2-butoxyethanol

Endpoint summary

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

100

Absorption rate - dermal (%):

30

Absorption rate - inhalation (%):

60

Additional information

INHALATION

Three studies performed with rats (two with F344 and one with SD rats) and 3 studies performed with B6C3F1 mice were reported. In one study, the distribution of 2-butoxyethanol (2BE) and its metabolites was studied in relation with time. This study clearly showed that the liver and the forestomach were the main target organs. The great amount of radiolabelling found in the gastro-intestinal tract demonstrated that 2BE was ingested during grooming and by muco-cilliary clearance from nasopharynx and not directly via inhalation route. However this mechanism alone cannot explain the large amounts found in the forestomach.  2BE metabolism led to the formation of a majority of butoxyacetic acid (BAA), ethylene glycol (EG) and 2BE glucoronide (BEG) conjugate along with 2 metabolites unidentified in small quantities. BAA and EG formation followed a saturable mechanism and increased doses of 2BE lead to a greater formation of BEG conjugate compared to BAA and EG. Like the other routes of administration, elimination via urinary route was rapid and predominant. A small amount of the administrated dose was eliminated via inhalation route in the form of CO₂(less than 10 %).

The blood half-life of 2BE was about 10 minutes in rats and 5 minutes in mice whatever the level of exposure. Unlike BAA which seemed to be eliminated by a saturable mechanism, elimination of 2BE followed a linear kinetic. When repeated doses of 2BE were administered, the rate of BAA elimination tended to decrease with increasing doses of 2BE.

In rats, elimination of BAA varied with the sex of animals: females tended to eliminate BAA slower. This difference between the sexes could be due to a difference in the renal excretion between males and females. This sex difference was not found in mice. A species difference was also reported, with mice eliminating 2 fold faster than rats. An age difference was also described in mice, the older mice eliminating BAA 10 fold slower than the younger mice for a unique administration of 2BE. When exposures were repeated, the difference between aged and young mice tended to disappear. After 3 months of daily exposure, no difference was seen for the elimination of BAA when age is considered.

DERMAL

Dermal uptake of 2-butoxyethanol is rapid.  Peak blood levels occur about 2 hours after application.   Metabolism, as with other routes, mainly leads to the formation of BAA and also to smaller quantities of BEG conjugate.  The half-life of metabolites in plasma was about 4 hours. The majority of metabolites were eliminated via urinary excretion and only very small amounts were found in faeces. A small fraction of administered 2BE was metabolised to CO2 and eliminated via respiration, this amount increasing with the increasing dose.  Otherwise, the amounts absorbed, the route of excretion, and the pattern of urinary metabolites was independent of dose, with urinary excretion of butoxyacetic acid the main route of elimination.  Water can also dramatically facilitate the percutaneous absorption of 2-butoxyethanol.  One study showed aqueous solutions in the range 40-80% penetrate twice as quickly as neat or more dilute solutions of 20% or less. However, a second study showed the rate of increase to be of the order of 15x when present as a 50% aqueous solution compared to neat material (albeit from a relatively low baseline level). Metabolism of 2 -butoxyethanol to 2 -butoxyacetic acid was found to be insignificant; dermal exposure to 2 -butoxyethanol will lead to systemic exposure of the parent (same) compound. A figure of 30% was selected for the dermal uptake in the EU risk assessment of this substance and is retained here.
ORAL
Numerous toxicokinetic studies have been performed in rats and mice and lead to the following conclusions:

Absorption of orally administered 2BE was rapid and essentially complete (assumed to be 100 %). Target organs in which the most radiolabeled compound was found were: the forestomach, the liver and the kidneys. The major metabolite of 2BE is BAA which is formed through a mechanism involving alcohol and aldehyde dehydrogenases which seems to be saturable. Other metabolites were, in order of magnitude: the glucuronide conjugate of 2BE (whose percentage increases relative to the dose at the expense of the BAA formation) and two minor metabolites, the sulphate-conjugate of 2BE and ethylene glycol (which was not observed in all studies). Elimination is rapid and occurs mainly by urinary excretion. A small amount of metabolised 2BE is eliminated as CO₂ in expired air (0 to 20 % for a high and low dose respectively). A small amount of unchanged 2BE (approximately 1 %) is also eliminated in expired air. In two studies, BAA, BEG and 2BE were found in bile. 2BE did not accumulate in tissues. The metabolic profile was not changed after repeated exposures compared to acute exposure. Age-related difference was observed: young rats eliminating 2BE via CO2 and urine (with significantly less BAA and more BEG) to a greater extent than adult rats.  Simultaneous administration of 2BE and a primary alcohol (ethanol, n-propanol or n-butanol) in sufficient quantity inhibits BAA formation through competition for the alcohol dehydrogenase enzyme.
OTHER ROUTES
Two studies have been performed via the intravenous route (one in rats, the other in mice), two studies via the intraperitoneal route and one via the subcutaneous route in rats. Target organs evidenced in the previous described studies were confirmed in these studies: spleen, liver, thymus and stomach. However, a slight difference was seen in the distribution of the substance between the forestomach and the glandular stomach after an IV injection. The distribution to stomach comes from systemic circulation and also from ingestion of 2BE (which could come from salivary glands).
In these studies, which are generally mechanistic studies, it was demonstrated that the BAA formation was the results of Alcohol Dehydrogenase and Aldehyde Dehydrogenase metabolism in the liver. This finding is validated by competitive inhibition studies performed with Ethanol. Inhibition of renal tubular anion transport caused a decrease in the renal excretion of BAA and therefore an increase of the 2BE toxicity.

