Cyclosiloxanes - Information Center

Health Fate & Exposure Data

2017
 

By Wolfgang Dekant, et al.  Dekant et al., developed a quantitative weight of evidence methodology to assess confidence in postulated mode(s) of action for adverse effects in animal toxicology studies and to assess the appropriateness of the adverse effects as relevant endpoints in human health risk assessments and for classification and labeling.  To demonstrate the applicability of the QWoE approach, the authors applied the methodology assessing two separate effects induced by inhalation of D4 (impaired female fertility and induction of benign uterine tumors observed in rats); The authors concluded that when evaluating human relevance of the molecular initiating/key events, the chain of key steps is broken at key step #3, decreased LH surge, due to the absence of an association between a decrease in prolactin and the LH surge in humans. Therefore, the mode of action for reproductive effects and the proliferative endometrial lesions is not relevant to humans, based on lack of a role for prolactin in human ovulatory function.

 
Toxicology letters series
Volume 279, Supplement 1, 20 October 2017, Pages 1-136
A series of new assessments pending publication in the peer-reviewed journal, Toxicology Letters, add further compelling evidence that octamethylcyclotetrasiloxane (D4) does not present a risk to human health.

These recent assessments are consistent with a large body of peer reviewed publications supporting the safety of D4 and independent government assessments in Australia and Canada concluding that the use of D4 does not pose a danger to human health. These publications provide further support that the use of D4 in consumer products does not warrant any marketplace restrictions, which would unnecessarily hinder trade and limit consumer choice without any corresponding human health benefit.

 

By Jean Domoradzki et al. They examined how rats absorbed, distributed, metabolized, and eliminated a single oral low dose of D4 and D5, offering a realistic oral exposure scenario. The previously developed multi-species and multi-dose route (MC-MD) PBPK model for examining the effects of D4 and D5 primarily describes effects from inhalation and dermal exposure. 

The study’s findings suggest differences in the metabolism of low and high oral doses of D4 and D5 and suggest the pharmacokinetics of D4 and D5 following oral dosing is different than inhalation or dermal exposure and require a refined model. This work by Domoradzki et al. allows for the refining the PBPK to better account for the effects of low dose oral exposure, which may be used in risk assessment to better define the internal dose of D4 and D5 following different routes of exposure. 

 

By Jerry Campbell, et al. In this paper, Campbell et al. incorporate data from studies reported by Domoradzki et al., of low-dose oral exposure to D4 and D5 into the MC-MD PBPK model. The authors incorporate data on kinetic activity in rats’ plasma, tissues, and exhaled breath after an oral dose of D4 or D5.  Using this data, the authors made additional refinements to the model with regards to metabolism in the liver and scaling, which allows the model to be used in uncertainty analysis. The authors’ refinements to the model can serve as the basis for animal to human extrapolation across all potential exposure routes to D4 and D5, including inhalation, dermal, and oral exposure.

 

By Allison Franzen et al. She summarizes the results of toxicity and mechanistic studies of D4. The review notes that studies have not found significant toxicological effects following acute dermal, oral, or inhalation exposures to D4, nor is D4 reported to be an eye irritant, skin irritant, or skin sensitizer. Liver effects reported in rats following inhalation exposure to D4 were not adverse, reversible and of no relevance to in determining human risk. Studies of D4’s potential endocrine activity suggest that D4 has very weak estrogenic activity, and effects of D4 on fertility as observed in rats are unlikely to be relevant to humans. 

 

By Paul Jean and Kathleen Plotzke. While most human exposure to D4 is dermal, inhalation exposure is the most common route for workers in a manufacturing facility. Jean and Plotzke evaluated the effects of chronic inhalation exposure to D4 on rats over a two year period. The animals were exposed to various levels of D4, ranging from 0 to 700ppm, for six hours a day, five days a week, for 104 weeks. Their study concludes that vapor inhalation exposure of D4 was generally well tolerated. The increased incidence of benign uterine adenomas was the only treatment-related neoplastic finding associated with chronic exposure to D4 and were only observed at the 700ppm D4 exposure level, which is significantly higher than any likely human exposure levels and unlikely to be relevant in humans.

 

By Paul Jean et al. They compare the effects on reproductive cyclicity of aging female rats of chronic inhalation exposure to D4 and D5. The authors find that while exposure to D4 and D5 can affect cyclicity, the results suggest that D4 and D5 are not classical dopamine agonists. These findings are important to understanding the results of chronic exposure to D4 and D5 in rats. The authors’ findings support that the D4 and D5-induced uterine tumors are specific to this strain of rat and are not biologically relevant to humans based on the distinct differences in reproductive systems, the high exposure levels and duration required for the tumors to occur.      

 

By Wolfgang Dekant et al. Previous research (Jean and Plotzke) found that at extremely high levels (700 ppm) of chronic inhalation exposure to D4, increases of certain tumors were seen in rats. In this paper, Dekant et al. examine potential modes of action for these effects and the biological relevance of these findings to humans. The authors find that the occurrence of uterine tumors is not relevant for human risk characterization because of key differences between human and rats, including differences in ovulation cycle regulation and no analogous endometrial lesion in women to the endometrial adenoma observed in the rats. Effects observed in the rat liver are not adverse and the lesion observed in rat kidneys has no counterpart in humans and should not be used to assess risk in humans.

 

By Robinan Gentry, et al. The authors conducted a global “harmonized” risk assessment to meet the various governments’ substance-specific risk assessment requirements. Gentry et al. incorporate global exposure information combined with a Monte Carlo analysis to determine the most significant routes of exposure. The multi-species, multi-route physiologically based pharmacokinetic (PBPK) model is included to estimate internal dose metrics, benchmark modeling is used to determine a point of departure POD, and a margin of safety (MOS) evaluation is used to compare the estimates of intake with the POD. Gentry et al. find that MOS were greater than 1,000 for workers, consumers, and the general public who may be exposed to D4 either in the workplace, through the use of consumer products containing D4, or to D4 released in the environment, indicating a lack of any anticipated significant risk of adverse effects.