Butan-1-ol

Endpoint summary

Link to relevant study record(s)

Reference

Endpoint:

basic toxicokinetics

Type of information:

other: review

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

data from handbook or collection of data

Objective of study:

absorption

distribution

excretion

metabolism

Metabolites identified:

yes

Butan-1-ol is readily absorbed through the skin, intestinal tract and lungs and is distributed almost uniformly throughout the organism. It is rapidly eliminated after metabolism primarily by alcohol and aldehyde dehydrogenases. After oxidisation to butyric acid and further degradation to shorter acids and ketones, the majority of butan-1-ol is excreted as carbon dioxide, excretion via urine and feces plays only a minor role.

Description of key information

Overall the available data demonstrated a rapid uptake of butanol with a distribution throughout the body followed by a fast and complete elimination from the system.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

100

Absorption rate - dermal (%):

50

Absorption rate - inhalation (%):

60

Additional information

Toxicokinetic properties

The toxicokinetic properties of butan-1-ol were assessed in the ECETOC JACC (2003). Butan-1-ol was concluded to be readily absorbed through the skin, intestinal tract and lungs and is distributed almost uniformly throughout the organism. It is rapidly eliminated after metabolism primarily by alcohol and aldehyde dehydrogenases. After oxidisation to butyric acid and further degradation to shorter acids and ketones, the majority of butan-1-ol is excreted as carbon dioxide, while excretion via urine and feces plays only a minor role.

 

Several studies were performed to evaluate the toxicokinetics of butan-1-ol.

n-[1-14C]Butanol was mixed with corn oil and administered by gavage to male Charles River CD (SD) rats in doses of 4.5, 45, or 450 mg/kg bw. The excretion of the n-[1-14C]Butanol was examined. The highest concentration of n-butanol in the plasma was 70.9 µg/mL at 1 h. n-Butanol disappeared from the plasma rapidly and at 4 h was below the limit of detection. The distribution in tissues was determined to have the highest concentrations in liver (3.88 % at 8 h), blood (0.74 % at 8 h), kidney (0.24 % at 4 h) and less than 0.12 % in other tissues. Radioactivity was eliminated rapidly in expired air as 14CO2. The elimination of the administered dose 450 mg/kg reached > 44 % within 4 h, 69.3 % after 8 h and 83.3 % at 24 h. Urinary radioactivity accounted for 4.4 % of the dose at 24 h. Fecal radioactivity was negligible at 4 and 8 h and was less than 1.0 % of the dose at 24 h. In the carcass remaining radioactivity was found to be at 4 h: 42.2 %, at 8 h: 27.2 % and at 24 h: 12.3 % (Di Vincenzo 1979).

 

Four male beagle dogs were exposed in groups of two to 50 ppm of n-butanol for 6 h via inhalation. The uptake curve shows that about 55 % of the inhaled vapor was absorbed through the lungs. The concentration of n-butanol in the blood was below the limit of detection both during and after the exposure. Expired air concentrations of n-butanol were essentially unchanged during the exposure (22 ppm). Shortly after dogs were removed from the exposure facility, the concentration of n-butanol in the expired air decreased rapidly and was below the limit of detection at 1 h postexposure (Di Vincenzo 1979).

 

In a study rats were exposed for 2 h to n-butanol vapours of 2000 ppm (= 6.1 mg/L air). The amount of the test substance in blood was determined to rise after exposure start and a decline after 50 min of exposure was detected. Blood concentration level of ca. 63 µM was measured after 5 min and ca. 81 µM at the final measurement after 90 min. The blood concentrations of butan-1-ol during the exposure period peaked after 25 min at ca. 114 µM (ACC 2004).