STUDIES IN HUMANS

Three studies were reported in which human volunteers were exposed to 2BE by the inhalation route. Theoretical absorption (calculated) of 2BE was found to be 80 %. However, measurements performed showed a real absorption of 55 to 60 %. This difference is explained by a “wash in / wash out” mechanism: due to its hydrophilic properties, 2BE is adsorbed to the surface of the respiratory tract during inspiration and it desorbed during exhalation leading to a decrease in the real uptake of substance.

A number of in vivostudies on volunteers and in vitro studies are available to quantify the dermal uptake of 2BE in humans. The in vitro studies, measuring the rate of absorption of liquid 2BE through human skin, gave results that varied by a factor of 25 (0.064 mg/cm²/hr for the lowest and 1.66 mg/cm²/hr for the highest). In vitro, rate of absorption is highly dependent on the concentration of the aqueous solution of 2BE used.  From the in vivo studies, one suggested an estimation of the skin penetration in the range: 7 to 96 nmol/min/cm² (0.008 mg/cm²/hr to 0.0114 mg/cm²/hr) for pure liquid 2BE. Another study performed with liquid 2BE showed that absorption was greater when the substance was in aqueous solution than when pure (dermal flux 1.34 mg/cm²/h and 0.26 mg/cm²/h respectively). This is consistent with data available in vitro and in animals. This observation needs to be borne in mind during risk characterisation.  If temperature and humidity conditions increased, the percutaneous uptake increased also (in contrast with the inhalation uptake which remained constant).

The half-life of 2BE in the bloodstream of humans was consistently around 1 hour in all studies whereas BAA half life was about 5 hours.

In one in vivostudy, percutaneous absorption of vapour 2BE was assessed. Depending on the external conditions during exposure, the internal dose of 2BE due to percutaneous absorption varies between 11 % and 39 %. The percentage of 11 % was found for “normal” conditions of use (temperature, humidity) and most scenarios found the percentage compared to inhalation to be in the range 10-15%.  A single observation of 39 % was found for the worst case of industrial use (high temperature, high humidity and wearing overalls).

PBPK modeling estimated that for a worst-case exposure to 2BE vapour (100 % of the body exposed and no cloths), percutaneous absorption would account for 15-27 % of the internal dose of 2BE. A figure of 60% is selected for inhalation absorption, which is in line with the conclusions drawn in the EU risk assessment (2006).

In a human volunteer study, venous blood samples were collected from 4 human male volunteers during and for 4 hours after a 2 hour exposure to 2-butoxyethanol vapour. Blood and urine were analysed for butoxyacetic acid (BAA). BAA levels peaked 2 -4 hours after exposure commenced with an average half life for elimination from blood of 4.3 hours.

OTHER DATA – INCLUDING PBPK MODELS

In vitro studies have showed that 2BE transformation to BAA is primarily via the alcohol dehydrogenase isotype 3. This enzyme is more active in females than in males.  Moreover, it has been demonstrated than metabolic rate in rat was 10 to 20 fold higher than in human.

Substantial work has been carried out to develop and refine a PBPK model using experimental data collected in humans and in animals to both populate and validate the model. The present model covers multiple exposure routes (inhalation, oral, dermal, iv), the differences between humans and animals, the kinetic parameters of the main metabolite BAA, and age related parameters to all of the modeling of chronic exposures. Recent studies have produced results which are consistent with the current PbPk model which can therefore be considered sufficiently validated for use in determining cross species toxicokinetic assessment factors.

DERMAL ABSORPTION

Five studies were reported on 2BE absorption properties via the dermal route including in vitro studies examining the percutaneous uptake of 2BE in various species, and at different concentrations in different solvents and with various patterns of application (occlusive or not occlusive). Under semi-occlusive conditions, dermal uptake of pure 2BE was between 20 and 30 % of the administrated dose. Dermal uptake of aqueous dilutions of 5, 10 and 20 % 2BE was similar to that of the pure substance. Uptake was increased and was maximal for the 40 and 80 % aqueous solutions of 2BE (from in vivo studies: 1.3 -1.4mg/cm2/hr from a 50% solution compared to 0.2 - 0.4mg/cm2/hr from pure 2BE; from in vitro studies: 0.8 - 1.9mg/cm2/hr from 10-50% solutions compared to 0.1 -0.9 mg/cm2/hr for pure 2BE.) The rate of penetration was less for pure substance than for concentrated aqueous solutions and less in in vivo studies compared to in vitro studies. Some in vitro studies demonstrated that dermal uptake for pig skin was 2 or 3 times slower than rat skin. The results found with human skin were more or less equivalent to those seen with pig skin.  If 2BE was administrated under non-occlusive conditions, the dermal uptake decreased dramatically (uptake 10 %), mainly because of the volatility of 2BE.