012). Designing green plasticizers: Influence of molecular geometry on biodegradation and plasticization properties. Chemosphere  86, 759– 766. http://dx.doi.org/10.1016/j.chemosphere.2011.10.054 Google Scholar CrossRef Search ADS PubMed  Erythropel H. C., Dodd P., Leask R. L., Maric M., Cooper D. G. ( 2013). Designing green plasticizers: Influence of alkyl chain length on biodegradation and plasticization properties of succinate based plasticizers. Chemosphere  91, 358– 365. Google Scholar CrossRef Search ADS PubMed  Erythropel H. C., Brown T., Maric M., Nicell J. A., Cooper D. G., Leask R. L. ( 2015). Designing greener plasticizers: Effects of alkyl chain length and branching on the biodegradation of maleate based plasticizers. Chemosphere  134, 106– 112. Google Scholar CrossRef Search ADS PubMed  Gravel S. P., McBride E. ( 2010). Dibenzoate plasticizers offer a safer, viable solution to phthalates. adhesives and sealants industry. Available at: https://www.adhesivesmag.com/articles/88751-dibenzoate-plasticizers-offer-a-safer-viable-solution-to-phthalates. Accessed November 29, 2017. Leung M. C. K., Phuong J., Baker N. C., Sipes N. S., Klinefelter G. R., Martin M. T., McLaurin K. W., Setzer R. W., Darney S. P., Judson R. S., et al.   ( 2016). Systems toxicology of male reproductive development: Profiling 774 chemicals for molecular targets and adverse outcomes. Environ. Health Perspect . 124, 1050– 1061. Google Scholar PubMed  Nardelli T. C., Erythropel H. C., Robaire B. ( 2015). Toxicogenomic screening of replacements for di(2-ethylhexyl) phthalate (DEHP) using the immortalized TM4 sertoli cell line. PLoS One  10, e0138421. Google Scholar CrossRef Search ADS PubMed  Sciencelab.com, Chemicals and Laboratory Equipment.1.4-Butanediol MSDS. Available at http://www.sciencelab.com/msds.php? msdsId=9923182. Accessed November 29, 2017. Thai D., Dyer J. E., Jacob P., Haller C. A. ( 2007). Clinical pharmacology of 1, 4-butanediol and gamma-hydroxybutyrate after oral 1, 4-butanediol administration to healthy volunteers. Clin. Pharmacol. Ther . 81, 178– 184. http://dx.doi.org/10.1038/sj.clpt.6100037 Google Scholar CrossRef Search ADS PubMed  © The Author(s) 2017. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Toxicological Sciences Oxford University Press

Response to Letter From Rainer Otter Regarding Albert O. et al. (2017). Identifying Greener and Safer Plasticizers: A Four-Step Approach

