Ethyl trans-2,2,6-trimethylcyclohexanecarboxylate

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics, other

Type of information:

other: Assessment of toxicokinetics based on available study data

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Assessment based on the results of guideline studies

Data source

Reference

Reference Type:

other: Assessment based on the results of guideline studies

Title:

Unnamed

Year:

2016

Materials and methods

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

Ethyl trans-2,2,6-trimethylcyclohexanecarboxylate

EC Number:

412-540-8

EC Name:

Ethyl trans-2,2,6-trimethylcyclohexanecarboxylate

Cas Number:

22471-55-2

Molecular formula:

C12 H22 O2

IUPAC Name:

ethyl trans-2,2,6-trimethylcyclohexanecarboxylate

Constituent 2

Reference substance name:

Ethyl cis-2,2,6-trimethylcyclohexane-1-carboxylate

Molecular formula:

C12H22O2

IUPAC Name:

Ethyl cis-2,2,6-trimethylcyclohexane-1-carboxylate

impurity 1

Reference substance name:

Unidentified impurities

Molecular formula:

Not specified.

IUPAC Name:

Unidentified impurities

Test material form:

liquid: viscous

Details on test material:

Sample name: ET-344 SP

Results and discussion

Any other information on results incl. tables

Physico-chemical properties:

Physical Form: Viscous Liquid

Molecular weight: ca. 198.3 g/mol

Water solubility: 31.2 mg/L at room temperature (Slightly soluble)

Fat Solubility: miscible in all proportions with standard fat at 37 °C

Partition coefficient: Log10 Pow = 4.51

Melting point: liquid at room temperature (Freezes at < -20C)

Boiling Point: 228 °C

Vapour pressure: 29.85 +/- 1.4 Pa at 20°C

Surface tension: 69.6 mN/m at 25°C (classified as surface active)

Readily biodegradable: Not readily biodegradable (approx 0%)

Mean Soil adsorption Coeff (K): 7.1 (5.26-10.7)

Hydrolysis: Not hydrolysed (less than 10% hydrolysis after 5 days at 50°C in pH 4, 7 and 9 buffer solutions)

Bioconcentration Factor (BCF): After 56 days were calculated to be 134 at a test concentration of 0.0085 mg/l and 159 at a test concentration of 0.085 mg/l. Not be considered to significantly accumulate in the tissues of common carp. 

 

Toxicological Profile:

Acute Rodent Exposure:

After single oral administration : not lethal at 2000 mg/kg.

After single dermal administration : not lethal at 2000 mg/kg.

Corrosive to skin: No

Irritating to skin: Classified as an irritant to skin

Testing for sensitising properties: Negative

Repeated Rodent Exposure:

28 day rat study:  Male and female rats received the test substance by gavage daily, formulated in Arachis oil for >28 days. In the main study, dose levels of 15, 150 and 1000 mg/kg/d for at least 28 days showed no mortality and no signs of accumulation or cumulative toxicity. Hepatic changes were mild and suggest adaptive metabolism. Male kidney alpha 2 microglobulin was indicated at all dose levels (NOEL<15 mg/kg/d) (fully reversible and of no human relevance).

Reprotoxicity rat study: Male and female rats were treated with THESARON at 100, 300 or 1000 mg/kg/d. There were no adverse health effects in the adults, minor lower body weights in pups at 1000 mg/kg/d was not considered as an adverse effect of the chemical. There were no reprotoxic effects. Effects in the kidney were consistent with the 28 day study.

Genotoxicity Bacterial, Mammalian Cell and In Vivo Exposure:

Bacterial mutagenicity: Negative

In CHL cells there was significant cytotoxicity at concentrations of 20 and 100 µg/mL (with and without S9 respectively – hence microsomes can detoxify the test item). There was no genotoxic effect of the test item in this CA assay.

In an in vivo micronucleus assay conducted in mice at 1250 mg/kg. Clinical signs and one premature death would indicate that systemic absorption had occurred, with some toxicity evident. Non-genotoxic.

