[3R-(3α,3aβ,7β,8aα)]-1-(2,3,4,7,8,8a-hexahydro-3,6,8,8-tetramethyl-1H-3a,7-methanoazulen-5-yl)ethan-1-one

Endpoint summary

Description of key information

A toxicokinetic assessment was conducted in accordance with REACH Annex VIII 8.8.1. Methyl cedryl ketone (MCK) is a mono constituent organic liquid.

A full ADME toxicokinetic study in the rat is not available. In vivo studies covering the oral route in rats are available (90-day repeated dose toxicity, pre-natal developmental toxicity). A dermal 90-day repeated dose toxicity study in the rat is available. A skin sensitisation study in mice (LLNA) and an in vitro skin irritation study with human epidermis is available. No studies via the inhalation route are available. For further details on study summaries, reference is made to the appropriate sections in the IUCLID 6 registration dossier.

Based on the physicochemical properties and information in the dossier, MCK is readily absorbed via the oral route; absorption via the dermal and inhalational routes is expected to be low. MCK may accumulate on repeated exposure and alicyclic ketones are typically reduced to the corresponding secondary alcohol and excreted primarily as glucuronic acid conjugates in the urine. The alpha-2u-globulin-mediated nephropathy noted in male rats is not relevant for human health risk assessment.

The default absorption rates of 50% (oral and dermal) and 100% (inhalation) are accepted for chemical risk assessment purposes.

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Absorption rate - oral (%):

50

Absorption rate - dermal (%):

50

Absorption rate - inhalation (%):

100

Additional information

In accordance with the ECHA Guidance on Information Requirements and Chemical Safety Assessment, Chapter R.7C Section R.7.12 (Endpoint Specific Guidance), the physicochemical properties can provide an insight into the potential behaviour of MCK in the body.

1.Physicochemical properties

Absorption - oral

The molecular weight of MCK (246 g/mol) is in the range of favourable oral absorption (<500 g/mol). The octanol/water partition coefficient (log Kow) of MCK (5.9 at 30°C) indicates it is highly lipophilic. Based on the chemical structure, MCK has no groups which will dissociate in a relevant pH range (2-10) so is likely to be present in a non-ionised form. The molecular weight of MCK is indicative of absorption after oral administration. This might occur by micellular solubilisation, due to the high log Kow and poor water solubility (6 mg/L at 23°C).

Absorption – dermal

The physical state of MCK, low vapour pressure (0.25kPa at 25°C; boiling point 320.9°C) and the molecular weight (246 g/mol) indicates that dermal absorption is possible. The water solubility (6 mg/L at 23°C) indicates low to moderate absorption while the high log Kow (5.9 at 30°C) is an indication for a high uptake into the stratum corneum, but a limited rate of penetration into the lower layers of the epidermis and dermis. In the final decision (CCH-D-2114453248-46-01), ECHA indicate “the water solubility and Log Kow of the registered substance are reported to be 6 mg/L and 5.9 respectively therefore suggesting low absorption through the skin into the systemic circulation”.

Absorption – inhalation

Due to the low vapour pressure of MCK (0.25kPa at 25°C; boiling point 320.9°C) respiratory exposure is expected to be low. However, some respiratory exposure may occur as MCK is used as a fragrance ingredient. The low water solubility (6 mg/L at 23°C) and high lipophilicity may enhance penetration in the lower respiratory tract.

Distribution/Metabolism/Excretion

Typically, lipid-soluble substances may reach all compartments and accumulate in fat. Based on the molecular weight and high lipophilicity, MCK will most likely distribute into tissues. Based on the chemical structure, there are no hydrolysable functional groups present, so in order to facilitate excretion, the highly lipophilic parent substance is likely to be converted to polar metabolites for excretion.

2. Information from other studies in the dossier

An in vitro human skin permeation study and milk transfer study in rats did not meet data quality requirements and were not included in the dossier.

