4-methylpentan-2-ol

Endpoint summary

Description of key information

Short description of key information on bioaccumulation potential result: 
The absorption and metabolism of methyl iso-butyl carbinol (MIBC) was investigated in rats in a GLP-compliant study.  MIBC was rapidly absorbed in rats following a single oral exposure and was rapidly metabolized to MIBK with subsequent metabolism to diacetone alcohol (DAA).

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

The low molecular weight (102.176 g/mol), log P_ow(1.57), and low water solubility along with the physical state (liquid) of methyl i-butyl carbinol (MIBC) favour its absorption via various routes of exposure (oral, dermal, and inhalation). Consistent with this prediction, pharmacokinetic analysis of MIBC demonstrated that the compound was rapidly absorbed into the systemic circulation of rats following oral administration, with maximum plasma concentrations occurring at 0.5 hours post-administration. Signs of toxicity observed in experimental animals following acute oral, dermal, or inhalation exposure to MIBC also are indicative of systemic absorption via these routes of exposure (Smyth et al., 1951; Blair, 1981). Following absorption, MIBC was slowly eliminated from plasma and remained detectable up to 9 hours post-dosing but not beyond 12 hours. The primary metabolite of MIBC was identified as methyl i-butyl ketone (MIBK) and the secondary metabolite as 4-hydroxymethyl-4-methyl-2-pentanone [i.e., diacetone alcohol (DAA)]. Seventy-seven percent (77%) of the administered dose of MIBC was metabolized to DAA via MIBK, demonstrating that MIBC is efficiently metabolized to DAA.  A relatively similar pharmacokinetic and metabolic profile was observed when rats were orally administered with MIBK. Moreover, the relative bioavailability and other pharmacokinetic parameters of MIBK and DAA were similar following either MIBK or MIBC administration (Guillaumat, 2004; Gingell et al., 2003).

As mentioned, metabolic data indicate that MIBC is rapidly metabolized to MIBK, which is subsequently metabolized to DAA, the major metabolite formed. MIBC has been reported to be metabolized to MIBK by alcohol dehydrogenase. Additionally, MIBK was reported to be metabolized to DAA via oxidation by the mixed function oxidase system. MIBK may be converted back to MIBC via reduction by ketone reductase; however such conversion has been reported to be negligible (<0.1% of the total dose). Hydroxylation products of MIBK, such as MIBC and DAA, are expected either to be conjugated with sulfate or glucuronic acid and excreted in urine or to enter intermediary metabolism to be converted to carbon dioxide. Based on the available metabolic data and taking into consideration its low molecular weight and log Pow value, MIBC is not expected to bioaccumulate. This conclusion is also supported by a recent publication (Saghir and Rick, 2008) showing no accumulation of MIBK (the primary metabolite of MIBC) in workers repeatedly exposed through inhalation.

Taken together, the data demonstrate that toxicological information on MIBK and /or DAA may be used as an appropriate surrogate for MIBC considering that MIBC is rapidly metabolized to MIBK and that the two substances share a common major metabolite, DAA.

Discussion on bioaccumulation potential result:

The mammalian metabolism of secondary alcohols proceeds primarily through their respective ketones. It has been demonstrated (Granvil et al., 1994) that MIBC is metabolized to methyl isobutyl ketone (MIBK: CAS No. 108-10-1) and subsequently to the primary metabolite of MIBK, 4-hydroxy-4-methyl-2-pentanone (HMP; CAS No. 123-42-2)[i.e. diacetone alcohol, DAA] in rats. In this study, no MIBC was detected in blood of rats following oral dosing although low concentrations of MIBC were found following inhalation exposure. Based on these preliminary findings, a study (Guillaumat, 2002; Gingell et al., 2003) was performed to confirm metabolism of MIBC to MIBK and to allow the use of the extensive toxicity database for MIBK to support the hazard assessment of MIBC.

Male Sprague-Dawley rats were orally dosed with MIBC or MIBK at a dose of 5 mmol/kg in corn oil (approximately 500 mg/kg). Following oral dosing of MIBC to rats, absorption is rapid with Cmax occurring at approximately 0.25 to 0.5 hours post-dosing. The half-life for MIBC in blood is approximately 2.3 hours. MIBC is rapidly metabolized to methyl isobutyl ketone (MIBK) and subsequently to the primary metabolite of MIBK, 4-hydroxy-4-methyl-2-pentanone (HMP). Plasma samples were collected at 0.125, 0.25, 0.5, 0.75, 1, 1.5, 3, 4.5, 6, 9 and 12 hours post-dosing. Plasma concentrations of MIBC, MIBK and HMP were measured at each time point. Selected pharmacokinetic parameters (non-compartmental) are listed in the following table:

Test Substance	Analyte	Cmax [mmole/L]	Time of Cmax[hr]	Half Life [hr]	AUC0-12hr  [mmole*hr/L]	% Total AUC
MIBK    Total AUC	MIBC	0.014	NA	4.657	0.089	0.05
	MIBK	0.644	0.25	2.529	3.558	20
	HMP	2.030	9	4.831	13.756	79
					17.436
MIBC    Total AUC	MIBC	0.588	0.5	2.256	0.819	6
	MIBK	0.450	1.5	1.571	2.268	17
	HMP	1.64	9	3.377	10.408	77
					13.495

NA = Not applicable; no peak concentration could be determined due to the low concentrations at each measurement.

Following oral dosing of either MIBC or MIBK, absorption is rapid with Cmax for both compounds occurring at approximately 0.25 to 0.5 hours post-dosing. The half-life for both compounds in blood was short (approximately 2.3 and 2.5 hours, respectively). MIBC was not detectable by 9 hours following MIBC dosing. Total exposure (based on AUC_0-12) to MIBK following dosing with either MIBC or MIBK was similar (2.3 and 3.6 mmol*h/l, respectively) as was exposure to HMP (10.4 and 13.8 mmol*h/l, respectively). Compared to MIBK and HMP, internal exposure to MIBC was minimal following dosing with MIBC (0.8 mmol*h/l), representing approximately 6% of the exposure to the three compounds over 12 hours. Therefore, the internal exposure to MIBC is minimal following MIBC dosing, and oral dosing of MIBC or MIBK results in similar internal exposure to MIBK and HMP.

The extent of metabolism of MIBC to MIBK can be determined by comparing the combined AUC for MIBK plus HMP, after administration of MIBC, to the combined AUC for these same materials after administration of MIBK. This analysis indicates the proportion of MIBC metabolized through MIBK to HMP is 12.676/17.314, or 73% of the administered dose of 5 mmole/kg. This value should be considered to be a lower estimate. It is likely that some MIBC is not absorbed or is rapidly excreted as a glucuronide or sulfate conjugate in the urine after oral bolus administration. This would decrease the amount available for metabolism to MIBK and HMP in the blood, as compared to that available after MIBK.