Isoeugenol, a fragrance ingredient used to impart a spicy, carnation-like odour to numerous consumer products, has been chosen for a full risk assessment principally because of its known skin sensitising properties. While this risk assessment attempts to address all possible endpoints, the low volumes of use of isoeugenol and low levels of inclusion in these consumer products have led to this risk assessment giving a preponderant emphasis to dermal sensitisation.
Isoeugenol (phenol, 1-methoxy-4-prop-1-enyl) CAS 97-54-1, EINECS 202-590-7 is low molecular weight (164.2) substance that is generally a viscous liquid although it congeals at temperatures below 28°C. It has moderate water solubility (700 - 810 mg/l) and low lipophilicity (log Pow: c. 2.1). It has a low estimated vapour pressure of 0.21 Pa at 25°C and a low calculated Henry's constant (log H: -1.37).
Isoeugenol is used as an ingredient in fragrances and is found in a wide variety of consumer products. These include perfumes, skin-care products, deodorants, soaps, shampoos, detergents and other household cleaning and maintenance products. Maximum levels of isoeugenol in household cleaning products have been collected from manufacturers and are 60 ppm in laundry detergents, 70 ppm in fabric conditioners, 40 ppm in hard surface cleaners and less than 10 ppm in toilet cleaners and dish-wash products.
Isoeugenol used in Europe is produced primarily inside the European Union in quantities estimated to be 25,600 kg/year. It is estimated that 35% of this (9,000 kg/year) is used in household cleaning and maintenance products.
Environmental Assessment
Exposure: The current risk assessment is made according to the HERA detergent scenario and the EUSES local and regional methodology, tier 1 approach. Highest regional levels were calculated to be 2.73 x 10-5 mg/kg in sediments, 5.83 x 10-6 mg/l in surface water and 6.73 x 10-7 mg/kg in soil.
Hazards: Isoeugenol is readily biodegradable. The only acute toxicity study carried out on aquatic organisms shows that is toxic to daphnids (48h-EC50: 7.5 mg/l).
Possible no effect levels: In the absence of test data, assessment factors and QSARs have been used to give PNECS of 4.8 µg/l for aquatic organisms, 16.6 µg/kg bw for terrestrial organisms and 23.5 µg/kg bw for sediment-dwelling organisms.
Risk characterisation: Risk characterisation: Margins of exposure are well below 1 for all local and regional environmental compartments. Regional risk characterisation ratios are 1.22 x 10-3 for aquatic organisms, 4.06 x 10-5 for soil and 1.16 x 10-3 for sediments. Even if we use the global volume of isoeugenol, all regional ratios are below 10-3.
Conclusion: Current use levels and volumes of isoeugenol in household cleaning products do not raise concern with regard to possible effects on the environment.
Human Health Assessment
Consumer exposure: This risk assessment has been restricted to direct or indirect exposure to consumers arising from the use of laundry detergents, fabric conditioners, hard surface cleaners, toilet cleaners, cleaning sprays and dish-washing products. In addition to considering exposure in terms of the quantities potentially entering the body, this assessment has focused on exposure in terms of the quantity likely to be deposited on the skin surface because this is the exposure factor that is critical to the induction of allergic contact dermatitis.
Highest exposures: Pretreatment cleaning of clothes with undiluted liquid detergent with no subsequent hand-rinsing and other kinds of accidental or unintentional exposure (0.7 µg/cm2) represent the highest potential skin doses likely to induce or elicit allergic contact sensitization. Hand washing using laundry pre-treatment liquids is estimated to give the highest levels of direct or indirect exposure in terms of quantities penetrating the skin (0.00093 µg/kg bw/day). Total aggregate systemic exposure from all routes and all exposure scenarios is estimated to not exceed 0.0014 µg/kg bw/day.
Hazards: Studies on animals and humans demonstrate that isoeugenol is a skin sensitiser of moderate allergenic potency.. This is substantiated by clinical data that show widespread under-lying allergy to isoeugenol although very few cases of allergy are clearly attributable to the presence of isoeugenol in any specific consumer products.
Isoeugenol is rapidly metabolised and eliminated. Oral toxicokinetic studies show no signs of metabolic saturation. Skin penetration studies in vitro and in vivo show isoeugenol rapidly penetrates the skin. Isoeugenol has a moderate acute toxicity by dermal and oral routes (LD50 values > 1500 mg/kg). Inhalation is not considered a significant route of exposure. Systemic toxicity studies have shown that levels of 800 mg/kg/day are well tolerated by rats although these studies do not meet modern testing requirements. Evidence that no adverse systemic effects occur at levels of 70mg/kg bw/day is evident from multi-generation reproduction toxicity studies in rats. Developmental toxicity studies in single and multiple generations of rats have shown that the developmental NOAEL is 500mg/kg bw/day which is about twice the level of maternal toxicity. Isoeugenol is negative in bacterial and mammalian genotoxicity screens except in some studies where there is evidence that the results are the results of procedural artefacts. There are no data on the carcinogenic potential of isoeugenol.
Isoeugenol shows moderate skin and eye irritancy but shows no significant phototoxicity or photoallergenic potential.
Critical end-points and threshold levels: Skin sensitisation and systemic toxicity were considered to be the critical end-points. A No Expected Sensitization Level (NESL) of 250 µg/cm2 has been determined using a weight of evidence approach from a large number of predictive tests carried out on animals and studies in human subjects. There is evidence to show that although the threshold for elicitation of allergic responses from non-occlusive exposure to prior-sensitised individuals may be as low as 80 µg/cm2, these thresholds cannot be used in risk assessment as they are neither reliable nor unique determinants of elicitation.
In the absence of a NOAEL from conventional systemic toxicity studies, two measures were taken as a basis for risk assessment. One was a NOAEL of 70mg/kg bw/day from multiple generation developmental toxicity studies. The other was the Threshold of Toxicological Concern (TTC) of 30 µg/kg bw/day based on a large data set NOAELs of substances that have been similarly classified chemical structures.
Risk characterisation: Margins of exposure for the induction of skin sensitization from different exposure scenarios were found to vary between over a million and above 350. Aggregate margins of exposure for systemic effects from all products combined were over ten million based on the NOEL and above ten thousand based on the TTC (which already incorporates other safety factors).
Conclusion: The use of isoeugenol at current levels in household cleaning products does not raise any safety concerns with regard to its potential to induce allergic contact dermatitis and adverse systemic effects.
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