 

An i.v. study in rats was conducted to evaluate the metabolite cascade of n-Butanol derived from hydrolysis of the n-butyl acetate and n-Butyric acid generated from oxidation of n-butanol. After the administration of n-butanol the initial blood samples collected contained a mean of 0.62 µmol/g of n-butanol, and the level of n-butanol declined rapidly in succeeding samples reaching concentrations below the method limit of detection (0.002 µmol/g) by 30 min following administration. The metabolite butyraldehyde was not detectable in blood and considered to be enzyme bound. The metabolite n-Butyric acid was detected and declined rapidly in the 30 min of analysis. The analyses of the study captured the rapid hydrolysis of n-butyl acetate to n-butanol, and the subsequent formation and elimination of n-butyric acid (ACC 2001).

 

In a study the kinetics of oxidation of n-butanol by purified rat liver alcohol dehydrogenase (ADH) was compared with the kinetics of elimination of the alcohol in rats in order to investigate the roles of ADH and other factors that contribute to the rates of metabolism of alcohols. The zero-order kinetics of elimination 1-butanol was determined to have a rate in vivo of 3.2 +/- 0.4 mmol/kg bw/h. The fraction of body weight from rats that is ‘‘water’’ accessible 1-butanol was determined to be r= 0.82 +/- 0.09 mL/g and 56 % of the elimination was due to ADH (Plapp 2015).

 

Data from six unpublished reports of experiments conducted in rats were utilized for development of a physiologically based pharmacokinetic (PBPK) model for the butyl series. The model was used to derive human equivalent concentrations (HECs) for n-butanol corresponding to the rat n-butyl acetate NOAELs. Data used for the model derivation was from intravenous (iv) kinetics of n-butyl acetate, n-butanol and n-butyric acid in the rat, and inhalation kinetics of n-butyl acetate (rat only) and n-butanol (rats and humans). The human model was validated only for the inhalation route for n-butanol. The model predicted blood kinetics of n-butyl acetate were in excellent agreement with the observed blood concentration time-course from studies. Predictions of blood n-butanol concentrations were also in relatively good agreement with observed concentrations. The general shape of the blood n-butanol concentration time-course after inhalation of butanol predicted by the model approximated the observed time-course fairly well. Model-predicted arterial n-butanol concentrations in male humans following inhalation of 100 ppm n-butanol at various exercise levels agreed well with observed concentrations. The HECs for rat (n-butyl acetate) NO(A)ELs of 500 ppm and 3000 ppm are 169 ppm and 1066 ppm for butanol, respectively (Teeguarden 2005).

 

In addition to the data available directly on n-butanol, data from the read-across substance butyl acetate were used for toxicokinetc assessment.

In a study rats were exposed for 2 h to butyl acetate vapours of 2000 ppm. The amount of the read-across substance in blood was determined to rise after exposure start and a decline after 50 min of exposure was detected. The blood concentrations of butyric acid showed a comparable course with an approx. 10 -fold higher concentrations of the alcohol. Blood concentration level of ca. 5 µM was measured after 5 min and ca. 4 µM at the final measurement after 60 min. The blood concentration of butyric acid during the exposure period peaked after 40 min at ca. 9 µM (ACC 2002).

 

An i.v. study in rats was conducted to evaluate the metabolite cascade of n-Butanol derived from hydrolysis of the n-butyl acetate and n-Butyric acid generated from oxidation of n-butanol. After the administration of the read-across substance (n-butyl acetate) the peak concentrations occurred in the initial 0.5 min samples (mean 0.65 µmol/g), but were at or below the limit of quantitation by 10 min after administration. n-Butanol derived from hydrolysis of the n-butyl acetate parent compound was present at a mean of 0.29 µmol/g in the initial blood samples, peaked at a mean of 0.37 µmol/g in the 1 min samples, and then declined slowly in concentration for the remainder of the study. The metabolite n-Butyric acid was detected and declined rapidly in the 30 min of analysis, while the metabolite butyraldehyde was not detected. The analyses of the study captured the rapid hydrolysis of n-butyl acetate to n-butanol, and the subsequent formation and elimination of n-butyric acid (ACC 2001).

