Reaction mass of (3E)-4-(2,6,6-trimethylcyclohex-2-en-1-yl)but-3-en-2-one and 4-(dodecylsulfanyl)-4-(2,6,6-trimethylcyclohex-1-en-1-yl)butan-2-one and 4-(dodecylsulfanyl)-4-(2,6,6-trimethylcyclohex-2-en-1-yl)butan-2-one

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics

Type of information:

other: assessment

Adequacy of study:

key study

Study period:

2015

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Well documented assessment of toxicokinetic behaviour of the substance.

Cross-reference

Reason / purpose for cross-reference:

reference to other study

Data source

Reference

Reference Type:

other company data

Title:

Unnamed

Year:

2015

Report date:

2015

Materials and methods

Objective of study:

other: general toxicokinetic assessment

Test guideline

Qualifier:

no guideline required

Principles of method if other than guideline:

Theoretical assessment of available toxicokinetic data

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

Not yet assigned

IUPAC Name:

Not yet assigned

Constituent 2

Reference substance name:

Reaction mass of (3E)-4-(2,6,6-trimethylcyclohex-2-en-1-yl)but-3-en-2-one and 4-(dodecylsulfanyl)-4-(2,6,6-trimethylcyclohex-1-en-1-yl)butan-2-one and 4-(dodecylsulfanyl)-4-(2,6,6-trimethylcyclohex-2-en-1-yl)butan-2-one

EC Number:

700-956-5

Molecular formula:

not applicable (reaction mass of constitutional isomers)

IUPAC Name:

Reaction mass of (3E)-4-(2,6,6-trimethylcyclohex-2-en-1-yl)but-3-en-2-one and 4-(dodecylsulfanyl)-4-(2,6,6-trimethylcyclohex-1-en-1-yl)butan-2-one and 4-(dodecylsulfanyl)-4-(2,6,6-trimethylcyclohex-2-en-1-yl)butan-2-one

Details on test material:

Assessment was made on the test substance. Detailed information on the 'test material identity' is provided in the toxicokinetic statement document including information on individual constituents.

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:

Based upon its structure, molecular weight and Log Kow value, absorption of orally administered test substance across the gastrointestinal mucosa would be expected. Acute and repeated dose toxicity studies in rats have shown evidence for the absorption of the test substance following oral administration; the results of these studies suggest some absorption across the gastrointestinal tract. The results from dermal studies in the rat provide no or limited evidence of absorption via this route.

Details on distribution in tissues:

Based on the physicochemical properties of the three main constituents, a wide distribution is expected. The high log Kow suggests partitioning to fat is probable. The lipophilicity of each constituent also suggests that they are likely to distribute into cells; the intracellular concentration is expected to be higher than the extracellular concentration particularly in fatty tissues.

Details on excretion:

The aqueous solubility of (E)-4-(2,6,6-trimethyl-2-cyclohexen-1-yl)-3-buten-2-one would allow its direct excretion in urine; although for 4-(dodecylthio)-4-(2,6,6-trimethyl-2-cyclohexen-1-yl)-2-butanone and 4-(dodecylthio)-4-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2-butanone this would be unlikely, given their poor water solubility. The size of (E)-4-(2,6,6-trimethyl-2-cyclohexen-1-yl)-3-buten-2-one would preclude its excretion via bile in the rat; the molecular weights of 4-(dodecylthio)-4-(2,6,6-trimethyl-2-cyclohexen-1-yl)-2-butanone and 4-(dodecylthio)-4-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2-butanone may allow direct excretion via the bile in the rat.

