3-methyl-2-pent-2-enylcyclopent-2-enone

Endpoint summary

Description of key information

No studies are available. The molecular weight, physico-chemical properties incl. water solubility and octanol-water partition coefficient of the substance suggest that oral, dermal and inhalative absorption may occur. Dermal absorption has been predicted to be ≤ 80%, using the Skin Absorption Model (SAM) developed by the Research Institute for Fragrance Materials (RIFM). Wide distribution within the water compartment of the body after systemic absorption is due to the lipophilicity of the test substance not expected. However, the distribution into cells particularly in fatty tissues is likely. Based on its log Pow the test substance is not considered to accumulate. The test substance might be metabolized after absorption. Excretion is expected to be predominantly via the urine.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

In accordance with Annex VIII, Column 1, Item 8.8 of Regulation (EC) No. 1907/2006 (REACH) and with Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2017), assessment of the toxicokinetic behaviour of the test substance was conducted to the extent that can be derived from the relevant available information on physico-chemical and toxicological characteristics. There are no studies available evaluating the toxicokinetic properties of the substance.

The test substance is a clear colourless liquid with a molecular weight of 164.25 g/mol and a water solubility of 1480 mg/L at 20 °C. Its vapour pressure has been determined to be 0.91 Pa at 20 °C and the log Pow is 2.8 at 35 °C.

Absorption

The major routes by which the test substance can enter the body are via the gastrointestinal tract, the skin, and the lung. To be absorbed, the test substances must transverse across biological membranes either by active transport mechanisms or - as being the case for most compounds - by passive diffusion. The latter is depending on compound properties such as molecular weight, lipophilicity, and water solubility (ECHA, 2017).

Oral

In general, low molecular weight (MW ≤ 500) and moderate lipophilicity (log Pow values of -1 to +4) are favourable for membrane penetration and thus absorption. The molecular weight of the test substance is relatively low with 164.25, favouring oral absorption of the compound. This is supported by the determined log Pow values of 2.8, being advantageous for oral absorption. In addition the good water solubility of 1.48 g/L leading to a ready dissolving of the compound in the gastrointestinal fluids favours oral absorption.

Moreover, the observation of systemic toxicity following exposure by any route is an indication for substance absorption; however, this is not able to provide any quantitative information.

In an acute oral toxicity study conducted with the test substance in rats marked signs of systemic toxicity were observed and mortalities occurred (Givaudan, 1971). At doses of 3000 and 4000 mg/kg bw the test substance caused areflexia (nociceptive and auditory reflex). The state of hypomotility was accompanied by muscle spasms, salivation, and pilo-erection. One animal died after 6 h, two more within 24 h after administration of the substance. In the surviving animals no symptoms could be observed 48 h after application. At a dose of 4500 mg/kg bw, identical symptoms were observed, although more pronounced. 4 animals were found dead within 6 h after application, 2 more animals died 24 h after application of the test substance. No symptoms occurred in the surviving animals 48 h after application. The LD50 value in this study was determined to be 4300 mg/kg bw. In a supporting study on acute oral toxicity (Moreno, 1977), 10 rats were dosed with 5000 mg/kg bw of cis-Jasmone. 4 animals were found dead within 24 h and 1 animal died 48 h after administration. No information regarding clinical signs is available from the study report. However, the LD50 was determined to be approx. 5000 mg/kg bw as 50% of the test animals died within the observation period. In addition, a Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test in rats according to OECD TG 422 was conducted (Givaudan, 2015). The test substance was administered in doses of up 15000 ppm (corresponding to 719.44 mg/kg bw/day for males and 762.59 mg/kg bw/day for females) in the diet. There was no mortality in any group and no treatment-related clinical signs were observed during the whole study period. In the pre-mating period, there was a dose-related and statistically significant reduction in mean food consumption for both. A treatment-related reduction in mean food consumption in females at all dose levels was also observed throughout the gestation period and the four days of lactation. As a consequence of the significantly reduced food intake, the mean body weight gain during the first week of treatment was reduced. Furthermore, the test item did not affect the functional activity of the treated animals and there was no adverse effect on clinical laboratory parameters. At necropsy, no obvious treatment-related effect was observed on reproductive organs/tissues weights in adult animals. However, at 15000 ppm there was hepatocyte hypertrophy and an increased weight of the liver in both sexes, cortical tubular changes and increased weight of the kidneys of males, atrophy and decreased weight (in both sexes) of the thymus, zona fasciculata vacuolation in the adrenals of males and decreased extramedullary haematopoiesis and decreased weight in the spleen of females. Based on body weight and weight gain as well as food consumption and gross pathology findings, the No-Observed-Adverse-Effect-Level (NOAEL) for parental/systemic toxicity was established at 1500 ppm, corresponding to 92.17 mg/kg bw/day for males and 96.63 mg/kg bw/day for females. As demonstrated by the acute oral and repeated dose toxicity studies, oral toxicity was observed with the test substance and thus absorption of the test substance via the gastrointestinal tract has evidently occurred.