 

Butyl acetate was orally administered to rats at 193 to 2237 mg/kg bw with one application and at 2000 and 3000 mg/kg bw with 2 or 3 administrations of 1000 mg/kg bw each. The blood level of butyl acetate and its metabolite butanol was monitored. In addition the amount of n-butyl acetate remaining in the stomach of one animal dosed with 1185 mg/kg bw (total dose 264 mg) was evaluated. N-butyl acetate gut content was found to be 212 mg, or 80 % of the administered dose after the one hour study period, showing a low bioavailability. In portal vein and carotid artery n-butyl acetate concentrations were near or below the limit of detection (0.0027 mM) after all but the 350 mg/kg bw single n-butyl acetate dose. n-butanol blood concentrations were higher than n-butyl acetate concentrations, consistent with significant metabolism of the acetate in GI tract tissues, blood and liver. Portal vein and arterial blood n-butanol concentrations were generally comparable but variability was high across dose groups. No clear relationship to administered dose, even as the dose increased 10 fold, was observed. The higher blood concentration of butanol compared to butyl acetate, showed a fast metabolism from butyl acetate to butanol (ACC 2007).

 

An investigation of the respiratory bioavailability in rats using combined gas uptake inhalation measurements, plethysmography and a blood sampling system was done. The animals were exposed to butyl acetate at a target concentration of 2000 ppm for 2 h. Blood samples were collected and analyzed for butyl acetate and it metabolites, including butanol. At the end of the 2 hour run, less than 14 % of the initial concentration of n-butyl acetate remained in the chamber. The butyl acetate peak in blood was achieved after 10 min (2.4 +/- 2.7 µg/mL) while butanol concentrations continued to climb to 8.2 +/- 3.1 µg/mL at 20 minutes. In general butanol concentrations were the highest detected in blood while butyric acid was below the limit of detection (ACC 2002).

 

In vivo pharmacokinetics in rats after intravenous administration of 30.2 mg/kg bw radiolabelled butyl acetate were evaluated. Blood and brain were analysed for butyl acetate and its metabolites. Butyl acetate concentration in blood and brain was low and declined rapidly. It was eliminated at 7.4 min from blood and at 4 min from brain. The main metabolite identified in blood and brain was [14C] n-butanol with maximal values of 52 and 79 µg equivalents/g tissue after ca. 2.6 min. These concentrations declined to undetectable levels after 20 min post dosing. Other metabolites were detected in the blood and to only a minor degree in the brain at levels well below that of butanol (Chemical Manufacturers Association 1997).

 

N-butyl acetate and n-butanol blood levels and blood clearance were analysed after inhalation exposure of rats via tracheal cannula to n-butyl acetate for 1 hour at 7000 ppm. In addition the half-life of the enzymatic hydrolysis reaction of n-butyl acetate in rat and human blood in vitro was determined. n-Butyl acetate reached nearly constant blood levels (140 µmol/L; 16.3 mg/L) during the 1 hour inhalation exposure to 7000 ppm n-butyl acetate. It could not be detected in the venous blood. After termination of exposure, n-butyl acetate disappeared completely from blood within 1 min. The half-life of n-butyl acetate in rat blood in vitro was determined to be 4 min in rats (hydrolytic cleavage of ester to n-butanol and acetic acid). In human blood, the half-life was somewhat longer (12 min). The metabolite n-butanol amounted to 480 µmol/L; 35.6 mg/L in the blood of exposed rats within 40 min. For n-butanol an elimination half-life of 5 min was determined for rat blood after inhalation exposure was terminated (Essig 1989).

