Letter to the Editor Regarding Albert O. et al. (2017). Identifying Greener and Safer Plasticizers: A Four-Step Approach

Letter to the Editor Regarding Albert O. et al. (2017). Identifying Greener and Safer... Albert et al. (2017) propose a 4-step approach for the design, characterization, and toxicological testing of alternatives to phthalate plasticizers. To illustrate their approach, activities of their lab to identify replacements for (Di-2(ethylhexyl) phthalate) are presented. However, the article contains claims that need to be challenged. Further, the process described for the identification of new and safer plasticizers suffers from considerable deficiencies. Consequently, significant data gaps for the alternatives proposed by the authors make it difficult to reach a conclusion on their safe use. The authors’ claim that the approach presented would constitute the first systematic process for the design of alternatives to (Di-2(ethylhexyl) phthalate) is clearly overstated and disregards the availability of proven and well-tested alternatives already in the market. LACK OF NEED TO DEMONSTRATE SAFE USE OF SUBSTITUTES The statement “…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 wrong and is contradicted by existing chemical legislations. The Canadian Environmental Protection Act (CEPA, 1999) or the European REACH regulation (Registration, Evaluation, Authorization and Restriction of Chemicals, Regulation (EC) No 1907/2006) apply for new and existing chemicals and include the need to provide hazard data to support risk assessment and risk management with the aim to ensure safe use of chemicals for the worker, the general population and the environment. The webpage of Environment and Climate Change Canada states: “Regulations were created to ensure that no new substances (chemicals, polymers, or animate products of biotechnology) are introduced into the Canadian marketplace before an assessment of whether they are potentially toxic has been completed, and any appropriate or required control measures have been taken.” The European chemicals legislation REACH requires producers or importers not only to provide data for hazard identification but also a Chemical Safety Report (REACH, Article 14) which is mandatory for any REACH registration of products with a production/import volume of 10 tons per year or more. CHARACTERIZATION OF PROPOSED ALTERNATIVES Glass transition temperature and tensile strength of test bars are parameters that are important but not sufficient to conclude on suitability of molecules as plasticizers. The hazard profile of the alternatives proposed by the authors is inconclusive. The OECD limit dose of 1000 mg/kg body weight per day (eg, OECD 407, 2008) was not covered and no justification was given, especially for butane-1, 4-diol dibenzoate (BDB). Thai et al. (2007) showed for butane-1-4-diol, a possible metabolite of BDB, rapid absorption and extensive metabolism in humans resulting in gamma-hydroxybutyric acid, also known as “liquid ecstasy”. In contrast to the limited testing data for the alternatives proposed by the authors, doses used in regulatory testing for the commercial plasticizers cited cover or even exceed the OECD limit dose. UNFOUNDED ALLEGATIONS AGAINST DINCH Apart from a questionable effect in rats, described as “hemorrhagic testes”, that was observed on postnatal day (PND) 8 but not on PND 21, the results presented and those published by Nardelli et al. (2017) and referenced by Albert et al., are very much in favor of the commercially available plasticizer DINCH. The entirety of the results published or cited by Albert et al. affirms the conclusion that DINCH is not an endocrine disruptor. As demonstrated by the authors, a variety of parameters were not affected by DINCH: organ weights and serum parameters of dams at weaning, markers of pup growth and organ weights of male and female pups, markers of female or male endocrine function (anogenital index, vaginal opening), serum hormone levels in female or male offspring (PND 21), ovarian and testicular steroidogenic gene expression (PND 21), histological examination of testes at PND 3 and PND 21, and number of normal gonocytes and the lack of an increase in multinucleated gonocytes. Hence, the postulated need for a “deeper exploration” of DINCH is not substantiated by a scientific rationale and is clearly contradicted by independent evaluations and regulatory peer-reviews as referenced by Otter (2016). Although the authors claim a “lack of peer-reviewed studies regarding its safety or potential toxicity” they contradict themselves by: acknowledging that EFSA, the European Food Safety Authority, has approved DINCH as food contact material following an in-depth regulatory peer-review of the complete studies citation of David et al. (2015), a repeat dose toxicity study covering the intravenous route to support the risk assessment of DINCH in medical device applications. ACKNOWLEDGMENT The author is a regulatory toxicologist employed by BASF SE, a producer of cyclohexane-1, 2-dicarboxylic acid, diisononyl ester (brand name: Hexamoll® DINCH). REFERENCES Albert O., Nardelli T. C., Hales B. F., Robaire B. ( 2017). Identifying greener and safer plasticizers: A 4-step approach. Tox. Sci . kfx156, https://doi.org/10.1093/toxsci/kfx156. CEPA (1999): https://www.canada.ca/en/environment-climate-change/services/canadian-environmental-protection-act-registry/related-documents.html; last accessed October 18, 2017. David R. M., White R. D., Larson M. J., Herman J. K., Otter R. ( 2015). Toxicity of Hexamoll® DINCH® following intravenous administration. Toxicol. Lett . 238, 100– 109. Google Scholar CrossRef Search ADS PubMed  Environment and Climate Change Canada, Evaluating new substances, Assessment and management of new substances in Canada. Available at: http://www.ec.gc.ca/subsnouvelles-newsubs/default.asp? lang=En&n=AB189605-1; last accessed: October 18, 2017. EU REACH Regulation (EC) 1907/2006, Available at: https://echa.europa.eu/regulations/reach/legislation; last accessed: October 18, 2017. Nardelli T. C., Albert O., Lalancette C., Culty M., Hales B. F., Robaire B. ( 2017). In utero and lactational exposure study in rats to identify replacements for di(2-ethylhexyl) phthalate. Sci. Rep . 7, article: 3862. http://dx.doi.org/10.1038/s41598-017-03979-0. OECD. ( 2008), Test No. 407: Repeated Dose 28-day Oral Toxicity Study in Rodents , OECD Publishing, Paris. Otter R. ( 2016). The publication “Cyclohexane-1, 2-dicarboxylic acid diisononyl ester and metabolite effects on rat epididymal stromal vascular fraction differentiation of adipose tissue” by Enrico Campioli, Tam B. Duong, François Deschamps, Vassilios Papadopoulos. Environ. Res . 144, 145– 156. Merits some critical comments. Environ Res: 144, 165–166. Google Scholar CrossRef Search ADS   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. Pharm. Ther . 81, 178– 184. http://dx.doi.org/10.1038/sj.clpt.6100037 Google Scholar CrossRef Search ADS   © 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