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Abstract

In the letter written by Dr Rainer Otter, an employee of BASF, the company that manufactures cyclohexane-1, 2-dicarboxylic acid, diisononyl ester (brand name: Hexamoll DINCH), a number of allegations are made regarding our manuscript entitled “Identifying Greener and Safer Plasticizers: a Four-Step Approach” (Albert et al., 2017). We will address below each of the five points raised by Otter. LACK OF NEED TO DEMONSTRATE SAFE USE OF SUBSTITUTES Our statement that “…there is no requirement imposed on manufacturers, in any jurisdiction, to ensure that the replacement chemicals do not have the deleterious effect(s) associated with the original chemicals.” is asserted by Otter to be incorrect. This is not the case. The cited statement includes a reference to the “deleterious effects associated with the original chemicals”. To the best of our knowledge, there are no requirements imposed on manufacturers to specifically investigate the endocrine disruptive properties of new plasticizers, in particular with respect to their well-described reproductive endpoints, such as testicular and ovarian histology after fetal/lactational exposure; there is a large consensus on the adverse effects of the phthalates on these endpoints in the peer-reviewed literature. In Canada, requirements for new chemicals vary as certain thresholds of annual production are met. There is a defined set of assays to which every new chemical is subject. Our message is that replacement chemicals do not have to be proven safer than the chemicals they are meant to replace. For these alternatives, there are no criteria to assess perturbations during gestational development under the Canadian Environmental Protection Act (CEPA). Usually, chemicals are assessed in adult animals, following acute exposure and generic endpoints are ascertained. In the case of phthalates, several studies have found that the window of highest susceptibility for deleterious effects extends beyond the types of studies required by CEPA. Similarly, REACH does not require testing of chemicals to establish that a replacement chemical is free of the deleterious effects caused by the chemical they are replacing. CRITERIA FOR DETERMINING THE CHARACTERISTICS OF CHEMICALS AS PLASTICIZERS Otter indicates that the characterization of glass transition temperature and tensile strength of test bars are important but not sufficient to conclude on the suitability of molecules as plasticizers. We agree; we never indicated that these were sufficient characteristics. Indeed, in our manuscript we refer to Erythropel et al. (2012, 2013, 2015), where the characterization of proposed alternatives was extensively justified with the aim of finding responsible and efficient replacements to DEHP. Chemical engineers focused their research on plasticizing properties, biodegradability, and leaching of the new chemicals, not on optimizing each compound for specific applications. Dibenzoate plasticizers have already been used as alternatives to phthalate plasticizers and are as compatible, if not better, than phthalates as plasticizers. They have been used for a “variety of applications worldwide for more than 40 years” (Gravel and McBride, 2010). One limitation is their poor biodegradability due to the ether group found in diethylene glycol dibenzoate, and di(propylene glycol) dibenzoate. 1, 4 butanediol dibenzoate was designed to eliminate this functional group that resulted in limited biodegradation by soil microorganisms. One of our criteria was to identify chemicals that facilitate the processing of polyvinyl chloride (for which phthalates and other plasticizers, including DINCH are used) and have ideal characteristics in terms of plasticizers function. Glass transition temperature is an indicator of when a polymer becomes more amenable to processing. These chemicals facilitate the processing of PVC and form resins of suitable physical characteristics. As with any plasticizer, this will require optimization for specific applications. INCONCLUSIVE HAZARD PROFILE The dosages used in both the in vivo acute toxicity study (step 3) and the in utero and lactational exposure study (step 4) were extensively justified in the article. These choices were based on environmental relevance, peer-reviewed literature and guided by OECD recommendations. The study cited by Otter (Thai et al., 2007) used a single oral dose of 25 mg/kg to adult men. This has no resemblance to the experimental approach we describe. Thai et al. also mention 1, 4 butanediol was “quickly absorbed and cleared” with time to maximal plasma concentration and elimination on the scale of minutes. Although “liquid ecstasy” sounds scary, 1, 4 butanediol is already used routinely as a solvent and in the manufacture of some types of plastics, elastic fibers and polyurethanes. Material Safety Data Sheet documents describe the LD50 for 1, 4 butanediol in rats as 1525 mg/kg (which is well beyond any expected exposure) (Sciencelab.com). THE QUESTIONABLE FAVORABLE PROFILE OF DINCH The effects of DINCH on testicular development at PND 8 were based on observations in 4 pups in each of the low and high treatment groups out of 11 and 13 litters, respectively. Experimenters were blinded to the treatment, and these findings were validated by an appropriate statistical analysis. Such effects have previously been observed in the literature after exposure to DEHP. Therefore, there is no scientific rationale substantiating the description of these effects as “unfounded” and “questionable”. Although the implications of hemorrhagic testes may not be fully understood, they are not normal and have been observed following exposure to phthalates in our studies and in others. Vascularization is an important process in early stage testis development and studies have supported the idea that vascular disruption is a key event in male reproductive developmental toxicity (Leung et al., 2016). Furthermore, the presence of hemorrhagic testes implies that something is inherently wrong with the testicular development program; we know that alterations in this program may play a role in testicular dysgenesis syndrome in adulthood and be manifested in other ways (infertility, testicular cancer). To simply disregard this finding as “questionable” would be a disservice to scientific