 

Conclusion on toxicokinetic properties of butanol

The studies on the read-across substance butyl acetate showed a rapid conversion into its metabolite butanol. This was demonstrated by highest concentration levels short time after dosing/exposure and a following rapid decline of butyl acetate in blood and brain down to the limit of detection within 10 min, e.g. elimination after 7.4 min from blood and 4 min from brain (Chemical Manufacturers Association 1997). While in the same time in the studies using only butyl acetate as test substance, butanol concentration was detected in e.g. blood samples shortly after exposure/administration and continued to rise after the butyl acetate concentration had peaked to reach concentrations higher than those of butyl acetate (e.g. ACC 2007). The half-life of n-butyl acetate in rat blood in vitro was determined to be 4 min in rats (hydrolytic cleavage of ester to n-butanol and acetic acid) (Essig 1989).

For n-butanol a fast start of uptake into blood was detected independent of the administration route, albeit the time needed to reach the concentration peak was slower dependent on route of administration, e.g. after oral application uptake was slower than after i.v. injection. The concentration reached a maximal level even if further substance was administered (ACC 2004) and started to decline afterwards. The zero-order kinetics of elimination for 1-butanol was determined to have a rate in vivo of 3.2 +/- 0.4 mmol/kg bw/h (Plapp 2015). The elimination was also demonstrated by the drop for butanol concentration in blood under the limit of detection within 30 min after i.v. injection and 1 h after inhalation exposure. Only after oral application a longer time (4 h) was observed for the decline under the detection limit, which was due to the slower uptake of butanol into blood. The distribution in tissues was determined after oral application to rats and had the highest concentrations in liver (3.88 % at 8 h), blood (0.74 % at 8 h), kidney (0.24 % at 4 h) and less than 0.12 % in other tissues. Butanol was mostly expired as C02, while urinary and fecal elimination only accounted for a small part. 24 h after oral application an elimination of 83.3 % was observed in rats (Di Vincenzo 1979).

Overall the available data demonstrated a rapid uptake of butanol with a distribution throughout the body followed by a fast and complete elimination from the system.

 

 

Dermal absorption

Dogs were exposed to n-[1-14C]Butanol dermally for 60 minutes. Breath and urine was collected for 8 hours. The dermal absorption and also the excretion of butanol was determined. After 60 min, 29 mg of n-butanol was absorbed through the skin of each dog. The absorption rate was 8.8 µg/min/cm2. The excretion of radioactivity was ca. 15 dpm in breath and ca. 3 dpm in urine. Skin absorption calculations were based on the 8-h excretion of radioactivity in the breath and urine of dogs dosed intravenously with n-[1-14C]butanol (1 mg/kg bw). For those animals the elimination is expressed as a percentage of the administered dose. About 15 % of the dose was eliminated in the breath as 14CO2 and 2.7 % was excreted in the urine. There was no unchanged n-butanol detected in the breath. The 8-h elimination of radioactivity in the breath and urine averaged about 17 % of the administered dose. The assumption was made that the metabolic fate and disposition of n-[14C]butanol is identical after iv or skin administrations (Di Vincenzo 1979).

 

For humans the ECETOC JACC (2003) described dermal absorption values. The absorption rate of butan-1 -ol across isolated human epidermis was 0.048 mg/cm ²/h compared to 0.57 mg/cm ²/h for ethanol and the in vitro absorption rate was determined to be 2.30 ± 0.52 mg/cm²/h; permeability constant of 2.84 ± 0.65 x 10 -3 cm/h for pure butan-1 -ol through normal split-thickness human thigh skin.

 

The dermal diffusion of chemical vapor of n-butanol was studied by the thermogravimetric analysis (TGA) method using neonatal pig skin. The penetration of the substance was also studied using conventional Franz diffusion cells and neat, liquid chemical. The diffusion coefficient of the Franz cell was 8.0 Dp*10^10, cm^2/s while it was determined to be 57.0 D*10^9, cm^2/s for TGA (Rauma 2009).

 

Calculation using Epi Suite 4.1 program DermWin (v.2.02) estimated a Kp = 0.00278 cm/h (DermWin 2017). The Kp value leads to a classification for dermal absorption as low, based on the “User Manual for the Internet Version of the Danish (Q)SAR Database” (Version 1, May 2005) (DermWin 2017).