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Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.

The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.

Diss Factsheets

Administrative data

Endpoint:
basic toxicokinetics, other
Type of information:
other: Evaluation of TK based on literature data
Adequacy of study:
key study
Study period:
expert statement
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data

Data source

Reference
Reference Type:
review article or handbook
Title:
Unnamed
Year:
2017
Report date:
2017

Materials and methods

Test material

Constituent 1
Chemical structure
Reference substance name:
Nonane-1,9-diol
EC Number:
223-517-5
EC Name:
Nonane-1,9-diol
Cas Number:
3937-56-2
Molecular formula:
C9H20O2
IUPAC Name:
nonane-1,9-diol

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:
Oral

1,9-Nonanediol possesses the phys/chem properties that favour absorption from the gastrointestinal tract (g.i. tract). According to the ECHA Guidelines (2014) molecules with molecular weights of less than 500 g/mole are small enough to be candidates for absorption by passive diffusion from the g.i. tract. The molecular weight of 1,9-nonanediol is 160.2 g/mole it is water soluble (5.7 g/L) and has an octanol-water partition coefficient (log Pow) of 1.69. This combination of aqueous and lipid solubility also generally favors absorption by the oral route.
Since there were no mortalities from 1,9-nonanediol in the acute oral toxicity study conducted it is not possible to corroborate this projection of oral absorption with information generated from in vivo studies.
Although the test item can be expected to be well absorbed, in the absence of experimental oral absorption data a default oral absorption value is used in derivation of DNELs as a worst case scenario. This is based on 100% absorption with a default factor of 2 in the case of oral to inhalation extrapolation giving an oral absorption value of 50%.

Dermal

Based on the phys/chem properties, 1,9-nonalnediol is likely to be absorbed after dermal application. According to the ECHA Guidelines (2014) molecules with molecular weights of less than 500 g/mole are capable of migration through the skin into systemic circulation. In addition, both water and lipid solubility influences the potential for dermal penetration. These factors have been used in various models for predicting dermal penetration.
The US EPA model (2007) is one of the most widely applied. It utilizes molecular weight and partition coefficient to predict the dermal permeability coefficient according to the following;
log(Kp) = 0.71 log Pow – 0.0061 MW – 2.72
where Kp is expressed in cm/h
The log Pow is 1.69 and the molecular weight (MW) is 160.2 g/mol. The resulting dermal permeability coefficient, (Log Kp) is -2.49 cm/h (Kp = 0.0032 cm/h).
This permeability coefficient can be used to estimate the amount of 1,9-nonanediol absorbed when applied to the skin. The following equation utilizes the dermal permeability coefficient (Kp), the concentration of test substance in water (Cw), the surface area of exposed skin (SA) the exposure time (ET) and a liter to cm3 conversion factor (CF1) to calculate the absorbed dose rate (ADR).
ADR = Cw x SA x ET x Kp x CF1
Solubilization of the test substance is necessary for dermal penetration, even if the substance is applied as a solid. For this calculation, the limit of solubility in water is used. The maximum solubility of 1,9-nonanediol in water is 5.7 g/L at 20°C and pH 6.6. Skin pH is 6.5 so it is considered appropriate to use this solubility value in the derivation. For the surface area 1 cm2 is used to generate a flux value that can be applied across a variety of applications with different surface area values. For 1,9 nonanediol the ADR is 0.018 mg/cm2/hr or 18 µg/cm2/hr. Thus, dermal exposure to 1,9-nonanediol would be expected to result in systemic exposure.
There are no experimental data available on the effects of dermal absorption of 1,9 nonanediol therefore it is not possible to corroborate this conclusion with information generated from in vivo studies.
Although the test item can be expected to be well absorbed, in the absence of experimental dermal absorption data a default dermal absorption value is used in derivation of DNELs as a worst case scenario. This is based on the oral absorption with a default factor of 1 in the case of oral to dermal extrapolation giving a dermal absorption value of 50%.

Inhalation

1,9-Nonanediol is a solid at room temperature. The vapor pressure of 1,9-nonanediol is low (0.0036 Pa at 20°C). However, if 1,9-nonanediol were aerosolized, absorption across the respiratory epithelium would likely be rapid based on its partition coefficient and small molecular weight. There are no experimental data on the effects of acute or long-term inhalation exposure to the test substance available.
In the absence of experimental data a default inhalation absorption value of 100% is used in derivation of DNELs.
Details on distribution in tissues:
The distribution of 1,9-nonanediol has not been characterized. The systemic effects noted after oral dosing are minimal and not specific enough to determine a distribution of absorbed material. After administration by the oral route, the compound would enter hepatic portal circulation resulting in distribution primary to the liver. Dermal absorption would result in general systemic exposure. By inhalation the distribution would also be expected to be more general as absorption by the lungs would result in distribution systemically via cardiac output.
The low molecular weight and polarity of 1,9-nonanediol makes bioaccumulation unlikely.
Details on excretion:
The low molecular weight and polarity of both 1,9-nonanediol and its metabolites will facilitate excretion via the urine. Material entering the ß-oxidation pathway may breakdown to CO2 with elimination via expired air.

