Ethylcyclohexane

Endpoint summary

Link to relevant study record(s)

Reference

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

1990

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Objective of study:

metabolism

Qualifier:

no guideline followed

Principles of method if other than guideline:

Urinary metabolism was studied in rats by GC-MS.

GLP compliance:

not specified

Radiolabelling:

no

Species:

rat

Strain:

Fischer 344

Sex:

male

Details on test animals or test system and environmental conditions:

Weight: 307 ± 10 g
Feed: ad libitum
Drinking water: ad libitum

Route of administration:

oral: gavage

Vehicle:

not specified

Duration and frequency of treatment / exposure:

once daily

Dose / conc.:

800 mg/kg bw/day (nominal)

No. of animals per sex per dose / concentration:

8 treated, 6 control

Control animals:

other: yes, water

Positive control reference chemical:

not required

Details on dosing and sampling:

Following the 14-day exposure period the rats were sacrified and histopathological examination was performed.
During the first 48 hours the rats were placed in metabolism cages and the urine collected. The samples were hydrolyzed and analysed by GC-MS.

Metabolites identified:

yes

Details on metabolites:

2c-hydroxy-4-ethylcyclohexanol, 2c-hydroxy-4t-ethylcyclohexanol, 2-hydroxy-4-ethylcyclohexane, trans-4-ethylcyclohexane, 2t-hydroxy-4t-ethylcyclohexanol, 2t-hydroxy-4c-ethylcyclohexanol

Conclusions:

The urinary metabolism of ECH administered by gavage was investigated in Fischer 344 rats.
The following urinary metabolites were identified: 2c-hydroxy-4-ethylcyclohexanol, 2c-hydroxy-4t-ethylcyclohexanol, 2-hydroxy-4-ethylcyclohexane, trans-4-ethylcyclohexane, 2t-hydroxy-4t-ethylcyclohexanol, 2t-hydroxy-4c-ethylcyclohexanol.

ECH did not undergo metabolism on the alkyl chain. Metabolism of the ring structure (dihydroxylation) was strongly favoured. Histopathological results revealed mild to moderate renal damage.

Executive summary:

The urinary metabolism of ECH administered by gavage was investigated in Fischer 344 rats.

The following urinary metabolites were identified: 2c-hydroxy-4-ethylcyclohexanol, 2c-hydroxy-4t-ethylcyclohexanol, 2-hydroxy-4-ethylcyclohexane, trans-4-ethylcyclohexane, 2t-hydroxy-4t-ethylcyclohexanol, 2t-hydroxy-4c-ethylcyclohexanol.

ECH did not undergo metabolism on the alkyl chain. Metabolism of the ring structure (dihydroxylation) was strongly favoured. Histopathological results revealed mild to moderate renal damage.

Description of key information

Experimental data:

The urinary metabolism of ECH administered by gavage was investigated in Fischer 344 rats.

The following urinary metabolites were identified: 2c-hydroxy-4-ethylcyclohexanol, 2c-hydroxy-4t-ethylcyclohexanol, 2-hydroxy-4-ethylcyclohexane, trans-4-ethylcyclohexane, 2t-hydroxy-4t-ethylcyclohexanol, 2t-hydroxy-4c-ethylcyclohexanol.

ECH did not undergo metabolism on the alkyl chain. Metabolism of the ring structure (dihydroxylation) was strongly favoured. Histopathological results revealed mild to moderate renal damage.

Theoretical assessment:

a)    Absorption

 

Oral absorption:

 

The low molecular weight (112.22) of ECH favours absorption in the gastro-intestinal tract by

passive diffusion, however, the low water solubility (6.3 mg/L) and the high log Pow (4.56)

of ECH render absorption in the gastro-intestinal tract by passive diffusion to be unlikely. ECH may be taken up by micellular solubilisation as ECH is poorly soluble in water and has a high log Pow. Therefore, for risk assessment purposes, the oral absorption of ECH is set at 50%.

The results of the toxicity studies with ECH do not provide reason to deviate from this proposed oral absorption percentage.

 

 

Dermal absorption:

 

Since the log Pow is high (4.56), ECH is expected to be taken up in the stratum corneum, but

further transfer to the epidermis is predicted to be low based on the low water solubility (6.3 mg/L). Between 1-100 mg/l absorption is anticipated to be low to moderate.

In consequence, 50 % dermal absorption is proposed for ECH.

 

Respiratory absorption:

 

The low water solubility (6.3 mg/L) enhances penetration to the lower parts of the respiratory

tract. In combination with the high log Pow (4.56) ECH is expected to be taken up by

micellular solubilisation in the lower respiratory tract. For risk assessment purposes the

inhalation absorption of ECH is set at 100%.

 

 

b)   Distribution

 

Although ECH may be expected to distribute widely throughout the body based on the small

molecular weight, the lipophilicity and low water solubility of ECH disfavour a wide distribution.

The lipophilicity of ECH also predicts that the intracellular concentration may be higher than the extracellular concentration, particularly in fatty tissues. Based on the relatively high lipophilicity ECH may accumulate. (1)

 

(1) Guidance for the implementation of REACH. Guidance on information requirements andchemical safety assessment. Chapter R.7c: Endpoint specific guidance. EuropeanChemical Agency, May 2008.

 

c)    Metabolism

 

The urinary metabolism of ECH administered by gavage was investigated in Fischer 344 rats.

The following urinary metabolites were identified: 2c-hydroxy-4-ethylcyclohexanol, 2c-hydroxy-4t-ethylcyclohexanol, 2-hydroxy-4-ethylcyclohexane, trans-4-ethylcyclohexane, 2t-hydroxy-4t-ethylcyclohexanol, 2t-hydroxy-4c-ethylcyclohexanol.

 

ECH did not undergo metabolism on the alkyl chain. Metabolism of the ring structure (dihydroxylation) was strongly favoured.

 

The metabolites are expected to be excreted via the urine as they are still expected to be low molecular weight compounds.

 

 

d)   Excretion:

 The metabolites are expected to be excreted via the urine as they are still expected to be low molecular weight compounds.

 Based on the present data no further conclusions about the toxicokinetic behavior of the substance can be drawn and no further assessment is possible.

 

 

 

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Absorption rate - oral (%):

50

Absorption rate - dermal (%):

50

Absorption rate - inhalation (%):

100