In Utero and Lactational Exposure Study in Rats to Identify Replacements for Di(2-ethylhexyl) Phthalate

Abstract

Di(2-ethylhexyl) phthalate (DEHP) and other phthalates are ubiquitous environmental contaminants with endocrine disrupting properties. Two novel plasticizers, 1,4 butanediol dibenzoate (BDB) and dioctyl succinate (DOS), have been proposed as potential replacements. Both have desirable properties as plasticizers and minimal in vitro biological effects. Herein, we present an in utero and lactational exposure study comparing DEHP with BDB, DOS, and 1,2-cyclohexane dicarboxylic acid diisononyl ester (DINCH), a commercial alternative. Timed-pregnant Sprague-Dawley rats were gavaged with vehicle or one of these chemicals at 30 or 300 mg/kg/day from gestational day 8 until postnatal day (PND) 21. The offspring were examined for effects on developmental and endocrine markers until PND 46. DEHP treatment (300 mg/kg) decreased heart weights in dams and induced a significant decrease in anogenital index and an increase in hemorrhagic testes and multinucleated gonocytes in PND 3 male pups. An increase in the incidence of hemorrhagic testes was also observed on PND 8 after exposure to DINCH (30 and 300 mg/kg). The only other effects observed were decreases in serum alanine transaminase and magnesium in BDB 30 exposed dams. These data suggest that both BDB and DOS are viable alternative plasticizers.

Designing Green Plasticizers: Linear Alkyl Diol Dibenzoate Plasticizers and a Thermally Reversible Plasticizer

“…Three of the four compounds were as effective, or indeed, more effective than commercially-available DEHP in all but one tested material property. In combination with previous studies that showed rapid environmental degradability [21,24,30] and a low toxicity profile [26,27,28,29,35], 1,5-pentanediol dibenzoate in particular stands out as a good candidate green plasticizer to replace DEHP, in addition to 1,3-propanediol dibenzoate and 1,6-hexanediol dibenzoate. Further, while 1,4-butanediol dibenzoate is not a good candidate for a drop-in replacement of DEHP, due to its observed material hardening, this study suggests its use as a reversible heat-activated plasticizer or processing aid, with excellent plasticizer properties at mildly elevated temperatures.…”

“…Further, the proposed diol dibenzoate compounds could be good green candidates to replace phthalates, given previous work that identified their rapid biodegradation by soil bacteria [21,24,30]. Several toxicological in-vitro studies have also suggested a low hazard associated with these compounds [26,27,28,29,35], yet a more thorough toxicological analysis would likely be needed to confirm these findings.…”

“…For any plasticizer to truly qualify as a suitable replacement for problematic commercial plasticizers such as DEHP, many aspects beyond plasticizer performance need to be addressed, and the principles of green chemistry can provide a good framework for such an assessment [16,17,43]. The discussed diol dibenzoate compounds showed good plasticizing effectiveness in PVC, andcoupled with the low toxicity profiles of the compounds in bacteria (except 1,3-PrDB) [25], mammalian cell in-vitro assays [26,27], and an in-vivo study of 1,4-BDB with a focus on reproductive toxicity [28,29], these compounds appear to be good green plasticizer candidates. However, further toxicity testing to meet regulatory needs is required.…”

“…Furthermore, all four diol dibenzoates showed low toxicity profiles to the bacteria utilized in the MicroTox ® assay (except 1,3-PrDB) [25] and low toxicity profiles in several mammalian cell line in-vitro assays [26,27]. Furthermore, 1,4-BDB was found to not significant alter adult male reproductive function in an in-vivo rat study [28,29].…”

How Green is Your Plasticizer?

“…For example, there is a lack of information regarding the toxicity of and the fate of the metabolites of alternative plasticizers (which is particularly important given that many of the negative health effects associated with DEHP are known to stem from its metabolites rather than the parent compound), including toxicological endpoints such as carcinogenicity and endocrine disruption [40]. As new concerns have been raised about some of these DEHP replacements, such as DINP [11,41,42,43,44,45], it is increasingly important to produce truly green replacement plasticizers, with the factors advancing hazard reduction playing a bigger role in plasticizer development. Furthermore, with hundreds of commercial plasticizers available today for numerous applications, it is important to ensure that these and new plasticizers are evaluated and designed systematically and thoroughly, to avoid the “regrettable substitution” of one problematic compound with another [35].…”