Dermal

The dermal uptake of liquids and substances in solution is generally expected to be higher than that of dry particles. Molecular weights below 100 g/mol favour dermal uptake, while for those above 500 g/mol the molecule may be too large. Thus, for the molecular weight level of the test substance (164.25 g/mol) dermal uptake can be expected to be moderate or even high. The Log P value of the test substance is optimal for dermal absorption. Also for dermal uptake sufficient water solubility is needed for the partitioning from the stratum corneum into the epidermis.

The dermal permeability constant Kp of the substance was estimated to be 0.0678 cm/h using the Skin Absorption Model (SAM) developed by the Research Institute for Fragrance Materials (RIFM; Shen et al., 2014) taking into account the measured log Pow of 2.8, the measured water solubility of 1468 mg/L and the molecular weight of 164.25 g/mol. Based on the calculated permeability constant, a maximum flux Jmax of 75.186 µg/cm2/h is anticipated which results in an absorption rate of ≤ 80%.

Data from an acute dermal toxicity study revealed no significant effect of the test substance at a dose level of 5000 mg/kg bw (Moreno, 1977). In fact, 10 rabbits were treated with 5000 mg/kg bw. No mortalities occurred and the only clinical sign of toxicity was diarrhoea in 1 animal. Against the background of the demonstrated toxic potency after oral exposure, the dermal toxicity seems to be of low magnitude. This is presumably due to a lower dermal uptake in contrast to oral absorption.

Inhalation

Moderate log Pow values (between -1 and 4) are favourable for absorption directly across the respiratory tract epithelium by passive diffusion. However, the test substance has a low vapour pressure of 0.91 Pa at 20 °C. Therefore, under normal use and handling conditions, inhalation exposure and thus availability for respiratory absorption of the substance in the form of vapour can be considered negligible.

Distribution

Distribution of a compound within the body depends on the physico-chemical properties of the substance especially the molecular weight, the lipophilic character and the water solubility. In general, the smaller the molecule, the wider is the distribution. If the molecule is lipophilic, it is likely to distribute into cells and the intracellular concentration may be higher than extracellular concentration particularly in fatty tissues (ECHA, 2017).

Since the test substance is lipophilic (log Pow 2.8) the distribution into cells is likely and the intracellular concentration may be higher than extracellular concentration particularly in fatty tissues, if the substance is absorbed systemically. Substances with log P values of 3 or less would be unlikely to accumulate in adipose tissues with the repeated intermittent exposure patterns normally encountered in the workplace but may accumulate if exposures are continuous. Once exposure to the substance stops, the substance will be gradually eliminated at a rate depending on the half-life of the substance (ECHA, 2017; Stryer, 1996).

Metabolism

No metabolism studies are available with the test substance itself. Prediction of compound metabolism based on physico-chemical data is difficult. Structure information gives some but no certain clue on reactions occurring in vivo. The potential metabolites following enzymatic metabolism were predicted using the QSAR OECD toolbox (v4.1; OECD, 2017). This QSAR tool predicts which metabolites may result from enzymatic activity in the liver and in the skin, and by intestinal bacteria in the gastrointestinal tract.