Metabolite characterisation studies

Details on metabolites:
In the absence of recent and robust experimental data on the disposition of any of these compounds, predictions are made according to the principles described REACH Chapter 7c, expert judgment and by using the in silico OECD QSAR Toolbox V4. The results are compared with a published paper on the metabolism of glycols in the rabbit (Gessner et al, 1960).
Once absorbed by any route, as a primary alcohol, the metabolism of 1,9-nonanediol is expected to follow the following metabolic pathways (Belsito et al, 2010)
• Conjugation of alcohol function(s) with glucuronic acid
• Oxidation of the alcohol function(s) to aldehyde then acid, producing a medium chain fatty acid which would be a substrate for ß-oxidation
• Excretion of the unchanged parent compound
The metabolic steps proposed above will increase the water solubility of the compounds and facilitate excretion in urine. Entry into the ß-oxidation pathway will sequentially remove 2-carbon units and ultimately result in breakdown to CO2 and elimination via expired air.
The metabolism of various glycols was investigated in the chinchilla rabbit (Gessner et al., 1960). The investigation used unlabelled test material and analysed only urine therefore there was no mass balance. However, following a single oral dose of 1,6 hexanediol a small amount of glucuronide conjugate and an unquantified amount of adipic acid (hexanedioic acid) was detected in the urine. Following a dose of 1,4 butanediol and 1,5-pentanediol less glucuronide was present but succinic and glutaric acids (butanedioic and pentanedioic acid) were found, respectively. These data support the hypothesis of an oxidative metabolic pathway and excretion of metabolites in urine for glycols.
The OECD QSAR Toolbox V4 was also used to predict the metabolism of all three compounds using the simulator of rat liver metabolism. The results are presented in Appendix 1. There is good agreement between the predictions based on expert judgement and by the OECD QSAR Toolbox V4, with an oxidative pathway being the major route of transformation.

Any other information on results incl. tables

Appendix 1: Predicted metabolism of 1,9-nonanediol using OECD Toolbox (V4) rat liver metabolism simulator

Metabolic process

1,9-nonanediol

Oxidation to aldehyde

9-hydroxynonanal

Oxidation to acid

9-hydroxynonanoic acid

Shortening of carbon chain (assumedviaß-oxidation)

7-hydroxyheptanoic acid

 

acetic acid

 

Applicant's summary and conclusion

Conclusions:
1,9-nonanediol can be assumed to be absorbable by the oral, dermal, and inhalation routes of exposure. 1,9-nonanediol is assumed to be rapidly metabolized by an oxidative pathway and/or conjugation with glucuronic acid. There is no evidence of the formation of reactive or toxic metabolites. 1,9-nonanediol is unlikely to bioaccumulate because of its extensive metabolism and rapid excretion.
The test item can be assumed to be absorbed by the oral, dermal, and inhalation routes of exposure, however default absorption values are used in the derivation of DNELs, according to REACH guidance R.8 page 19.
Executive summary:

1,9-Nonanediol is a medium chain diol with a molecular weight of 160.3 g/mole. It is a solid at room temperature with a vapour pressure of 0.0036 Pa at 20°C. It has an octanol water partition coefficient of 1.69 and is soluble in water at 5.7 g/L at 20°C, pH 6.64. With these physical/chemical (phys/chem) properties, oral, dermal and inhalation exposures are all potential routes of exposure.

Once absorbed, the metabolism of 1,9-nonanediol is expected to be oxidative. The first step is oxidation of the alcohol function to give rise to the mono or dicarboxylic acid equivalents of the parent compound. These compounds may be excreted directly in urine, conjugated with glucuronic acid or enter into the ß-oxidation pathway. Within this system, aliphatic carboxylic acids undergo conjugation with acetyl CoA and oxidation of the bond between the 2ndand 3rdcarbons adjacent to the carboxylic acid. This oxidation then leads to the ultimate cleavage at the site of oxidation to release two carbons in the form of acetyl-CoA. This process continues in a cyclic fashion two carbons at a time until all of the carbons in the fatty acid are converted to acetyl-CoA, which enters the endogenous citric acid cycle.

The metabolic steps proposed above will increase the water solubility of the compounds and facilitate rapid excretion in urine. Entry into the ß-oxidation pathway will sequentially remove 2-carbon units and ultimately result in breakdown to CO2and elimination via expired air.

The mode of action of 1,9-nonanediol has not been determined. 1,9-Nonanediol has limited chemical and biological reactivity and no defined mode of action for adverse effects. 1,9-Nonanediol is not acutely toxic, is non-irritating to skin and eye, is not a skin sensitiser, not genotoxic and has no structural alerts for protein or DNA binding or cancer. As a result, there is no basis for identifying analogues based on common modes of action. Therefore, selection of analogues for read across is based primarily on structural similarity.