Comments on “Ambient and Dosed Exposure to Quaternary Ammonium Disinfectants Causes Neural Tube Defects in Rodents”

The article “Ambient and Dosed Exposure to Quaternary Ammonium Disinfectants Causes Neural Tube Defects in Rodents” by Hrubec et al. (Hrubec et al., 2017) reports on a study of quaternary ammonium compounds (QACs). The study suffers from critical shortcomings, asserts conclusions unsupported by data and is contradicted by robust toxicology data sets on the QACs. Hrubec et al. fail to account for significant confounding factors to which any observed developmental effects may be attributable. Neural tube closure is a dynamic process that can be delayed by many influences. Factors that can affect such developmental outcomes, in the absence of chemical exposure, include maternal stress from handling and transporting bred mice (Brown, Johnston, & Niswander, 1972), environmental conditions resulting in hyperthermia (Webster & Edwards, 1984), low humidity (Brown, Johnston, & Murphy, 1974), noise (Kimmel, Cook, & Staples, 1976) and odors (Bruce, 1961) during critical development stages. In the studies reported in Hrubec, mice were dosed orally and “ambiently” although ambient exposures were not quantified. Oral ingestion of QACs (which are corrosive) undoubtedly contributed stress. Furthermore, for experiments 1 and 2, ethanol was used as a disinfectant, a substance known to cause neural tube defects (Kotch & Sulik, 1992). The authors speculatively attribute biological effects to “ambient exposure” to QACs as noted above, without measuring such exposure. Stress from handling and dosing, movement between rooms and facilities and other factors are likely contributors to observed developmental delays. The exceptionally high rate of neural tube defects in control animals raises questions regarding similar defects in the test animals since those effects may reflect the animal population or other conditions to which both control and test groups were subjected. Hrubec et al. do not report essential information for assessing and supporting their conclusions. The authors omit basic information routinely reported in robust toxicology studies such as clinical signs and other measures of animal well-being. They state that “maternal and paternal toxicity was not observed at the doses used in these experiments” but no data are provided to support this statement. This unsupported assertion lacks credibility, because toxic effects among the test animals would be expected from the reported oral doses, which approached 50% of the published mean Lethal Dose (LD50) in some experiments (Office of Prevention, Pesticides and Toxic Substances, US EPA, 2006a). The study suffers from a lack of controlled cleaning/disinfection procedures used during individual experiments. In one experiment, the disinfectant used was changed during the experiment. Given this study's limitations and variable procedures (noted at www.quats.org), coupled with undefined “ambient” exposures, any attempt to replicate this work would prove fruitless. QAC data have been fully and independently reviewed by multiple regulatory authorities, including the US Environmental Protection Agency (Office of Prevention, Pesticides and Toxic Substances, US EPA, 2006a, 2006b) and the European Chemicals Agency (ECHA, 2015a, 2015b). Both have publicly available summaries of developmental and reproductive studies performed on QACs and concluded that QACs are safe to humans as registered and labeled and that developmental or reproductive risks from QACs are negligible. Existing, robust and vetted QAC toxicology data confirm the absence of human reproductive issues and no reliable, peer-reviewed scientific data suggest otherwise. It is regrettable that Hrubec et al. ignored the wealth of independently reviewed data on this endpoint. The Alkyl Dimethylbenzyl Ammonium Chloride (ADBAC) and Didecyl Dimethyl Ammonium Chloride (DDAC) Steering Committees operate under the auspices of the Consumer Specialty Products Association. Member companies are Lonza, Inc., Mason Chemical, a subsidiary of Pilot Chemical; and Stepan Company. Toxicology Regulatory Services has provided toxicology services related to these substances for more than 25 years and is under contract by the ADBAC and DDAC Steering Committees and the Consumer Specialty Products Association.