1,6-dichlorohexane

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics

Type of information:

other: Expert statement

Adequacy of study:

key study

Study period:

2013-01-16

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Expert statement, no study available

Data source

Reference

Reference Type:

other: Expert statement

Title:

Unnamed

Year:

2013

Report date:

2013

Materials and methods

Test guideline

Qualifier:

no guideline followed

Guideline:

other: Expert statement

Principles of method if other than guideline:

Expert statement

GLP compliance:

yes

Test material

Test material information

Constituent 1

Reference substance name:

1,6-dichlorohexane

EC Number:

218-491-7

EC Name:

1,6-dichlorohexane

Cas Number:

2163-00-0

Molecular formula:

C6H12Cl2

IUPAC Name:

1,6-dichlorohexane

Test material form:

other: Colourless liquid

Test animals

Details on test animals or test system and environmental conditions:

not applicable

Administration / exposure

Details on exposure:

not applicable

Duration and frequency of treatment / exposure:

not applicable

Doses / concentrations

Remarks:

Doses / Concentrations:
not applicable

No. of animals per sex per dose / concentration:

not applicable

Positive control reference chemical:

not applicable

Details on study design:

not applicable

Details on dosing and sampling:

not applicable

Statistics:

not applicable

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:

Generally, oral absorption is favoured for molecular weights below 500 g/mol. This characteristic combined with the moderate lipophilic log Pow value and water solubility allow dissolution of 1,6-dichlorohexane in the gastro-intestinal fluids and contact with the mucosal surface.
Administered in traganth in an acute oral toxicity study performed on rats, 1,6-dichlorohexane lead to a LD50 of 2675 mg/kg bw. Furthermore, long-term administration of 1,6-dichlorohexane in a reproduction/developmental toxicity screening study indicate that the compound became bioavailable. Following oral administration hydrolysis of 1,6-dichlorohexane cannot be excluded under the acidic milieu of the stomach and the slightly basic milieu of the intestine. Potential hydrolysis products are chlorohexanol and 1,6-hexanediol.
Based on the vapour pressure of approximately 11 Pa 1,6-dichlorohexane might become available for inhalation. If the substance would reach the lungs in its vapour or gaseous state, absorption directly across the respiratory tract epithelium by passive diffusion is likely to occur due to its moderate log Pow value and water solubility. In an acute inhalation toxicity study rats were exposed to a saturated vapour atmosphere of 1,6-dichlorohexane. As no mortality and no specific effects of systemic toxicity were observed these results indicate that systemic availability after inhalation might be low.
Similarly, based on physico–chemical properties of 1,6-dichlorohexane dermal penetration is estimated to be low to moderate. Due to lipophilicity of the substance uptake into the stratum corneum is estimated to be high. However, low water solubility of 1,6-dichlorohexane limit the partition from stratum corneum into the epidermis. These assumptions based on the physicochemical properties of 1,6-dichlorohexane are further supported by the results achieved from
an acute dermal toxicity study performed on rabbits. During this study no test item related mortality and no specific effects of systemic toxicity were observed. The LD50 was >2000 mg/kg bw. However, 1,6-dichlorohexane caused skin irritation, which in turn may favour direct absorption into the systemic circulation.
Taken together, physico-chemical properties and experimental data indicate bioavailability of 1,6-dichlorohexane via oral route and, to a less extend via dermal and inhalation route.

Details on distribution in tissues:

Assuming that 1,6-dichlorohexane is absorbed into the body following oral intake to some extend, it may be distributed into the interior part of cells due to its moderate lipophilic properties and in turn the intracellular concentration may be higher than extracellular concentration particularly in adipose tissues. No target organ was identified and no embryotoxicity/teratogenicity was observed in the reproduction and developmental performance. However, penetration through the placenta could not entirely be excluded. Reduced body weight and postnatal mortality of the offspring observed during lactation is estimated to be a consequence of maternal systemic toxicity. Based on their BCF values both, the parent molecule 1,6-dichlorohexane and its possible hydrolysis products have no potential to bioaccumulate in the human body.

Details on excretion:

As discussed above, 1,6-dichlorohexane may be hydrolysed and/or metabolised and will probably not be excreted in its original form. Dependent on the molecular weight of the metabolism products renal or biliary excretion is favoured. Generally, characteristics favourable for urinary excretion are low molecular weights (~300 g/mol), good water solubility and ionization of the molecule at the pH of the urine, which is applicable for the conjugated metabolites (glucuronides and sulphates). Renal excretion was also shown for metabolites of adipic acid (urea, glutamic acid, lactic acid among others, Rusoff, I.I. et al., 1960). On the
other hand, metabolites with a higher molecular weight, like glutathione adducts, are expected to be active secreted in the bile and excreted in the faeces.

Metabolite characterisation studies

Details on metabolites:

The chlorine atoms of 1,6-dichlorohexane are estimated to be substituted by glutathione abiotically as well as enzymatically. 1,6-dichlorohexane might further be hydrolysed slowly after being in contact with an aqueous solution as well as enzymatically. The first potential degradation product, chlorohexanol is estimated to be converted abiotically or by glutathione transferase into hexanol glutathione, which might be degraded to mercapturic acid in order to ultimately facilitate excretion. Furthermore, O-conjugation with glucuronic acid or sulphate is expected to occur which is in turn applicable for 1,6-hexanediol, the
second potential hydrolysis product. Oxidation of 1,6-hexanediol by ADH and AlDH is an alternative metabolic pathway resulting in adipic acid, which in turn will enter the β-oxidation pathway (Rusoff, I.I. et al., 1960). There is no indication for metabolic activation as no induction of mutation as well as chromosomal aberration was observed in the in vitro genotoxicity assays in the presence of a metabolic activation system.

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): no bioaccumulation potential based on study results
Based on physico-chemical characteristics, particularly water solubility and octanol-water partition coefficient absorption via oral route and to a less extend via dermal and inhalation route is likely to occur. Intracellular concentration is likely to be higher than extracellular due to the moderate lipophilicity of 1,6-dichlorohexane. Hydrolytic and metabolic conversion into chlorohexanol and 1,6-hexandiol might occur and conjugation of Phase I-metabolites may further increase hydrophilicity. Excretion via urine is assumed to be the main excretion pathway of potential metabolites formed due to their molecular weight. However, biliary excretion could not be excluded for glutathione adducts of 1,6-dichlorohexane. Bioaccumulation of 1,6- dichlorohexane itself and its potential metabolites is not likely to occur based on their physico-chemical properties.