Registration Dossier

Administrative data

Endpoint:
dermal absorption in vitro / ex vivo
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: The study is peer-reviewed published. However, experiments were not conducted with GLP compliance.

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
2000
Report Date:
1999

Materials and methods

Test guideline
Qualifier:
no guideline available
Principles of method if other than guideline:
Dermal penetration of skin samples determined by Franz cell technology with liquid scintillation counting and detection of radiolabeled metabolites by HPLC.
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
As per IUCLID5 Sections 1.1. - 1.4.
Radiolabelling:
yes
Remarks:
by 14-C epichlorohydrin

Test animals

Species:
other: rat, mouse and human skin in vitro.
Strain:
other: Fisher 344 rat and C3H mouse skin.
Sex:
male
Details on test animals and environmental conditions:
Fisher rats (~ 250 gm) and C3H mice (~ 25 gm) were aquired from Central Laboratories for Blood Banks, Amserdam, The Netherlands. The animal room was maintained 22 +/- 2 degrees C and 60 +/- 15% relative humidity with a 12 hr light/dark cycle. A standard rodent diet and de-ionized water were supplied ad libitum.

Administration / exposure

Type of coverage:
other: occluded and nonoccluded
Vehicle:
acetone
Duration of exposure:
24 hr
Doses:
636 mM
No. of animals per group:
Three animals served as skin donors per dose point.
Control animals:
yes
Remarks:
for control skin.
Details on study design:
Fresh full-thickness healthy human breast skin was from five female Caucasian patients aged 17 - 41 years. The skin was maintained on ice following removal and transport to the laboratory where it was used within three hours of removal. The skin samples from rodents was used within two hours of removal. Excess subcutaneous tissue was removed fro the skin samples with a scalpel. The skin was placed on a dissecting board and full-thickness skin circles cut out using a circular steel cutter. Mouse skin was used full-thickness while rat and human skin samples were dermtomized. The skin samples were mounted epidermis side up in a flow-through diffusion cell system for the dermal penetration studies.

Results and discussion

Signs and symptoms of toxicity:
not specified
Remarks:
Study was in vitro.
Dermal irritation:
not specified
Remarks:
Study was in vitro.
Absorption in different matrices:
No data
Total recovery:
Based on mass balance total recovery was 83 - 90% depending on species.
Percutaneous absorptionopen allclose all
Dose:
636 mM
Parameter:
percentage
Absorption:
ca. 37.8 %
Remarks on result:
other: 24 hr
Remarks:
human skin
Dose:
636 mM
Parameter:
percentage
Absorption:
ca. 67.2 %
Remarks on result:
other: 24 hr
Remarks:
Rat skin
Dose:
636 mM
Parameter:
percentage
Absorption:
ca. 80.3 %
Remarks on result:
other: 24 hr
Remarks:
Mouse skin
Conversion factor human vs. animal skin:
Approximately 2 to 4-fold less depending on species.

Any other information on results incl. tables

Permeability Constant              (in 10 -6 cm/hr)

_____________________________________

Human skin                            136 + 28

Rat Skin                                 402 + 22

Mouse Skin                            577 + 86

Applicant's summary and conclusion

Conclusions:
The skin absorption/penetration of 1,6-Hexanediol Diglycidylether (HDDGE) based on in vitro measurment was approximately 2 to 4-fold less for human breast skin samples compared to rodent skin. In human skin, approximately 20% of the absorbed HDDGE is metabolised, primarily to the mono-diol metabolite.
Executive summary:

1,6 -Hexanediol Diglycidylether (HDDGE) was evaluated for dermal absorption/penetration and metabolism using human, mouse and rat skin samples with diffusion cell in vitro technology and HPLC analysis. The skin absorption/penetration of HDDGE based on in vitro measurment was approximately 2 to 4-fold less for human breast skin samples compared to rodent skin. In human skin, approximately 20% of the absorbed HDDGE is metabolised, primarily to the mono-diol metabolite.