O-isopropyl ethylthiocarbamate

Endpoint summary

Link to relevant study record(s)

Reference

Endpoint:

basic toxicokinetics in vitro / ex vivo

Type of information:

other: Expert statement

Adequacy of study:

key study

Study period:

03 NOV 2022

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: expert statement based on the ECHA Guidance R.7c

Objective of study:

absorption

distribution

enzyme clearance

excretion

Qualifier:

no guideline required

Principles of method if other than guideline:

expert assessment of ADME based on the ECHA Guidance R.7c
There are no ADME studies available for O-isopropyl ethylthiocarbamate (IPETC, CAS 141-98-0). The toxicokinetic profile was not determined by actual absorption, distribution, metabolism or excretion measurements. Rather, toxicokinetics of IPETC was assessed based on the physical-chemical properties in combination with results of toxicity studies.

GLP compliance:

no

Details on absorption:

Oral absorption
Absorption by passive diffusion is favoured for substances with moderate log P values (between -1 and 4). With a log P of 2.3, IPETC is likely to follow this route of absorption. Additionally, based on the low molecular weight (< 200 g/mol) and due to the solubility in water, IPETC may also be absorbed by passing through aqueous pores or being carried through the epithelial barrier by the bulk passage of water.
So, based on these physico-chemical properties a high oral absorption is assumed. This is also confirmed by the available oral toxicity studies, where systemic toxic effects including mortality were observed (OECD 425, OECD 408, OECD 422, OECD 414). This confirms a systemic availability of the substance after oral exposure.
Based on the information given above, an oral absorption rate of 100 % is assumed for IPETC.

Dermal absorption
Absorption in the stratum corneum is favoured for substances with a molecular weight below 100 g/mol and very unlikely for chemicals with a molecular weight above 500 g/mol. To cross the lipid-rich stratum corneum a certain degree of lipophilicity is required (Log P > 0). IPETC has a molecular weight of 147 g/mol and a log P of 2.3. Based on the rather low molecular weight (147 g/mol) and the log P above 0 (2.3), IPETC might be able to be absorbed by the stratum corneum. To partition from the stratum corneum into the viable part of the epidermis, a substance must be sufficiently soluble in water (> 1 mg/L). IPETC has a water solubility of 2.65 g/L. Thus, penetration into the deeper, viable layers of the epidermis is very likely.
In toxicological studies IPETC was shown to be skin irritating (OECD 439), which may additionally favour dermal absorption.
All in all, based on the physico-chemical properties and the toxicological profile of IPETC, a dermal absorption rate of 100 % is assumed.

Respiratory absorption
As the substance is a liquid, no inhalable particles occur. Due to the vapour pressure of 950 Pa at 20°C, IPETC has a moderate volatility and may thus be available for inhalation as a vapour. Penetration to the lower respiratory tract is favoured for substances with low water solubility, which do not dissolve in the mucus lining the respiratory tract. The moderate water solubility indicates that IPETC may dissolve in the mucus to a certain degree. However, penetration of IPETC to the alveolar region of the lung cannot be ruled out. Having a log P value of 2.65, absorption directly across the respiratory tract epithelium by passive diffusion is favoured for IPETC. Furthermore, the water solubility also favours absorption by passing through aqueous pores or being carried through the epithelial barrier by the bulk passage of water.
Based on the available data, it can be concluded that respiratory exposure is possible. If respiratory exposure takes place, a high systemic availability can be predicted. As worst case, 100 % inhalation absorption is assumed.

Details on distribution in tissues:

Distribution and Accumulation
Due to the rather low molecular weight and its water solubility, IPETC is expected to be widely distributed in the body via blood circulation. Based on the log P of below 3 no accumulation in fatty tissue or stratum corneum is expected.

Details on excretion:

The rather low molecular weight (below 300 g/mol) and good water solubility of IPETC favours urinary excretion. Most of these substances will be filtered out of the blood by the kidneys as conjugated metabolites from phase II metabolism

Conclusions:

The absorption rate of IPETC is assumed to be 100 % via the oral, dermal and inhalation route. The substance is expected to be distributed widely through the body via blood circulation. The main excretion route is urinary excretion.

Executive summary:

In order to assess the toxicological behaviour of IPETC, the available physico-chemical and toxicological data have been evaluated. The substance is expected to be well absorbed after oral exposure, based on its water solubility and its LogPow of 2.3. As substance is a liquid, no inhalable particles occur. However, due to the vapour pressure of 950 Pa at 20°C, IPETC has a moderate volatility and may thus be available for inhalation as a vapour and if respiratory exposure takes place, a high systemic availability can be predicted. Based on the rather low molecular weight (147 g/mol) and the log P above 0 (2.3), IPETC might be able to be absorbed by the stratum corneum. Concerning its distribution in the body, IPETC is expected to be widely distributed via blood circulation. Based on the log P of below 3 no accumulation in fatty tissue or stratum corneum is expected. Its low molecular weight (below 300 g/mol) and good water solubility favours urinary excretion. Most of these substances will be filtered out of the blood by the kidneys as conjugated metabolites from phase II metabolism.