Absorption (oral)

In a 90-day repeated dose toxicity study, MCK was administered to Wistar Crl:WI(Han) rats (10/sex/dose) by gavage in corn oil at dose levels of 0, 25, 80 and 250 mg/kg bw/day daily (OECD 408/GLP). On histopathological analysis, there were induced findings in the liver, thyroid and kidney in males and females at 250 mg/kg bw/day. The effects in liver and thyroid were considered adaptive and/or confined to groups dosed at 250 mg/kg bw/day. The effects in the kidney were related to alpha2u-globulin nephropathy in male rats and not relevant for humans. The NOAEL (male/female) was 80 mg/kg bw/day.

In a pre-natal developmental toxicity study (equivalent or similar to OECD 414/GLP), MCK was administered to 25 Sprague Dawley; Crl:CD (SD) IGS BR VAF/Plus females by gavage in corn oil at dose levels of 0, 25, 50, or 100 mg/kg bw/day from days 7 through 17 of gestation. Some effects were noted e.g. clinical signs, food consumption, reduction body weight gains from GD 7-10, in maternal animals only. The NOAEL (maternal) was 100 mg/kg bw/day; the NOAEL (developmental) was 50 mg/kg bw/day.

Based on these studies, the substance is readily absorbed via the oral route. For chemical safety assessment purposes, based on the physicochemical properties and information in the dossier, a default oral absorption of 50% is accepted.

Absorption (dermal)

In a 90-day repeated dose toxicity study (OECD 411/GLP), MCK was applied to the shaved skin of four groups of Crl:CD(SD)IGS BR male and female rats (15/sex/group) at dose levels of 0, 50, 150, 300 mg/kg bw/day, 6 -7 hours/day for 7 days/week during a 13 week period, with a 4 week recovery period. There were no effects noted except pathology in the male kidneys (indicator of the male alpha2u-globulin nephropathy noted in the oral study above) and dermal irritation; the latter effects were dose dependent but were resolved upon sacrifice or were almost fully resolved during weeks 14 -15 of the recovery phase. The NOAEL (male/female) was 300 mg/kg bw/day. The data from this study indicates that extended lower dose exposure may cause local dermal irritation, which could increase absorption. However, the in vitro skin irritation study using human epidermis tissue indicated that MCK is a non-irritant; human skin is typically less permeable than rabbit/rat skin. A skin sensitisation study in the mouse indicated that MCK is classified for skin sensitisation (Category 1B), so despite the high log Kow, which may limit systemic exposure, some dermal uptake occurs. In their draft decision (CCH-D-2114435755-43-01), ECHA concluded that “the sensitising property of the registered substance leads to the corresponding adverse effects seen on the skin of the test animals”, in reference to the effects noted in the repeated dose dermal toxicity study.

The ECHA guidance criteria (Chapter R.7C) state that 10% dermal absorption is used when the molecular weight of the substance is >500 and the log Kow is <-1 or >4, otherwise 100% dermal absorption is used. In general, dermal absorption will not be higher than oral absorption, so for chemical safety assessment purposes a dermal absorption rate of 50% is accepted.

Absorption (inhalation)

There are no inhalation studies available for the substance. For chemical safety assessment, based on the physicochemical properties, the default inhalation absorption rate of 100% is accepted.

Distribution/Metabolism/Excretion

Based on the dermal irritation noted in the repeated dose dermal toxicity study, MCK may persist in the stratum corneum, due to its high lipophilicity; it may accumulate upon repeated oral exposure also, based on the liver effects noted in the 90-day oral toxicity study. In the final decision (CCH-D-2114453248-46-01), it was stated that “ECHA accordingly considers that the kidney is a target organ of the registered substance”. However, as the sub-chronic oral and dermal studies indicate, these effects were only observed in male rats and indicate that the substance induces alpha-2u-globulin-mediated nephropathy, which is not relevant for human health risk assessment. There is no direct evidence to indicate the metabolic pathway or route of excretion of the substance; alicyclic ketones are typically reduced to the corresponding secondary alcohol and excreted primarily as glucuronic acid conjugates in the urine (WHO, 2003). The liver effects noted in males at 250 mg/kg bw/day may indicate an overloading of the metabolic pathway, so the liver could become a depot for insufficiently metabolised substance.

Safety evaluation of certain food additives / prepared by the fifty-ninth meeting of the Joint FAO/WHO Expert Committee on Food Additives, 2003. (WHO food additives series 50)