Letter to the Editor Regarding Albert O. et al. (2017). Identifying Greener and Safer Plasticizers: A Four-Step Approach

Toxicological Sciences , Volume Advance Article – Dec 8, 2017

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Publisher
Oxford University Press
Copyright
© 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
ISSN
1096-6080
eISSN
1096-0929
D.O.I.
10.1093/toxsci/kfx273
Publisher site
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Abstract

Albert et al. (2017) propose a 4-step approach for the design, characterization, and toxicological testing of alternatives to phthalate plasticizers. To illustrate their approach, activities of their lab to identify replacements for (Di-2(ethylhexyl) phthalate) are presented. However, the article contains claims that need to be challenged. Further, the process described for the identification of new and safer plasticizers suffers from considerable deficiencies. Consequently, significant data gaps for the alternatives proposed by the authors make it difficult to reach a conclusion on their safe use. The authors’ claim that the approach presented would constitute the first systematic process for the design of alternatives to (Di-2(ethylhexyl) phthalate) is clearly overstated and disregards the availability of proven and well-tested alternatives already in the market. LACK OF NEED TO DEMONSTRATE SAFE USE OF SUBSTITUTES The statement “…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 wrong and is contradicted by existing chemical legislations. The Canadian Environmental Protection Act (CEPA, 1999) or the European REACH regulation (Registration, Evaluation, Authorization and Restriction of Chemicals, Regulation (EC) No 1907/2006) apply for new and existing chemicals and include the need to provide hazard data to support risk assessment and risk management with the aim to ensure safe use of chemicals for the worker, the general population and the environment. The webpage of Environment and Climate Change Canada states: “Regulations were created to ensure that no new substances (chemicals, polymers, or animate products of biotechnology) are introduced into the Canadian marketplace before an assessment of whether they are potentially toxic has been completed, and any appropriate or required control measures have been taken.” The European chemicals legislation REACH requires producers or importers not only to provide data for hazard identification but also a Chemical Safety Report (REACH, Article 14) which is mandatory for any REACH registration of products with a production/import volume of 10 tons per year or more. CHARACTERIZATION OF PROPOSED ALTERNATIVES Glass transition temperature and tensile strength of test bars are parameters that are important but not sufficient to conclude on suitability of molecules as plasticizers. The hazard profile of the alternatives proposed by the authors is inconclusive. The OECD limit dose of 1000 mg/kg body weight per day (eg, OECD 407, 2008) was not covered and no justification was given, especially for butane-1, 4-diol dibenzoate (BDB). Thai et al. (2007) showed for butane-1-4-diol, a possible metabolite of BDB, rapid absorption and extensive metabolism in humans resulting in gamma-hydroxybutyric acid, also known as “liquid ecstasy”. In contrast to the limited testing data for the alternatives proposed by the authors, doses used in regulatory testing for the commercial plasticizers cited cover or even exceed the OECD limit dose. UNFOUNDED ALLEGATIONS AGAINST DINCH Apart from a questionable effect in rats, described as “hemorrhagic testes”, that was observed on postnatal day (PND) 8 but not on PND 21, the results presented and