Registration Dossier

Administrative data

Link to relevant study record(s)

Description of key information

No specific toxicokinetic (TK/ADME) investigations, or studies on potential metabolites, were available at the time of this review. However, physical chemical and mammalian toxicity data were available for evaluation from which a reasoned scientific opinion on the TK/ADME parameters of this substance may be predicted.

An on-line literature search did not reveal any further data that might aid in this prediction.

Key value for chemical safety assessment

Bioaccumulation potential:
low bioaccumulation potential
Absorption rate - oral (%):
50
Absorption rate - dermal (%):
10
Absorption rate - inhalation (%):
100

Additional information

1. Key physical chemical data   

The substance was very soluble in water (475 - 500 g/L) and had an estimated partition coefficient of Log Pow is -3.5, indicative of a highly lipophobic substance. Further, the surface tension was 31.9 mN/m, the substance was therefore considered to be surface active.

2. Mammalian toxicity data 

The mammalian toxicity data evaluated were:

- acute oral and dermal toxicity

- in vivo skin irritation,

- in vivo eye irritation,

- Ames test, chromosome aberration test and in vitro gene mutation test

- Magnusson & Kligman (M&K) Maximisation Study in the Guinea Pig, and

- 28 -day repeat oral dose and a combined repeat oral dose toxicity and reproduction/developmental screening study.

Acute toxicity by either route was not evident, with an LD50 greater than 2000 mg/kg bw. The substance was not a skin sensitiser and was not irritating to the skin but was an eye irritant. The genotoxicity studies conducted on the substance (with or without metabolic activation) demonstrated no genotoxic potential.  

For repeat-dose oral toxicity the systemic NO(A)EL was reported to be 150 mg/kg bw/day in a 28-day study and for reproductive and developmental toxicity was greater than 300 mg/kg bw/day (the highest dose tested, with water used as the vehicle). The substance was clearly not toxic to reproduction or fetal development. The high dose effects seen in the 28-day study (at 1000 mg/kg bw/day) were slight effects on adult body weight performance and water intake which were not considered to be toxicologically significant. Some notable changes in the forestomach (epithelial acanthosis associated with hyperkeratosis) were seen primarily at the highest treatment level (1000 mg/kg bw/day) and were indicative of gastric irritation. The findings on the forestomach need to be treated with caution because there is the real possibility that local effects (e.g. irritation via the test substance and/or mechanical irritation caused by oral gavage dosing) were most probably the key factors in the pathology seen. Such conclusions have been arrived at by regulatory agencies for other substances where local irritant effects on the rat forestomach were evident and discounted as not-relevant to man (EFSA, 2011; Proctor et al, 2007). Taking this into consideration, the effects on the rat forestomach, evident in the repeat dose oral gavage study on the substance, are most likely rat specific local effects and therefore not relevant for use in human risk assessments. A NOAEL of ≥1000 mg/kg bw/day may be considered more appropriate. 

3. Opinion on TK/ADME  

Absorption and distribution

The relative lipophobicity, and high water solubility, indicates that the substance may not be rapidly absorbed (limiting systemic availability), compared to more lipophilic substances, after either oral or dermal exposure. Although absorption via aqueous channels and passive diffusion might be expected. With water solubility in the range 475 - 500 g/L and an estimated Log Pow of -3.5, the substance may be too hydrophilic to cross the lipid rich environment of the stratum corneum and as such dermal uptake for this substance would be low. The data from the acute toxicity studies provide little evidence of acute absorption via the GI tract and skin. The repeat oral dosing studies demonstrated local rat forestomach irritation but apparently little, if any, systemic toxicity. The data suggest limited systemic exposure and indicate that distribution, bioavailability and bioaccumulation might also be limited. The physical chemistry data suggest that it is unlikely that acute inhalation exposure (i.e. not expected to present an exposure risk) would result in toxicity considering the very low toxicity evident in the studies presented. 

Metabolism

It is predicted, from the both the physical chemistry and toxicity data, that metabolism would likely be primarily via the liver. The nature of the effects seen after repeated oral exposure, and the relatively low toxicity seen, further suggest that potential metabolites may also be of no or very low toxicity in the animal models used. The data from the genotoxicity studies (with S9-mix, i.e. induced metabolic activation) support this opinion.

Excretion

Given the physical chemical nature of the substance, and expected limited bioavailability and bioaccumulation, it is likely that excretion, of parent and/or metabolites, would be most likely via the faeces and urine.

4. Conclusions

The physical chemical characteristics of the substance, the lack of acute oral or dermal toxicity and the nature of the repeat dose oral toxicity findings suggest that absorption of ASME may be limited and therefore bioavailability and bioaccumulation would also be limited in the animal models studied. Thus, because of the expected limited oral absorption of ASME it may be predicted that excretion would be primarily via the faeces and urine. In the absence of experimental data on adsorption, default values of 50% (oral) 10 % (dermal) and 100% (inhalation) are used for risk assessment.

5. References

EFSA (2011). Scientific Opinion on the re-evaluation of butylated hydroxyanisole – BHA (E 320) as a food additive. European Food Safety Authority. EFSA Journal 9 (10):2392.

Proctor, DM, Gatto, NM, Hong SJ and Allamneni KP (2007). Mode-of-Action Framework for Evaluating the Relevance of Rodent Forestomach Tumors in Cancer Risk Assessment. Toxicological Sciences 98, 313–326.