Bioaccumulation:

In a bioaccumulation study in common carp, with the test item in the aquatic media. The study concluded: The Bioconcentration Factors (BCF) for ET-344 SP after 56 days were calculated to be 134 at a test concentration of 0.0085 mg/l and 159 at a test concentration of 0.085 mg/l. The best material, ET-344SP, cannot be considered to significantly accumulate in the tissues of common carp.

 

Evaluation and Assessment, based on studies and available data

 

ABSORPTION by the dermal route:

The pure test item is irritant to skin, which would indicate that there is at least some potential for systemic absorption from dermal exposure. The water solubility of 31.2 mg/L is relatively low, but the fat solubility is high (based on the statement that the miscible with fat in all proportions); with a relatively low molecular size and the solubility data and a Log P of 4.51, it is above the threshold for relatively high skin penetration (4.0). The relatively high Log P results in high ability to penetrate stratum corneum, and a low solubility in aqueous matrix of the epidermal and subepidermal tissues limits the flux. The potential for skin penetration is considered to be low to moderate. A dermal absorption rate of < 40% was obtained for this substance using the RIFM’s Skin Absorption Model (SAM) (reference: Jie Shen, Lambros Kromidas, Terry Schultz and Sneha Bhatia (2014). An in silico skin absorption model for fragrance materials. Food and Chemical Toxicology. 74: 164–176. http://dx.doi.org/10.1016/j.fct.2014.09.015).

 

ABSORPTION by the oral route:

Examination of the data from the repeat dose oral studies gave an indication of there being good evidence for oral bioavailability by the oral route for the test item. The slight water solubility and LogP of 4.5 suggests some intestinal bioavailability but not a rapid absorption. The biological effects (lethality in mice from about 1250 mg/kg and a NOEL of <15 mg/kg/d for kidney changes in rats) following administration of test item confirms bioavailability.As a worst case, a default value of 100% oral absorption will be used for the chemical safety assessment.

ABSORPTION by the inhalation route:

The relatively low volatility suggests a low risk of inhalation exposure. The physico-chemistry suggests any test item in the vapour phase would probably be poorly absorbed (LogP>4.0); the low concentrations in air from the test item at room temperature would not be expected to be of any concern. A value of 50% inhalation absorption will be used for the chemical safety assessment.

 

Other Biological Assays:

Relatively low water solubility combined with relatively high toxicity to fish indicates ready partitioning from water into fish, with rapid absorption by aquatic organisms (partitioning into the lipid of the organisms from the water phase when no other organic material is present in the test system). However, the bioaccumulation data shows it is not considered to significantly accumulate, indicating an efficient metabolism and elimination.

 

SUMMARY: Potential for Bioavailability and Bioaccumulation

The studies performed and the available physicochemical data are consistent with an organic molecule with some bioavailability but no significant indication or evidence for potential for toxicity or bioaccumulation.

The physical properties and mammalian data indicate moderate bioavailability. Low melting point and surface activity can also facilitate bioavailability. Evidence from in vitro cytotoxicity shows reduced toxicity in the presence of S9 liver enzymes; also rats given >28 days of a daily dose of the maximum normal dose of 1000 mg/kg/d, had no major toxic or reprotoxic effects; this indicates a lack of bioaccumulation. Hepatic changes suggest adaptation to detoxification without adverse effects. The physicochemical and biological data suggests that absorbed chemical would be metabolised to non-toxic metabolites and eliminated by excretion in urine. Additional excretion via the bile is plausible but has no evidence.

The repeat dose mammalian studies showed no significant toxicity at 1000 mg/kg/d but some minor rodent-specific effects at the low dose of 15 mg/kg/d. This data shows that there was no indication of cumulative toxicity and a lack of any significant systemic or local toxicity. If there was accumulation of this chemical, then toxicity would become evident (the mouse MN study showed potential for lethality if the dose is high enough).

There were no studies that suggest any evidence of bioaccumulation in mammals; a study in fish did not show significant accumulation.