Metabolite characterisation studies

Details on metabolites:

The absorbed test substance would be subject to biotransformation. (E)-4-(2,6,6-trimethyl-2-cyclohexen-1-yl)-3-buten-2-one could undergo aromatic or aliphatic hydroxylation and subsequent glucoronidation thereby promoting biliary elimination of this conjugate with excretion in faeces. Alternatively, the alcohol moiety may be oxidised to carboxylic acid which would increase the polarity of the molecule and promote urinary excretion. Hydroxylation of the methyl groups or reduction of the carbonyl group and subsequent glucoronidation would promote also excretion. Epoxidation is possible with hydration and conjugation to glucuronide or sulphate prior to excretion. Alternatively following epoxidation, conjugation with glutathione and elimination is possible.
4-(dodecylthio)-4-(2,6,6-trimethyl-2-cyclohexen-1-yl)-2-butanone and 4-(dodecylthio)-4-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2-butanone are likely to share the same metabolic pathways discussed above but in addition could undergo S-dealkylation or S-oxidation prior to conjugation to glutathione or glucoronidation and subsequent excretion.

Any other information on results incl. tables

Substance is an a liquid with constituents molecular weight range: of 192.297 to 394.697. The range of solubilities are from insoluble (< 0.01 mg/L) to moderately soluble in water (106 mg/L at 25°C) and possesses a Log Kow values 9.67 to 9.77 and 3.85 at pH 7 and 25°C respectively.

Applicant's summary and conclusion

Conclusions:

Interpretation of results: other: no bioaccumulation potential based on physico chemical properties and toxicity studies
There are no toxicokinetic studies available. The toxicokinetic assessment is based on theoretical estimation taking into account the physicochemical properties of the substance and the data from in vivo and in vitro studies available. Interpretation of the data suggests that there is no bioaccumulation potential.

Executive summary:

Absorption: Based upon its structure, molecular weight and Log Kow value, absorption of orally administered test substance across the gastrointestinal mucosa would be expected. Acute and repeated dose toxicity studies in rats have shown evidence for the absorption of the test substance following oral administration; the results of these studies suggest some absorption across the gastrointestinal tract. The results from dermal studies in the rat provide limited or no evidence of absorption via this route.

 

Distribution: Based on the physicochemical properties of the three main constituents, a wide distribution is expected. The high log Kow suggests partitioning to fat is probable. The lipophilicity of each constituent also suggests that they are likely to distribute into cells; the intracellular concentration is expected to be higher than the extracellular concentration particularly in fatty tissues.

 

Metabolism: The absorbed test substance would be subject to biotransformation. (E)-4-(2,6,6-trimethyl-2-cyclohexen-1-yl)-3-buten-2-one could undergo aromatic or aliphatic hydroxylation and subsequent glucoronidation thereby promoting biliary elimination of this conjugate with excretion in faeces. Alternatively, the alcohol moiety may be oxidised to carboxylic acid which would increase the polarity of the molecule and promote urinary excretion. Hydroxylation of the methyl groups or reduction of the carbonyl group and subsequent glucoronidation would promote also excretion. Epoxidation is possible with hydration and conjugation to glucuronide or sulphate prior to excretion. Alternatively following epoxidation, conjugation with glutathione and elimination is possible. 4-(dodecylthio)-4-(2,6,6-trimethyl-2-cyclohexen-1-yl)-2-butanone and 4-(dodecylthio)-4-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2-butanone are likely to share the same metabolic pathways discussed above but in addition could undergo S-dealkylation or S-oxidation prior to conjugation to glutathione or glucoronidation and subsequent excretion.

 

Excretion: The aqueous solubility of (E)-4-(2,6,6-trimethyl-2-cyclohexen-1-yl)-3-buten-2-one would allow its direct excretion in urine; although for 4-(dodecylthio)-4-(2,6,6-trimethyl-2-cyclohexen-1-yl)-2-butanone and 4-(dodecylthio)-4-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2-butanone this would be unlikely, given their poor water solubility. The size of (E)-4-(2,6,6-trimethyl-2-cyclohexen-1-yl)-3-buten-2-one would preclude its excretion via bile in the rat; the molecular weights of 4-(dodecylthio)-4-(2,6,6-trimethyl-2-cyclohexen-1-yl)-2-butanone and 4-(dodecylthio)-4-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2-butanone may allow direct excretion via the bile in the rat.