3-Methoxy-3-methylbutyl acetate

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics, other

Type of information:

other: Evaluation of toxicokinietcs based on available data

Adequacy of study:

key study

Study period:

NA

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

data from handbook or collection of data

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:

Oral:
According to the ECHA Guidance Chapter R.7c (2017), molecules with molecular weights of less than 500 g/mol are small enough to be candidates for absorption by passive diffusion from the gastrointestinal tract. The molecular weight of MMB-AC is 160.21 g/mol, it is water soluble (58.3 g/L) and has an octanol-water partition coefficient (log Kow) of 1.6. This combination of aqueous and lipid solubility favors absorption by the oral route. Based on the hydrolysis data for MMB-AC, the substance is expected to be hydrolytically stable (pH-stable) in the small intestine and stomach.
The hypothesis for oral absorption is substantiated by observed negative effects (mortality, clinical signs) in the acute toxicity oral test. However, this negative effects were only observed in animals in test groups > 2000 mg/kg, thus the substance is not classified according to CLP.
Based on the available information, it is reasonable to assume that 100% of MMB-AC will gain systemic circulation by the oral route of administration. However, in the absence of experimental absorption data and in accordance with the ECHA Guidance R.8 (2012) a default value of 50% for oral absorption will be used in the derivation of DNELs.

Dermal:
Based on the physical/chemical properties, MMB-AC is likely to be absorbed after dermal application. According to the ECHA Guidance Chapter R.7c (2017), molecular weights of less than 500g/mol are capable of migration through the skin into systemic circulation. In addition, both water and lipid solubility influences the potential for dermal penetration. Based on the hydrolysis data for MMB-AC, the substance is regarded to be stable at pH 4 and thus penetration of the substance as such is expected.
The hypothesis for dermal absorption cannot be substantiated by toxicity studies since MMB-AC is not classified for dermal toxicity.
In the absence of experimental absorption data and in accordance with the ECHA Guidance R.8 (2012), a default value of 50% for dermal absorption will be used in the derivation of DNELs.


Inhalation:
MMB-AC is a liquid at room temperature with limited volatility. The vapour pressure of MMB-AC is 2.58 hPa at 25°C, which limits the likelihood of significant systemic exposure by inhalation of vapors. However, if MMB-AC is aerosolized, absorption across the respiratory epithelium would likely be rapid based on its partition coefficient and low molecular weight.
In the absence of experimental absorption data, a worst case absorption percentage of 100% has been taken into account for the inhalation route.

Details on distribution in tissues:

The distribution of MMB-AC has not been characterized. Following oral exposure MMB-AC would enter hepatic portal circulation resulting in initial distribution to the liver. Given its size and water solubility, MMB-AC and/or its metabolites is expected to freely distribute systemically via the blood. Effects observed in the repeated dose toxicity study substantiate this hypothesis. In these study treatment-related decreases in RBC in males and females, decreases in Hb and Ht in females were noted in the 1000 mg/ kg groups. In addition, in the acute toxicity oral test, hunched posture, lethargy, decreased respiratory rate, increased salivation and ataxia was observed amongst treated rats, ptosis was seen in all rats treated with 2500 mg/kg and above, comatose-like conditions was seen amongst rats treated at 4000 and 5000 mg/kg and in the 4000 mg/kg test group increased lacrimation was observed in four animals. These observations provide evidence for an effect of the substance on the central nervous system, which is an indirect indication that the substance can cross the blood-brain-barrier.
No adverse effects where observed for reproduction and developmental toxicity.
Dermal absorption would result in general systemic exposure. The hypothesis for dermal absorption cannot be substantiated by toxicity studies since MMB-AC showed no adverse effects in the acute toxicity dermal test.
By inhalation, the distribution would also be expected to be more general as absorption by the lungs would result in distribution systemically via cardiac output. No experimental data are available to substantiate this hypothesis.

Details on excretion:

The polarity and water solubility of MMB-AC would facilitate its rapid excretion in urine. Any of the metabolic steps described above would further increase its polarity and thus enhance urinary excretion. Following of the possible Phase II reaction the molecular weight of the compound could increase to ~330 g/mol and therefore could be eliminated in faeces via bile (for rats, while a higher molecular weight is necessary in humans (~500 g/mol*)).

*Yang et al.; Prediction of Biliary Excretion in Rats and Humans Using Molecular Weight and Quantitative Structure–Pharmacokinetic Relationships; The AAPS Journal, Vol. 11, No. 3, 2009

Metabolite characterisation studies

Details on metabolites:

Once absorbed, MMB-AC is likely to be rapidly hydrolysed by esterases to the corresponding alcohols and carboxylic acid. It will be expected that MMB-AC will be hydrolysed by ester hydrolysis to 3-Methoxy-3-methyl-1-butanol (CAS 56539-66-3). This substance is registered according to REACH and the metabolism of MMB is described (theoretically) in the REACH registration dossier of the substance* . It is expected, that a substantial amount of MMB will undergo ether-bond cleavage to the 3-Methyl-1,3-butandiol (CAS 2568-33-4) and formaldehyde and formic acid. 3-Methyl-1,3-butandiol is fully water soluble and can be expected to be excreted fast. Glycoles are known to be consumed by oxidation to the aldehyde and further to the carboxylic acid. All metabolites can be expected to be excreted via urine or enter metabolic pathways to produce CO2.
Hydroxy and acid groups produced from Phase I metabolism could be subject to Phase II conjugate reactions to give glucuronide and sulphate conjugates.

*https://echa.europa.eu/de/registration-dossier/-/registered-dossier/10042 (ECHA, 2019)

Any other information on results incl. tables

The physical/chemical properties of MMB-AC are listed in the table below. These data show that MMB-AC is a small, polar, water soluble molecule.

MMB-AC
Molecular formula	C8H16O3
Molecular Weight	160.21
Physical state	Liquid at 20°C and 1013 hPA
Melting/Freezing point (°C)	< - 100
Boiling point (°C)	187.3 at 1013 hPA
Density (g/cm3)	0.957 at 20°C
Vapor pressure (Pa)	258 at 25°C
Water solubility (g/L)	58.3 at 20°C
Partition coefficient (log Kow)	1.6 at 25°C

Applicant's summary and conclusion

Conclusions:

MMB-AC can be assumed to be absorbed by the oral, dermal, and inhalation routes of exposure therefore systemic exposure is likely. However, in the absence of experimental data default absorption values are used in the derivation of DNELs, according to REACH guidance R.8.
MMB-AC is likely to be rapidly metabolized to hydroxy and acid metabolites which could then be conjugated.
MMB-AC is unlikely to bioaccumulate because of its polarity, extensive metabolism and rapid excretion.