Nerol

Endpoint summary

Description of key information

Absorption:

Nerol is likely to be well absorbed by dermal route because it is a small molecule and it has an optimal partition coefficient (log Kow = 2.76) for dermal absorption. Also, with a water solubility between 100 and 10000 mg/L, dermal absorption is anticipated to be moderate. Moreover, skin penetration may be enhanced by exposure to nerol because it is irritating to skin. Nerol was found to be skin sensitizing which proves that some uptake has occurred. However, in an acute dermal toxicity study, LD₅₀was higher than 5000 mg/kg bw in rabbits which means that nerol has low acute toxicological potential by this route of exposure. Thus, dermal absorption of nerol is likely to be moderate but it is not expected to lead to acute toxicological systemic effects.

Nerol is soluble in water and it is a small molecule (molecular weight around 200) therefore, it can easily dissolve into the gastrointestinal fluids and be absorbed by passive diffusion within the gastrointestinal tract; nerol is expected to be almost completely absorbed by oral route. The acute oral gavage toxicity study identified evidence of systemic toxicity, i.e. exophthalmia, hyperreflexiveness, restlessness, lethargy and the loss of righting reflex were observed but at very high and lethal doses (up to 9800 mg/kg bw). Oral bioavailability is confirmed in a combined repeated dose toxicity study with reproduction/developmental toxicity screening test where toxicological effects were observed such as reduced bodyweight gain at the highest dose tested.

No study by inhalation was performed. However, considering the low vapour pressure of nerol (<500 Pa), exposure to nerol by inhalation is likely to be very limited.

 

Thus, indications of oral uptake of nerol at high doses are given while dermal uptake would be more limited.

Distribution:

Nerol is a small molecule and is water soluble which indicates that nerol could be widely distributed.

Metabolism/excretion:

Nerol is a 10-carbon terpene primary alcohol. It was part of the substances reviewed in aliphatic branched-chain saturated and unsaturated alcohols, aldehydes, acids, and related esters group in the WHO food additives series 52. It is supposed to be readily absorbed from the gastrointestinal tract. After absorption, the substance can be expected to be distributed rapidly throughout the body, metabolized, and excreted as polar metabolites in the urine, faeces, and expired air.

Nerol is efficiently detoxicated by two principal pathways in animals. In one route, the alcohol is successively oxidized to the corresponding aldehyde and carboxylic acid, the latter of which is selectively hydrated or reduced. In a second route, the aldehyde undergoes reduction to the corresponding alcohol that is substrate for omega-oxidation to eventually yield diacid and the reduced or hydrated analog. Polar metabolites formed via these two pathways will be efficiently excreted primarily in the urine as the glucuronic acid conjugates (See document attached).

In rat microsomes, the C-8 methyl group of nerol utilizes NADP+ and O2 and undergoes stereoselective omega-hydroxylation to yield the (E)-isomer of the corresponding diol. Rat lung microsomes have been shown capable of omega-hydroxylation of nerol; a similar reaction has been reported for nerol with rabbit liver microsomes.

To summarise, nerol is expected to be rapidly metabolized by hydrolysis and oxidation with subsequent conjugation and excretion, primarily as urinary metabolites.

Accumulative potential:

Nerol bioaccumulation is not expected to occur, since it is efficiently metabolized to yield to polar metabolites that are excreted mainly in the urine.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

There is few reliable and relevant information source in which the toxicokinetic properties (absorption, distribution, metabolism, elimination) of nerol were investigated. These data are completed and confirmed by the physicochemical properties and the results from the available toxicological data following the guide given in the REACH guidance document R.7c:

Nerol is a monoconstituent having a relatively low molecular weight of 154. It is a liquid with a high water solubility of about 773 mg/L and has moderate lipophilic properties (log Pow = 2.76). Vapour pressure was determined to be about 60 Pa at 20°C. Detailed information can be found in section 4 of nerol IUCLID dossier.

 

Absorption:

 

Nerol is likely to be well absorbed by dermal route because it is a small molecule and it has an optimal partition coefficient (log Kow = 2.76) for dermal absorption. Also, with a water solubility between 100 and 10000 mg/L, dermal absorption is anticipated to be moderate. Moreover, skin penetration may be enhanced by exposure to nerol because it is irritating to skin. Nerol was found to be skin sensitizing which proves that some uptake has occurred. However, in an acute dermal toxicity study, LD₅₀was higher than 5000 mg/kg bw in rabbits which means that nerol has low acute toxicological potential by this route of exposure. Thus, dermal absorption of nerol is likely to be moderate but it is not expected to lead to acute toxicological systemic effects.

Nerol is soluble in water and it is a small molecule (molecular weight around 200) therefore, it can easily dissolve into the gastrointestinal fluids and be absorbed by passive diffusion within the gastrointestinal tract; nerol is expected to be almost completely absorbed by oral route. The acute oral gavage toxicity study identified evidence of systemic toxicity, i.e. exophthalmia, hyperreflexiveness, restlessness, lethargy and the loss of righting reflex were observed but at very high and lethal doses (up to 9800 mg/kg bw). Oral bioavailability is confirmed in a combined repeated dose toxicity study with reproduction/developmental toxicity screening test where toxicological effects were observed such as reduced bodyweight gain at the highest dose tested.

No study by inhalation was performed. However, considering the low vapour pressure of nerol (<500 Pa), exposure to nerol by inhalation is likely to be very limited.

 

Thus, indications of oral uptake of nerol at high doses are given while dermal uptake would be more limited.

Distribution:

 

Nerol is a small molecule and is water soluble which indicates that nerol could be widely distributed.

Metabolism/excretion:

Nerol is a 10-carbon terpene primary alcohol. It was part of the substances reviewed in aliphatic branched-chain saturated and unsaturated alcohols, aldehydes, acids, and related esters group in the WHO food additives series 52. It is supposed to be readily absorbed from the gastrointestinal tract. After absorption, the substance can be expected to be distributed rapidly throughout the body, metabolized, and excreted as polar metabolites in the urine, faeces, and expired air.

Nerol is efficiently detoxicated by two principal pathways in animals. In one route, the alcohol is successively oxidized to the corresponding aldehyde and carboxylic acid, the latter of which is selectively hydrated or reduced. In a second route, the aldehyde undergoes reduction to the corresponding alcohol that is substrate for omega-oxidation to eventually yield diacid and the reduced or hydrated analog. Polar metabolites formed via these two pathways will be efficiently excreted primarily in the urine as the glucuronic acid conjugates (See document attached).

In rat microsomes, the C-8 methyl group of nerol utilizes NADP+ and O2 and undergoes stereoselective omega-hydroxylation to yield the (E)-isomer of the corresponding diol. Rat lung microsomes have been shown capable of omega-hydroxylation of nerol; a similar reaction has been reported for nerol with rabbit liver microsomes.

To summarise, nerol is expected to be rapidly metabolized by hydrolysis and oxidation with subsequent conjugation and excretion, primarily as urinary metabolites.

Accumulative potential:

 

Nerol bioaccumulation is not expected to occur, since it is efficiently metabolized to yield to polar metabolites that are excreted mainly in the urine.

 

References:

Flavor and Fragrance High Production Volume Chemical Consortia, 2004, Revised Test Plan for Terpenoid Primary Alcohols and Related Esters 

Aliphatic branched-chain saturated and unsaturated alcohols, aldehydes, acids, and related esters, WHO Food Additives Series 52