Final Report on the Safety Assessment of Acetyl Triethyl Citrate, Acetyl Tributyl Citrate, Acetyl Trihexyl Citrate, and Acetyl Trioctyl Citrate

Abstract

Acetyl Triethyl Citrate, Acetyl Tributyl Citrate, Acetyl Trihexyl Citrate, and Acetyl Trioctyl Citrate all function as plasticizers in cosmetics. Additionally, the Trihexyl and Trioctyl forms are described as skin-conditioning agents-emollients, although there are currently no reported uses of Acetyl Trihexyl Citrate or Acetyl Trioctyl Citrate. Acetyl Triethyl Citrate and Acetyl Tributyl Citrate are used in nail products at concentrations up to 7%. Recognizing that there are no reported uses of Acetyl Trihexyl or Trioctyl Citrate, if they were to be used in the future, their concentration of use is expected to be no higher than that reported for Acetyl Triethyl and Tributyl Citrate. These ingredients were sufficiently similar in structure that safety test data on one were considered applicable to all. Approximately 99% of orally administered Acetyl Tributyl Citrate is excreted-intermediate metabolites include acetyl citrate, monobutyl citrate, acetyl monobutyl citrate, dibutyl citrate, and acetyl dibutyl citrate. In acute, short-term, subchronic, and chronic feeding studies, these ingredients were relatively nontoxic. Differences from controls were either not statistically significant or not related to any organ toxicity. Ocular exposures produced moderate reactions that cleared by 48 hours after instillation. Dermal application was not toxic in rabbits. In a guinea pig maximization test, Acetyl Triethyl Citrate was a sensitizer whereas Acetyl Tributyl Citrate was not. Limited clinical testing of Acetyl Triethyl Citrate and Acetyl Tributyl Citrate was negative for both skin irritation and sensitization. These clinical data were considered more relevant than the guinea pig maximization data, suggesting to the Cosmetic Ingredient Review Expert Panel that none of these ingredients would be a sensitizer. Physiologic effects noted with intravenous delivery of Acetyl Triethyl Citrate or Acetyl Tributyl Citrate include dose-related decreases in blood pressure and intestinal muscular spasms. These ingredients were not genotoxic in bacterial or mammalian test systems. No significant differences in tumor induction (lymphomas) were noted in rats fed Acetyl Tributyl Citrate for 2 year. Acetyl Tributyl Citrate was not a developmental or reproductive toxicant in studies in mice and rats. Based on all the available data, these ingredients were considered safe as used in cosmetics.

Pharmacokinetic Properties of Acetyl Tributyl Citrate, a Pharmaceutical Excipient

“…According to a report on the safety of ATBC, approximately 99% of 14C-ATBC orally administered to rats was excreted in urine (59–70%), feces (25–36%), and expired air (2%) within 48 h [3]. As reported in previous research, the metabolism of ATBC occurred rapidly in the present study.…”

“…As reported in previous research, the metabolism of ATBC occurred rapidly in the present study. The metabolites mentioned in the previous report included acetyl citrate, monobutyl citrate, acetyl monobutyl citrate, dibutyl citrate, and acetyl dibutyl citrate [3]. Thus, the metabolites are mainly generated via hydrolysis and any significant toxic issues are not expected based on their chemical structures.…”

“…The toxicity of ATBC has been investigated thoroughly in animals. Research showed that the acute oral LD50 for ATBC in mice or rats was greater than 25 g/kg and that ATBC was not associated with any significant reproductive toxicity in mice or rats [3]. The European Commission stated that the no-observed adverse effect level of ATBC was 100 mg/kg bw/day (C7/GF/csteeop/ATBC/080104 D(04)).…”

Pharmacokinetics and Metabolism of Acetyl Triethyl Citrate, a Water-Soluble Plasticizer for Pharmaceutical Polymers in Rats

“…In terms of acute oral toxicity, the LD50 for ATEC was reported to be approximately 7 mL/kg in rats and cats [6]. ATEC doses of 6–12 mL/kg caused progressive lowering of the blood pressure [7]. In a study of short-term oral toxicity, feeding rats a diet containing 1–4 g/kg of ATEC for 6 weeks did not affect growth or induce toxicity [6].…”

“…However, concerns have been raised about potential blood pressure lowering effects of ATEC [7]. In addition, acetyl tributyl citrate (ATBC), which is structurally similar to ATEC, was shown to induce intestinal cytochrome P450 3A4 and affect female reproduction at a low dose [11].…”