Registration Dossier

Diss Factsheets

Administrative data

Link to relevant study record(s)

Reference
Endpoint:
basic toxicokinetics, other
Remarks:
There are no studies available in which the toxic kinetic properties of N-acetylhexanelactam are investigated.
Type of information:
other: There are no studies available in which the toxic kinetic properties of N-acetylhexanelactam are investigated. Thus a kinetic assessment based on available data is provided.
Executive summary:

There are no studies available in which the toxic kinetic properties of N-acetylhexanelactam are investigated. Thus a kinetic assessment based on the following data is provided:

Phys-chem data:

Molecular weight: 155.19

Melting point: - 30°C

Boiling point: 236-258°C

Water solubility: 81.7 g/L at 20°C

LogPow: 0.95 at 23°C

Vapor pressure: 2.7 Pa at 10°C

Biodegradability:

Readily biodegradable: Complete microbial degradation to CO2observed. 

Toxicity:

Acute oral toxicity: Rats treated at ≥ 1600 mg/kg exhibited toxicity (mortality and clinical sign) within 3 days after treatment. No effect was seen at day 4 onwards. No macroscopically changes was found in survived animals.

Acute dermal toxicity: No effect found in rats treated at 2000 mg/kgRepeated dose toxicity (28-day oral): NOAEL of 1000 mg/kg bw; Increased liver associated withhepatocellular hypertrophywas found in treated rats. This effect was reversible and thus interpreted as adaptive to increased metabolic capacity.

Toxicokinetic profile:

a) Adsorption and distribution:

N-acetylhexanelactam is considered as orally bioavailable, indicated as the effects found in the acute oral toxicity study in rats. Furthermore, according to “ECHA Guidance on information requirements and chemical safety assessment – Chapter 7c: Endpoint specific guidance (2017)” a low molecular weight (MW≤500) and moderate lipophilicity (log Pow values of -1 to +4) are favorable for membrane penetration and thus absorption. The molecular weight of N-acetylhexanelactam is relatively low with 155.19 g/mol, favoring oral absorption of the compound. This is supported by the determined log Pow value of 0.95, being advantageous for oral absorption. In addition, the water solubility of 81.7 g/L leading to a ready dissolving of the compound in the gastrointestinal fluids favors oral absorption. Once adsorbed, a rapid distribution in the body is expected due to the given molecular size and amphiphilic character (Log Pow and water solubility).

The bioavailability by dermal route is considered to be less efficient than by oral since no effect was found in acute dermal toxicity study in rats, in which the animalswere dermally treated at 2000 mg/kg bw for 24 hours.

The inhalation exposure is considered to be of no relevance, because the vapor pressure is low. N-acetylhexanelactam is used only under strictly controlled conditions by professionals and therefore exposure to aerosol is not likely to occure.

b) Distribution:

Distribution of a compound within the body depends on the physicochemical properties of the substance especially the molecular weight, the lipophilic/hydrophilic character and the water solubility. In general, the smaller the molecule, the wider is the distribution. If the molecule is lipophilic, it is likely to distribute into cells and the intracellular concentration may be higher than extracellular concentration particularly in fatty tissues (ECHA Guidance on information requirements and chemical safety assessment – Chapter 7c: Endpoint specific guidance, 2017). Since N-acetylhexanelactam is considered as hydrophilic (log Pow 0.95), the distribution into cells is not very likely and the extracellular concentration may be higher than intracellular concentration particularly in fatty tissues, if the substance is absorbed systemically. Substances with log Pow values of 3 or less would be unlikely to accumulate in adipose tissues with the repeated intermittent exposure patterns normally encountered in the workplace.

b) Metabolism:

N-acetylhexanelactam undergoes an extensive metabolism, which can be derived from the following evidences:

- N-acetylhexanelactam is readily biodegradable.

- In the available subacute toxicity studies, liver were identified as the target, whereas the findings are to be interpreted as adaptation to increased metabolic capacity.

c) Elimination:

No significant bio-accumulating property can be obtained based on the given water solubility and LogPow values. The elimination is considered to be rapid and efficient, because the animals treated at 2000 mg/kg in the acute oral toxicity studies recovered within 4 days. Also the findings in the repeated dose toxicity study is supporting efficient elimination, because the effect in the liver was not more present after the recovery period. Additionally, as described in “ECHA Guidance on information requirements and chemical safety assessment – Chapter 7c: Endpoint specific guidance, 2017” the considerable water solubility and the low log Pow of the substance contributes to urinary excretion as the most favorable excretion route and therefore, a bio-accumulating potential can be excluded.