Hepatic metabolism

25 hepatic metabolites were predicted for the test substance. Primarily, hydroxylation of the alkenyl side chain and the cyclopentene ring system occurs in the liver. In general, hydroxyl groups make a substance more water-soluble and susceptible to metabolism by phase II-enzymes. Conjugation with glucuronic acid after the reduction step has been demonstrated for compounds with similar structures, e.g. cyclohexanone, isophorone and carvone (Belsito et al., 2012). In rats reaction of the nucleophile glutathione with the secondary alcohol resulting from the initial reduction step of cyclopentanone was also observed, leading to the formation of 2-hydroxy cyclopentylmercapturic acid (James and Waring, 1971). However, it was demonstrated that the relative rate of glutathione addition is significantly reduced for substances with a methyl substitution in β-position to the endocyclic double bond of the cyclopentene ring. Since this is the case for cis-Jasmone (IUPAC name: (Z)-3-methyl-2-(pent-2-en-1-yl)cyclopent-2-enone), addition of glutathione can be expected to be slow (Portoghese et al., 1989). The data for structurally similar cyclopentene derivatives thus support the predictions of potential hepatic metabolites.

Skin metabolism

In contrast to the significant number of hepatic metabolites, only 1 dermal metabolite was predicted for the test substance. Reduction of the ketone function to a hydroxyl group in the cyclopentene ring takes place in skin.

Microbial activity in the gastrointestinal tract

Up to 51 metabolites were predicted to result from all kinds of microbiological metabolism for the test substance. Most of the metabolites were found to be a consequence of the degradation of the molecule by opening of the cyclopentene ring or breaking down the alkenyl side chain.

Excretion

Only limited conclusions on excretion of a compound can be drawn based on physico-chemical data. Due to metabolic changes, the finally excreted compound may have few or none of the physico-chemical properties of the parent compound. In addition, conjugation of the substance may lead to very different molecular weights of the final product. The molecular weight (< 300 g/mol) and the water solubility of the test substance are properties favouring excretion via urine (ECHA, 2017). Moreover, the expected addition of glucuronic acid and, to a smaller degree, glutathione after reduction of the ketone function in the cyclopentene ring system, also favours excretion via the kidneys in the urine (Belsito et al., 2012). Thus the test substance is expected to be excreted predominantly via this pathway.

References

Belsito et at. (2012). A toxicologic and dermatologic assessment of cyclopentanones and cyclopentenones when used as fragrance ingredients; Food and Chemical Toxicology 50 (2012) S517–S556

ECHA (2017). Guidance on information requirements and chemical safety assessment - Chapter 7c: Endpoint specific guidance; Version 3; June 2017; European Chemicals Agency, Helsinki, Finland

Givaudan (1971). Acute Toxicity Givaudan Product "Giv. 1 - 0985" Jasmone; Testing laboratory: Battelle Geneva, Switzerland; Report no. Giv 1 0985; Company owner: Givaudan International SA; Report date: 1971-06-10

Givaudan (2015). Jasmone Cis – Dose-range finding toxicity study followed by a combined 28-day oral (dietary admixture) repeated dose toxicity study with the reproduction/developmental toxicity screening test in the rat.; Testing laboratory: WIL Research Europe-Lyon 329 Impasse du Domaine Rozier Les Oncins 69210 Saint-Germain-Nuelles France.; Report no. AB20642; Company owner: Givaudan UK Ltd Kennington Road Ashford Kent TN24 0LT United Kingdom.; Report date: 2015-08-12

James, S.P. and Waring, R.H. (1971). The metabolism of alicyclic ketones in the rabbit and rat. Xenobiotica 1, 573–580.

Moreno (1977). Acute Oral Toxicity in Rats, Dermal Toxicity in Rats; Testing laboratory: M B Research Laboratories, Inc.; Report no. 77-1547; Company owner: RIFM

OECD (2017). OECD QSAR Toolbox, Version 4.1, http://www.qsartoolbox.org

Portoghese et al. (1989). Reactivity of glutathione with α,β-unsaturated ketone flavouring substances. Food and Chemical Toxicology 27 (12), 773–776

Shen et al. (2014). An in silico skin absorption model for fragrance materials. Food and Chemical Toxicology 74 (2014) 164-176

Stryer, L. (1996). Biochemie. 4. Auflage. Heidelberg Berlin Oxford: Spektrum Akademischer Verlag.