5-methylheptan-3-one

Endpoint summary

Description of key information

Physical data as well as information from toxicological data indicate that 5-methylheptan-3-one is absorbed and metabolized in the body. Furthermore, there are no indications for accumulation and the substance or its metabolites are likely eliminated from the body.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

 A toxicokinetic assessment based on the physical properties (see ECHA Guidance on Information Requirements and Chemical Safety Assessment, R7c, 28.11.2012) and toxicity data was performed. NOTE: this is mostly a generic assessment based on general statements in the guidance document that are derived from physical parameters.

ABSORPTION

Based on the low molecular weight (ca. 130 g/mol), the structure, and physical data (medium water solubility, moderate log Pow value) of the compound (5-methyl-heptan-3-one), absorption through aqueous pores or bulk passage with water through the epithelial barrier and absorption by passive diffusion may occur, and the substance may dissolve into gastrointestinal fluids. The structure of the constituent indicates that ionization is not an issue; hence, pH will have no effect on absorption. Oral toxicity data show systemic effects (neurotoxicity) [1]. This is a further indication that the substance is absorbed.

Even though the compound (5-methyl-heptan-3-one) has “low volatility” based on its vapour pressure (270 Pa at 20°C) and its boiling point (159°C), it can be available for inhalation as vapour (max. vapour concentration at 20°C 2600 ppm[2]. Due to its moderate log Pow value (between 0 and 4) and its medium water solubility, the substance may be taken up via the respiratory tract and absorption may occur directly across the respiratory tract epithelium by passive diffusion. Inhalative toxicity studies with detailed observations are not available.

Physical data, i.e. physical state (liquid) and low molecular weight indicate that the substance may also be absorbed via the skin. The water solubility of the substance (1.92g/L) falls between 100-10’000 mg/l, a range where dermal absorption is anticipated to be moderate to high. In addition, the log Pow of 2.15 favours dermal absorption (values between 2 and 3 are optimal). Since the substance is not a surfactant (surface tension above 10 mN/m), dermal uptake and penetration is not expected to be enhanced by surface active properties. Dermal toxicity studies are not available. The substance has been observed to be mildly skin irritating and may cause defatting and dermatitis after prolonged repeated exposure[2]. Damage to the skin surface may enhance penetration.

DISTRIBUTION

From the small size and medium water solubility of the molecule, wide diffusive distribution in the body is expected. From its log Pow value (>0), the molecule is likely to distribute into cells.

In a newly performed subchronic oral toxicity guideline study [3], neurotoxicity was not observed. A previous subchronic oral toxicity study performed on only few male animals per dose [1] indicated a distribution into the central nervous system (CNS).

ACCUMULATION

5-methyl-heptan-3-one has a log Pow value under 3. Therefore, it would be unlikely to accumulate with the repeated intermittent exposure patterns normally encountered in the workplace but may accumulate if exposures are continuous. Once exposure to the substance stops, it will be gradually eliminated at a rate dependent on the half-life of the substance.

METABOLISM

No experimental data are available on the metabolism of 5-methyl-heptan-3-one. Other ketones have been shown to have neurotoxic effects and this effect was linked to the formation of gamma-diketones as metabolites[2]. For 5-methyl-heptan-3-one it was hypothesized that the metabolite 3-methylheptane-2,5-dione is formed [2] which may have led to the effects observed in the study cited in the distribution section.

ELIMINATION

From physical data, elimination via urine and exhaled air are likely the most prevalent pathways of excretion. Based on indications from the read-across substance 2-hexanone, the substance may be exhaled as CO2 and its metabolites may be excreted via the urine.

INDICATIONS FROM READ-ACROSS SUBSTANCES

Several studies on absorption, metabolism and elimination are available for 2-hexanone [2]: The substance is readily absorbed via the oral, dermal and inhalative route. Observed distribution of the substance was widespread in the body. Neurotoxicity of 2-hexanone is known to be caused by the metabolite 2,5-hexandione. Elimination takes place mainly as CO2via exhalation and excretion in the form of its metabolites via the urine.

2-hexanone has physical properties that likely favour absorption in comparison to 5-methyl-heptan-3-one (higher water solubility, higher vapour pressure, lower boiling point). However, the general pattern may be similar.

REFERENCES

[1]    C.B. Salocks et. Al., Subchronic neurotoxicity of 5-methyl-3-heptanone in rats: Correlation of behavorial symptoms and neuropathology.Toxicologist 10, 121, 1990.

[2] Douglas C., Topping et al., Ketones of six to thirteen carbons in Bingman, E., Cohrssen, B., Powell C. H. (eds.), 2001, Patty's Toxicology, 5th Edition, John Wiley & Sons, Inc., New York, NY, USA.

[3] Nováková, Jana., Ethylamylketon 90-day Oral Toxicity Study in Wistar Rats., MediTox s.r.o study report 18/15/C, 2016-09-16.