Conclusion:

The registration substance is bioavailable via oral route, less efficient via dermal route. Extensive metabolism and efficient elimination can be expected. A negligible bio-accumulating property can be reliably predicted.

Description of key information

There are no studies available in which the toxic kinetic properties of N-acetylhexanelactam are investigated. Thus a kinetic assessment based on the following data is provided:

Phys-chem data:

Molecular weight: 155.19

Melting point: - 30°C

Boiling point: 236-258°C

Water solubility: 81.7 g/L at 20°C

LogPow: 0.95 at 23°C

Vapor pressure: 2.7 Pa at 10°C

Biodegradability:

Readily biodegradable: Complete microbial degradation to CO2observed. 

Toxicity:

Acute oral toxicity: Rats treated at ≥ 1600 mg/kg exhibited toxicity (mortality and clinical sign) within 3 days after treatment. No effect was seen at day 4 onwards. No macroscopically changes was found in survived animals.

Acute dermal toxicity: No effect found in rats treated at 2000 mg/kgRepeated dose toxicity (28-day oral): NOAEL of 1000 mg/kg bw; Increased liver associated with hepatocellular hypertrophy was found in treated rats. This effect was reversible and thus interpreted as adaptive to increased metabolic capacity.

Toxicokinetic profile:

a) Adsorption and distribution:

N-acetylhexanelactam is considered as orally bioavailable, indicated as the effects found in the acute oral toxicity study in rats. Furthermore, according to “ECHA Guidance on information requirements and chemical safety assessment – Chapter 7c: Endpoint specific guidance (2017)” a low molecular weight (MW≤500) and moderate lipophilicity (log Pow values of -1 to +4) are favorable for membrane penetration and thus absorption. The molecular weight of N-acetylhexanelactam is relatively low with 155.19 g/mol, favoring oral absorption of the compound. This is supported by the determined log Pow value of 0.95, being advantageous for oral absorption. In addition, the water solubility of 81.7 g/L leading to a ready dissolving of the compound in the gastrointestinal fluids favors oral absorption. Once adsorbed, a rapid distribution in the body is expected due to the given molecular size and amphiphilic character (Log Pow and water solubility).

The bioavailability by dermal route is considered to be less efficient than by oral since no effect was found in acute dermal toxicity study in rats, in which the animalswere dermally treated at 2000 mg/kg bw for 24 hours.

The inhalation exposure is considered to be of no relevance, because the vapor pressure is low. N-acetylhexanelactam is used only under strictly controlled conditions by professionals and therefore exposure to aerosol is not likely to occur.

b) Distribution:

Distribution of a compound within the body depends on the physicochemical properties of the substance especially the molecular weight, the lipophilic/hydrophilic character and the water solubility. In general, the smaller the molecule, the wider is the distribution. If the molecule is lipophilic, it is likely to distribute into cells and the intracellular concentration may be higher than extracellular concentration particularly in fatty tissues (ECHA Guidance on information requirements and chemical safety assessment – Chapter 7c: Endpoint specific guidance, 2017). Since N-acetylhexanelactam is considered as hydrophilic (log Pow 0.95), the distribution into cells is not very likely and the extracellular concentration may be higher than intracellular concentration particularly in fatty tissues, if the substance is absorbed systemically. Substances with log Pow values of 3 or less would be unlikely to accumulate in adipose tissues with the repeated intermittent exposure patterns normally encountered in the workplace.

c) Metabolism:

N-acetylhexanelactam undergoes an extensive metabolism, which can be derived from the following evidences:

- N-acetylhexanelactam is readily biodegradable.

- In the available subacute toxicity studies, liver were identified as the target, whereas the findings are to be interpreted as adaptation to increased metabolic capacity.

d) Elimination:

No significant bio-accumulating property can be obtained based on the given water solubility and LogPow values. The elimination is considered to be rapid and efficient, because the animals treated at 2000 mg/kg in the acute oral toxicity studies recovered within 4 days. Also the findings in the repeated dose toxicity study is supporting efficient elimination, because the effect in the liver was not more present after the recovery period. Additionally, as described in “ECHA Guidance on information requirements and chemical safety assessment – Chapter 7c: Endpoint specific guidance, 2017” the considerable water solubility and the low log Pow of the substance contributes to urinary excretion as the most favorable excretion route and therefore, a bio-accumulating potential can be excluded.

Conclusion:

The registration substance is bioavailable via oral route, less efficient via dermal route. Extensive metabolism and efficient elimination can be expected. A negligible bio-accumulating property can be reliably predicted.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential

Additional information

Categories Display