Description of key information

In order to assess the toxicological behaviour of IPETC, the available physico-chemical and toxicological data have been evaluated. The substance is expected to be well absorbed after oral exposure, based on its water solubility and its LogPow of 2.3. As the substance is a liquid, no inhalable particles occur. However, due to the vapour pressure of 950 Pa at 20°C, IPETC has a moderate volatility and may thus be available for inhalation as a vapour and if respiratory exposure takes place, a high systemic availability can be predicted. Based on the rather low molecular weight (147 g/mol) and the log P above 0 (2.3), IPETC might be able to be absorbed by the stratum corneum. Concerning its distribution in the body, IPETC is expected to be widely distributed via blood circulation. Based on the log P of below 3 no accumulation in fatty tissue or stratum corneum is expected. Its low molecular weight (below 300 g/mol) and good water solubility favours urinary excretion. Most of these substances will be filtered out of the blood by the kidneys as conjugated metabolites from phase II metabolism.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

100

Absorption rate - dermal (%):

100

Absorption rate - inhalation (%):

100

Additional information

General

There are no ADME studies available for O-isopropyl ethylthiocarbamate (IPETC, CAS 141-98-0). The toxicokinetic profile was not determined by actual absorption, distribution, metabolism or excretion measurements. Rather, toxicokinetics of IPETC was assessed based on the physical-chemical properties in combination with results of toxicity studies.

Substance's physico chemical properties

CAS no. 141-98-0

Moelcular weight [g/mol]: 147

Physical state: liquid

Water solubility (25°C): 2.65 g/L

Log P (30°C): 2.3

Vapour pressure (20°C): 950 Pa

Oral absorption

Absorption by passive diffusion is favoured for substances with moderate log P values (between -1 and 4). With a log P of 2.3, IPETC is likely to follow this route of absorption. Additionally, based on the low molecular weight (< 200 g/mol) and due to the solubility in water, IPETC may also be absorbed by passing through aqueous pores or being carried through the epithelial barrier by the bulk passage of water.

So, based on these physico-chemicalproperties a high oral absorption is assumed. This is also confirmed by the available oral toxicity studies, where systemic toxic effects including mortality were observed (OECD 425, OECD 408, OECD 422, OECD 414). This confirms a systemic availability of the substance after oral exposure.

Based on the information given above, an oral absorption rate of 100 % is assumed for IPETC.

Dermal absorption

Absorption in the stratum corneum is favoured for substances with a molecular weight below 100 g/mol and very unlikely for chemicals with a molecular weight above 500 g/mol. To cross the lipid-rich stratum corneum a certain degree of lipophilicity is required (Log P > 0). IPETC has a molecular weight of 147 g/mol and a log P of 2.3. Based on the rather low molecular weight (147 g/mol) and the log P above 0 (2.3), IPETC might be able to be absorbed by the stratum corneum. To partition from the stratum corneum into the viable part of the epidermis, a substance must be sufficiently soluble in water (> 1 mg/L). IPETC has a water solubility of 2.65 g/L. Thus, penetration into the deeper, viable layers of the epidermis is very likely.

In toxicological studies IPETC was shown to be skin irritating (OECD 439), which may additionally favour dermal absorption. 

All in all, based on the physico-chemical properties and the toxicological profile of IPETC, a dermal absorption rate of 100 % is assumed.

 

Respiratory absorption

As the substance is a liquid, no inhalable particles occur. Due to the vapour pressure of 950 Pa at 20°C, IPETC has a moderate volatility and may thus be available for inhalation as a vapour. Penetration to the lower respiratory tract is favoured for substances with low water solubility, which do not dissolve in the mucus lining of the respiratory tract. The moderate water solubility indicates that IPETC may dissolve in the mucus to a certain degree. However, penetration of IPETC to the alveolar region of the lung cannot be ruled out. Having a log P value of 2.65, absorption directly across the respiratory tract epithelium by passive diffusion is favoured for IPETC. Furthermore, the water solubility also favours absorption by passing through aqueous pores or being carried through the epithelial barrier by the bulk passage of water.

Based on the available data, it can be concluded that respiratory exposure is possible. If respiratory exposure takes place, a high systemic availability can be predicted. As worst case, 100 % inhalation absorption is assumed.

 

Distribution and Accumulation

Due to the rather low molecular weight and its water solubility, IPETC is expected to be widely distributed in the body via blood circulation. Based on the log P of below 3 no accumulation in fatty tissue or stratum corneum is expected.