investigation. This is not the first report of toxicity in rodents following exposure to DINCH. Hyperplasia/hypertrophy of thyroid follicles and increases in testicular weight have been reported previously in regulatory documents at 107/128; 325/389; 1102/1311 mg/kg/d in males and females, respectively, in Wistar rats (ECHA, 2016). This same document reports a decrease in AGD/AGI in male pups exposed to DINCH, albeit at a high dose. Other published studies refer to alterations in adipocyte differentiation. Although the toxicity profile of DINCH appears to be less severe than that of DEHP, together these findings suggest DINCH does have biological activity. THE NEED FOR FURTHER STUDIES OF DINCH AS A POTENTIAL ENDOCRINE DISRUPTOR Otter affirms that DINCH is not an endocrine disruptor. There are a limited number of peer-reviewed articles devoid of conflict of interest on DINCH toxicity. The postulate that DINCH should be considered as a safe alternative to DEHP is based on the denial of the observed effects on testicular development in our study and of the growing array of literature raising concern about its endocrine disruptive properties (Boisvert et al., 2016; Campioli et al., 2015; 2017; Nardelli et al., 2015). Although our studies propose alternatives, and as mentioned by Otter, in many ways support the use of DINCH as a chemical having fewer effects than DEHP, there is no consensus in the field about the safety of DINCH. This can be due to a variety of reasons, including different species/strains of species used as models, window and route of exposure, and dose. There are studies suggesting DINCH may have endocrine disrupting properties and it is our responsibility as a scientific community to further explore this possibility, understand its relevance to human health, and generate a consensus as to whether DINCH, or any other alternative, is a viable replacement for plasticizers with well-established deleterious effects on human health. As previously stated, todays’ legislations do not include specific investigations of the well-documented effects of currently used plasticizers on the endocrine and reproductive systems. We therefore stand by our statement that the effects of DINCH need further investigation. Our article was intended to present a framework by which new chemicals should be developed and tested that is applicable to any chemical. Although DINCH, DEHP, DOS, and BDB were used as a “case-study”, the conceptual idea is that identifying responsible replacements prior to their being marketed is good practice and one that should become the norm. REFERENCES Albert O., Nardelli T., Hales B. F., Robaire B. ( 2017). Identifying greener and safer plasticizers: A 4-step approach. Toxicol. Sci . Advanced access published August 2, 2017. doi: 10.1093/toxsci/kfx156. Boisvert A., Jones S., Issop L., Erythropel H. C., Papadopoulos V., Culty M. ( 2016). In vitro functional screening as a means to identify new plasticizers devoid of reproductive toxicity. Environ. Res . 150, 496– 512. http://dx.doi.org/10.1016/j.envres.2016.06.033 Google Scholar CrossRef Search ADS PubMed  Campioli E., Duong T. B., Deschamps F., Papadopoulos V. ( 2015). Cyclohexane-1, 2-dicarboxylic acid diisononyl ester and metabolite effects on rat epididymal stromal vascular fraction differentiation of adipose tissue. Environ. Res . 140, 145– 156. http://dx.doi.org/10.1016/j.envres.2015.03.036 Google Scholar CrossRef Search ADS PubMed  Campioli E., Lee S., Lau M., Marques L., Papadopoulos V. ( 2017). Effect of prenatal DINCH plasticizer exposure on rat offspring testicular function and metabolism. Sci. Rep . 7, 11072. Google Scholar CrossRef Search ADS PubMed  ECHA (European Chemicals Agency). ( 2016). Analysis of the most appropriate risk management option: 1, 2-cyclohexane dicarboxylic acid diisononyl ester. Available at: https://www.echa.europa.eu/documents/10162/fc77bffd-e7ec-4846-b080-11de2564e582. Accessed November 29, 2017. Erythropel H. C., Maric M., Cooper D. G. ( 2012). Designing green plasticizers: Influence of molecular geometry on biodegradation and plasticization properties. Chemosphere  86, 759– 766. http://dx.doi.org/10.1016/j.chemosphere.2011.10.054 Google Scholar CrossRef Search ADS PubMed  Erythropel H. C., Dodd P., Leask R. L., Maric M., Cooper D. G. ( 2013). Designing green plasticizers: Influence of alkyl chain length on biodegradation and plasticization properties of succinate based plasticizers. Chemosphere  91, 358– 365. Google Scholar CrossRef Search ADS PubMed  Erythropel H. C., Brown T., Maric M., Nicell J. A., Cooper D. G., Leask R. L. ( 2015). Designing greener plasticizers: Effects of alkyl chain length and branching on the biodegradation of maleate based plasticizers. Chemosphere  134, 106– 112. Google Scholar CrossRef Search ADS PubMed  Gravel S. P., McBride E. ( 2010). Dibenzoate plasticizers offer a safer, viable solution to phthalates. adhesives and sealants industry. Available at: https://www.adhesivesmag.com/articles/88751-dibenzoate-plasticizers-offer-a-safer-viable-solution-to-phthalates. Accessed November 29, 2017. Leung M. C. K., Phuong J., Baker N. C., Sipes N. S., Klinefelter G. R., Martin M. T., McLaurin K. W., Setzer R. W., Darney S. P., Judson R. S., et al.   ( 2016). Systems toxicology of male reproductive development: Profiling 774 chemicals for molecular targets and adverse outcomes. Environ. Health Perspect . 124, 1050– 1061. Google Scholar PubMed  Nardelli T. C., Erythropel H. C., Robaire B. ( 2015). Toxicogenomic screening of replacements for di(2-ethylhexyl) phthalate (DEHP) using the immortalized TM4 sertoli cell line. PLoS One  10, e0138421. Google Scholar CrossRef Search ADS PubMed  Sciencelab.com, Chemicals and Laboratory Equipment.1.4-Butanediol MSDS. Available at http://www.sciencelab.com/msds.php? msdsId=9923182. Accessed November 29, 2017. Thai D., Dyer J. E., Jacob P., Haller C. A. ( 2007). Clinical pharmacology of 1, 4-butanediol and gamma-hydroxybutyrate after oral 1, 4-butanediol administration to healthy volunteers. Clin. Pharmacol. Ther . 81, 178– 184. http://dx.doi.org/10.1038/sj.clpt.6100037 Google Scholar CrossRef Search ADS PubMed  © The Author(s) 2017. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com

Journal

Toxicological SciencesOxford University Press

Published: Dec 8, 2017

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