those published by Nardelli et al. (2017) and referenced by Albert et al., are very much in favor of the commercially available plasticizer DINCH. The entirety of the results published or cited by Albert et al. affirms the conclusion that DINCH is not an endocrine disruptor. As demonstrated by the authors, a variety of parameters were not affected by DINCH: organ weights and serum parameters of dams at weaning, markers of pup growth and organ weights of male and female pups, markers of female or male endocrine function (anogenital index, vaginal opening), serum hormone levels in female or male offspring (PND 21), ovarian and testicular steroidogenic gene expression (PND 21), histological examination of testes at PND 3 and PND 21, and number of normal gonocytes and the lack of an increase in multinucleated gonocytes. Hence, the postulated need for a “deeper exploration” of DINCH is not substantiated by a scientific rationale and is clearly contradicted by independent evaluations and regulatory peer-reviews as referenced by Otter (2016). Although the authors claim a “lack of peer-reviewed studies regarding its safety or potential toxicity” they contradict themselves by: acknowledging that EFSA, the European Food Safety Authority, has approved DINCH as food contact material following an in-depth regulatory peer-review of the complete studies citation of David et al. (2015), a repeat dose toxicity study covering the intravenous route to support the risk assessment of DINCH in medical device applications. ACKNOWLEDGMENT The author is a regulatory toxicologist employed by BASF SE, a producer of cyclohexane-1, 2-dicarboxylic acid, diisononyl ester (brand name: Hexamoll® DINCH). REFERENCES Albert O., Nardelli T. C., Hales B. F., Robaire B. ( 2017). Identifying greener and safer plasticizers: A 4-step approach. Tox. Sci . kfx156, https://doi.org/10.1093/toxsci/kfx156. CEPA (1999): https://www.canada.ca/en/environment-climate-change/services/canadian-environmental-protection-act-registry/related-documents.html; last accessed October 18, 2017. David R. M., White R. D., Larson M. J., Herman J. K., Otter R. ( 2015). Toxicity of Hexamoll® DINCH® following intravenous administration. Toxicol. Lett . 238, 100– 109. Google Scholar CrossRef Search ADS PubMed  Environment and Climate Change Canada, Evaluating new substances, Assessment and management of new substances in Canada. Available at: http://www.ec.gc.ca/subsnouvelles-newsubs/default.asp? lang=En&n=AB189605-1; last accessed: October 18, 2017. EU REACH Regulation (EC) 1907/2006, Available at: https://echa.europa.eu/regulations/reach/legislation; last accessed: October 18, 2017. Nardelli T. C., Albert O., Lalancette C., Culty M., Hales B. F., Robaire B. ( 2017). In utero and lactational exposure study in rats to identify replacements for di(2-ethylhexyl) phthalate. Sci. Rep . 7, article: 3862. http://dx.doi.org/10.1038/s41598-017-03979-0. OECD. ( 2008), Test No. 407: Repeated Dose 28-day Oral Toxicity Study in Rodents , OECD Publishing, Paris. Otter R. ( 2016). The publication “Cyclohexane-1, 2-dicarboxylic acid diisononyl ester and metabolite effects on rat epididymal stromal vascular fraction differentiation of adipose tissue” by Enrico Campioli, Tam B. Duong, François Deschamps, Vassilios Papadopoulos. Environ. Res . 144, 145– 156. Merits some critical comments. Environ Res: 144, 165–166. Google Scholar CrossRef Search ADS   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. Pharm. Ther . 81, 178– 184. http://dx.doi.org/10.1038/sj.clpt.6100037 Google Scholar CrossRef Search ADS   © 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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