 

SUMMARY: Potential for Distribution and Metabolism

There were no studies performed to specifically study distribution or metabolism. However, the relatively low water solubility and LogP of 4.51, plus the mammalian data, suggest this type of chemistry would be relatively bioavailable in animals (by oral or dermal exposure) but would not tend to partition onto lipid tissues due to rapid elimination. The apparent rapid metabolism would allow rapid excretion in urine. The evidence from in vitro assays indicated lower toxicity in the presence of liver enzymes (S9); also the repeat dose rodent studies of >28 days showed indications of metabolism and elimination via the urine (being a lipophilic substance, it is very likely that it is rapidly metabolised to a water soluble form and eliminated in the urine). Minor kidney changes even at the lowest dose level in male rats have no consequences for human health, but do show evidence of passage through kidney tubules. The fish studies show high toxicity indicating the expected rapid absorption of the lipophilic substance, but no significant BCF, demonstrating rapid elimination, which must be the result of metabolism to water soluble non-toxic substances. These data support the concept of a chemical which is detoxified in biological systems. Hence THESARON is considered to be rapidly distributed in mammals, but eliminated by metabolism and excretion, considered to be mainly eliminated in urine.

The biodegradation study with sewage sludge did not show rapid biodegradation, there was no significant hydrolysis at temperatures of <50°C, and the high Koc suggests a low mobility in soil. These data suggest the chemical may not be eliminated rapidly in the environment. High toxicity to fish, but a relatively low water solubility (allowing rapid dilution in the environment) suggest there is not a high risk in environmental exposure scenarios but in case of a high level of contamination of water, local environmental toxicity could occur, but the low BCF shows that rapid metabolism in fish, with a high Koc (with good soil absorption) would make long term effects in fish or other aquatic organisms very unlikely.

 

CONCLUSIONS:

The physicochemical and biological data on THESARON suggest it is bioavailable, it would be distributed systemically, but would be rapidly metabolised and not tend to partition into lipid tissues, it appears to be metabolised and eliminated (probably in the urine) relatively rapidly.

 

Applicant's summary and conclusion

Conclusions:

The physicochemical and biological data on THESARON suggest it is bioavailable, it would be distributed systemically, but would be rapidly metabolised and not tend to partition into lipid tissues, it appears to be metabolised and eliminated (probably in the urine) relatively rapidly.

Executive summary:

There were no studies performed to specifically study distribution or metabolism. However, the relatively low water solubility and LogP of 4.51, plus the mammalian data, suggest this type of chemistry would be relatively bioavailable in animals (by oral or dermal exposure) but would not tend to partition onto lipid tissues due to rapid elimination. The apparent rapid metabolism would allow rapid excretion in urine. The evidence from in vitro assays indicated lower toxicity in the presence of liver enzymes (S9); also the repeat dose rodent studies of >28 days showed indications of metabolism and elimination via the urine (being a lipophilic substance, it is very likely that it is rapidly metabolised to a water soluble form and eliminated in the urine). Minor kidney changes even at the lowest dose level in male rats have no consequences for human health, but do show evidence of passage through kidney tubules. The fish studies show high toxicity indicating the expected rapid absorption of the lipophilic substance, but no significant BCF, demonstrating rapid elimination, which must be the result of metabolism to water soluble non-toxic substances. These data support the concept of a chemical which is detoxified in biological systems. Hence THESARON is considered to be rapidly distributed in mammals, but eliminated by metabolism and excretion, considered to be mainly eliminated in urine.

The biodegradation study with sewage sludge did not show rapid biodegradation, there was no significant hydrolysis at temperatures of <50°C, and the high Koc suggests a low mobility in soil. These data suggest the chemical may not be eliminated rapidly in the environment. High toxicity to fish, but a relatively low water solubility (allowing rapid dilution in the environment) suggest there is not a high risk in environmental exposure scenarios but in case of a high level of contamination of water, local environmental toxicity could occur, but the low BCF shows that rapid metabolism in fish, with a high Koc (with good soil absorption) would make long term effects in fish or other aquatic organisms very unlikely.