4-Octanol, 3-amino-

Endpoint summary

Description of key information

Short description of key information on bioaccumulation potential result: 
in vitro human skin penetration study
Modelling of kinetics based on Structure activity relationships.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

100

Absorption rate - dermal (%):

50

Additional information

Absorption

Considering the structure, molecular weight of 145 and Log Pow of 1.3, 3 -amino-4 -octanol appears likely to be absorbed through the gut wall according to ‘Lipinski’s Rule of 5’ (1).

The acute oral toxicity of 3 -amino-4 -octanol is moderate with an LD50 of 550 mg/kg in rats, and all deaths occurring within one day of dosing. Other than a red discoloration of the intestinal tract in the animals that died during the study, there were no gross histopathological findings. Therefore death was likely to have been caused by systemic effects rather than local irritation/corrosion.

In a 28 day oral gavage study evidence of systemic toxicity considered to be treatment related was observed in the highest dose group (250 mg/kg) (increased liver weight, alterations in serum liver enzyme levels, liver vacuolation, altered clinical chemistry parameters such as serum glucose, potassium and chloride).

Considering the evidence of systemic toxicity and the physical chemical properties it appears that the compound will be absorbed following oral administration.

3 -amino-4 -octanol fits the classification as corrosive and so it could be expected that dermal absorption subsequent to the corrosive action of the material is possible. In a repeated dose dermal irritation/toxicity study conducted with test material pH adjusted to 9.5 a NOEL for both local dermal effects and body weight change was 100 mg/kg bw. Since the only effects recorded were bodyweight gain and irritation/corrosion it is not possible to state whether the test material became systemically available following dermal application. In the murine LLNA, the material was demonstrated to be a weak skin sensitiser indicating some degree of dermal penetration may be occurring although it is not possible to comment on the subsequent systemic availability. These data indicate that at high concentrations (>85%) 3 -amino-4 -octanol may be capable of penetrating the skin, however due to the corrosivity, prolonged exposure to such concentrations are unlikely to occur.

In an in vitro study using human skin, the dermal penetration of 3 -amino-4 -octanol was studied using concentrations of 0.5 and 10% at a pH of 9. These concentrations were chosen because they represent the levels of 3 -amino-4 -octanol in metal working fluid. the pH of 9 is generally the highest pH of metal working fluids. Thus these exposure conditions mimic those to which workers will likely be faced when handling metal working fluids containing 3 -amino-4 -octanol. Due to the corrosivity of 3 -amino-4 -octanol it was not possible to test more concentrated solutions. In this study, over the course of 24 hours approximately 50% and 20% of the 0.5 and 10% solutions penetrated the skin, respectively. However, whilst the penetration through the skin was greater for the 0.5% concentration, the flux was greater for the 10% concentration (11.3 microgram/cm2/h, compared to 1.22 microgram/cm2/hour). There was also a lag time of between 2 and 4 hours before the material appeared in the receptor fluid for both test concentrations.

These data indicate that 3 -amino-4 -octanol is capable of penetrating the skin, and that lower concentrations result in a higher percentage of the dose penetrating, but at a lower flux. It also shows that there is a significant lag phase prior to penetration through the skin. Were a worker to spill this material onto their skin, then removal within 2 hours should significantly limit the penetration of the material through the skin.

The vapour pressure of 3 -amino-4 -octanol is very low indicating that vapour is unlikely to be a significant source of exposure. Due to the envisaged use of the material it is plausible that aerosols containing XU-12314.00 may be generated. Considering the potential for absorption in the gut and the Log Pow it is plausible that some inhaled material could be absorbed.

Distribution

Based on the water solubility and Log Pow it seems likely that the material will have a tendency to partition into the body water. Consistent with this, the predicted volume of distribution (Vd) for 3 -amino-4 -octanol is 2.4 L/kg via the ADME Boxes QSAR application (v4.03, Pharma Algorithms Inc., CA). Considering the effects observed in the liver in the 28-day repeat dose oral toxicity study it seems that liver is a target organ and this is probably be due to its metabolic capabilities and its gatekeeper role between the enterohepatic and systemic blood supply following oral exposure.

Metabolism

3 -amino-4 -octanol is a saturated alkanolamine. Related compounds, such as 2-aminopropanol (AMP), are not metabolized in the rat (3). It is therefore assumed that 3 -amino-4 -octanol is likely to be fairly metabolically stable, however possible routes of metabolism could involve aliphatic oxidation and/or Phase II conjugation by glucuronidation, sulfation or amino acid conjugation.

Excretion

3 -amino-4 -octanol is water soluble and has a relatively low molecular weight, therefore it is likely that the absorbed parent compound and any metabolites will be excreted in the urine. Other saturated alkanolamines such as AMP and diisopropanolamine (DIPA) are rapidly eliminated, primarily via the urine (91% and 97% of the administered dose, respectively) (3, 4).  

 

References

1)           C. A. Lipinski, F. Lombardo, B. W. Dominy, P. J. Feeney, Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings, Adv. Drug Del. Rev., 2001, 46, 3-26.

2)           EPA (2007). EPI (Estimation Programs Interface) EPI Suite: a Windows® based suite of physical/chemical property and environmental fate estimation models developed by the EPA’s Office of Pollution Prevention Toxics and Research Corporation http: //www. epa. gov/opptintr/exposure/pubs/episuite. htm.

3)           Saghir SA, Clark AJ, McClymont EL, Staley JL, Pharmacokinetics of aminomethylpropanol in rats following oral and a novel dermal study design. Food Chem. Toxicol., 46, 678-687 (2008).

4)           Saghir SA, Frantz SW, Spence MW, Nolan RJ, Lowe ER, Rick DL, Bartels MJ, Pharmacokinetics and bioavailability of diisopropanolamine (DIPA) in rats following intravenous or dermal application. Food Chem. Toxicol., 45, 2047-2056 (2007).