1,6-dichlorohexane

Endpoint summary

Description of key information

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.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

Toxicological profile of 1,6-dichlorohexane

An acute oral toxicity study conducted with 1,6-dichlorohexane using rats revealed a LD50 value of 2675 mg/kg bw. In an acute inhalation toxicity study rats were exposed to saturated vapour atmosphere of 1,6-dichlorohexane. No mortality and no clinical signs could be observed. In an acute dermal toxicity study with rats a LD50 of >2000 mg/kg bw was determined for 1,6-dichlorohexane.

In an in vivo skin irritation and corrosion study, 1,6-dichlorohexane caused skin irritation effects when applied to rabbit skin. No corrosive effects were observed. An eye irritation test performed with 1,6-dichlorohexane on rabbits showed that the substance was not considered to be an eye irritant. Within the acute inhalation study available 1,6-dichlorohexane was not found to be irritating to the respiratory system. A LLNA study revealed that 1,6-dichlorohexane has no skin sensitizing properties.

1,6-dichlorohexane did not induce reverse mutations neither in two bacterial reverse mutation tests (Ames test) with five Salmonella typhimurium strains nor in a mammalian cell gene mutation assay (Mouse lymphoma assay) both in the presence and in the absence of a metabolic activation system. In a further in vitro micronucleous test 1,6-dichlorohexane did not cause an increase in the frequency of micronucleated CHO-cells and was therefore considered as not mutagenic in this test.

A 14-day dose range finding study using oral administration of 1,6-dichlorohexane was performed in male and female CD rats in order to obtain first information on the toxic potential of the test item after long-term administration to allow a dose-setting for a reproduction/developmental toxicity screening test (OECD 421). The chemical was administered orally (by gavage) once a day for a total of 14 days at 0 (vehicle control), 100, 300 and 1000 mg/kg bw/day. One male and one female animal of the high dose group died on day 6. The test substance caused a reduced food intake and, in turn, a reduced body weight in male and female rats treated with the intermediate and high dose. Reduced motility was noted from the first or second treatment day onwards - in relation to the dose - in a few to all male and female animals at 100, 300 or 1000 mg/kg bw/day. Ptosis was observed in all animals of both sexes treated with 300 and 1000 mg/kg bw/day. Ataxia was noted in all high dose male and female animals. In addition, slight to moderate salivation was noted in four of five males (including the prematurely deceased male) and in the four surviving females on one to five test days. Macroscopic inspection during necropsy revealed no test item-related changes in the surviving male and female rats at any tested dose level. Necropsy of the prematurely deceased high dose male rat revealed a dark-red discolouration in the left lobe of the lungs.

Necropsy of the prematurely deceased high dose female rat revealed a haemorrhagic snout, haemorrhagic eyes, slightly reddened lungs, two haemorrhagic foci in the stomach and reddish contents in the small intestines. Based on these results the following three doses were selected for the aforementioned reproduction/developmental toxicity screening study: 70, 210 and 630 mg/kg bw/day.

The main study revealed no mortality of male and female animals/dams exposed to 1,6-dichlorohexane. Test item related salivation and piloerection appeared in the intermediate and high dose group.Reduced motility and ptosis were noted in all animals treated with 630 mg/kg bw/day during the first test week.A significant decrease in food consumption and, in turn, a reduced body weight in males and females was observed in the intermediate and high dose group during the first test week.No test item-related influences were noted on weights of testes and epididymides of the male rats. The histomorphological examination of the reproductive organs testes, epididymides and ovaries after treatment with 70, 210 or 630 mg/kg bw/day did not reveal any morphological lesions which are considered to be related to the test item.There were no differences between the control group and the animals treated with 70 and 210 mg/kg bw/day in the reproductive performance of female animals and in delivery data of dams. At 630 mg/kg bw/day, a slightly increased post-implantation loss of 17.5 % was noted. A statistically significant reduction compared to the control was noted in the live birth index. A test item related effect on the offspring development was observed in the significantly higher number and percentage of extra uterine mortality in 630 mg/kg bw/day group. Significantly reduced mean litter weight was observed in the intermediate and high dose group. A significant reduction of total litter weight was noted in the high dose group. These effects were probably a consequence of the observed maternal systemic effect (reduced body weight and food consumption). However, no structural or visceral malformations were observed in the offspring at any dosage level. Based on these observations the respective NOAEL for male and female rats was set to 210 mg/kg bw/day. The NOAEL for reproductive performance of the male and female rats was evaluated to be 210 mg/kg bw/day and the NOAEL for the offspring was determined to be 70 mg/kg bw/day. The lower NOAEL for the offspring compared to maternal animals is however estimated to be a consequence of maternal systemic toxicity.

 

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 physico-chemical 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.

 

Distribution

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.

 

Metabolism

The chlorine atoms of 1,6-dichlorohexane are estimated to be substituted by glutathione abiotically as well as enzymatically. 1,6-dichlorohexane is further estimated to be slowly hydrolysed 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.

 

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 actively secreted in the bile and excreted in the faeces.

 

Summary

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.

References

 

ECHA (2008), Guidance on information requirements and chemical safety assessment, Chapter R.7c: Endpoint specific guidance.

 

Marquardt H., Schäfer S. (2004). Toxicology. Academic Press, San Diego, USA, 2nd Edition.

 

Rusoff II, Baldwin RR, Domingues FJ, Monder C, Ohan WJ, Thiessen R Jr. (1960) Intermediary metabolism of adipic acid.Toxicol Appl Pharmacol. 2:316-30.