Registration Dossier

Administrative data

Endpoint:
dermal absorption
Type of information:
other: Expert statement
Adequacy of study:
key study
Study period:
2011-2012
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: An extensive Assessment of the toxicological behaviour of 1,1'-dithiobis[hexahydro-2H-azepin-2-one] was performed, taking into account the chemical structure, the available physico-chemical-data and the available (eco-)toxicological data.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2012
Report Date:
2012

Materials and methods

Test guideline
Qualifier:
no guideline required

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
not applicable in this expert statement
Radiolabelling:
other: not applicable in this expert statement

Test animals

Species:
other: not applicable
Strain:
other: not applicable
Details on test animals and environmental conditions:
not applicable in this expert statement

Administration / exposure

Type of coverage:
other: all routes of administration are discussed in the expert statement
Duration of exposure:
not applicable in this expert statement
Doses:
not applicable
No. of animals per group:
not applicable
Details on study design:
not applicable

Results and discussion

Percutaneous absorption
Remarks on result:
other: 1,1'-dithiobis[hexahydro-2H-azepin-2-one] is expected to be absorbed following dermal exposure into the stratum corneum to a certain extent & into the epidermis, due to its molecular weight and LogPow. However, systemic toxicity is expected to be low.

Any other information on results incl. tables

Absorption following dermal exposure

In order to cross the skin, a compound must first penetrate into the stratum corneum and may subsequently reach the epidermis, the dermis and the vascular network. The stratum corneum provides its greatest barrier function against hydrophilic compounds, whereas the epidermis is most resistant to penetration by highly lipophilic compounds. Substances with a molecular weight below 100 are favourable for penetration through the skin and substances above 500 are normally not able to penetrate. The substance must be sufficiently soluble in water to partition from the stratum corneum into the epidermis. Therefore if the water solubility is below 1 mg/l, dermal uptake is likely to be low. Additionally LogPow values between 1 and 4 favour dermal absorption (values between 2 and 3 are optimal; TGD, Part I, Appendix VI). Above 4, the rate of penetration may be limited by the rate of transfer between the stratum corneum and the epidermis, but uptake into the stratum corneum will be high. Above 6, the rate of transfer between the stratum corneum and the epidermis will be slow and will limit absorption across the skin. Uptake into the stratum corneum itself may be slow. Moreover vapours of substances with vapour pressures below 100 Pa are likely to be well absorbed and the amount absorbed dermally is most likely more than 10% and less than 100 % of the amount that would be absorbed by inhalation. If the substance is a skin irritant or corrosive, damage to the skin surface may enhance penetration. During the whole absorption process into the skin, the compound can be subject to biotransformation.

In case of 1,1'-dithiobis[hexahydro-2H-azepin-2-one], the molecular weight is above 100 and below 500, which indicates a low potential to penetrate the skin. However, the low vapour pressure can be judged advantageous for dermal uptake. Based on this knowledge, 1,1'-dithiobis[hexahydro-2H-azepin-2-one] is expected to be absorbed following dermal exposure into the stratum corneum and into the epidermis, due to its molecular weight and its LogPow. However, the systemic toxicity of 1,1'-dithiobis[hexahydro-2H-azepin-2-one] via the skin is assumed to be low and this has been proven with the results of the acute dermal toxicity study, which showed no mortality after dermal application of 2000 mg/kg bw in rats.

Applicant's summary and conclusion

Conclusions:
An extensive Assessment of the toxicological behaviour of 1,1'-dithiobis[hexahydro-2H-azepin-2-one] was performed (expert statement), taking into account the chemical structure, the available physico-chemical-data and the available (eco-)toxicological data.
Executive summary:

In order to assess the toxicological behaviour of 1,1'-dithiobis[hexahydro-2H-azepin-2-one], the available and predicted physico-chemical data have been evaluated. The substance is expected to be well absorbed after oral exposure, based on its low molecular weight, its high water solubility and its LogPow of 2.25. Concerning the absorption after exposure via inhalation, as the chemical has really low calculated vapour pressure and a high boiling point (248.6°C), it is clear, that the substance has a low availability for inhalation. Given its lipophilicity (LogPow of 2.25), if any of the substance is available for inhalation, it is expected to be absorbed directly across the respiratory tract epithelium. 1,1'-dithiobis[hexahydro-2H-azepin-2-one] is expected to be absorbed following dermal exposure into the stratum corneum to a certain extent and into the epidermis, due to its molecular weight and its LogPow. However, the systemic toxicity via the skin is assumed to be low and this has been proven with the results of the acute dermal toxicity study, which showed no mortality after dermal application of 2000 mg/kg bw in rats. The substance is not expected to bear accumulative potential. 1,1'-dithiobis[hexahydro-2H-azepin-2-one] is expected to be metabolised via the Cytochrome P450 group of metabolizing enzymes and subsequently eliminated via the bile as glucuronic acid conjugates or, due to its high water-solubility and its low molecular weight oxidised or unchanged via the urine.