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Toxicological information

Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Findings are from a 90-day oral toxicity study conducted in accordance with OECD Guideline and under GLP conditions.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2004
Report date:
2006

Materials and methods

Objective of study:
toxicokinetics
Test guideline
Qualifier:
according to guideline
Guideline:
other: OECD TG 408
Principles of method if other than guideline:
Method: other: OECD TG 408
GLP compliance:
yes

Test material

Constituent 1
Chemical structure
Reference substance name:
Resorcinol
EC Number:
203-585-2
EC Name:
Resorcinol
Cas Number:
108-46-3
Molecular formula:
C6H6O2
IUPAC Name:
benzene-1,3-diol
Details on test material:
Resorcinol (AO11), >95% purity

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female

Administration / exposure

Route of administration:
oral: gavage
Duration and frequency of treatment / exposure:
90 day(s)
Doses / concentrations
Remarks:
Doses / Concentrations:
Males: 0, 40, 80 and 250 mg/kg/day Females: 0, 40, 80 and 250 mg/kg/day
No. of animals per sex per dose / concentration:
Males: 40 Females: 40
Details on study design:
The study was designed to comply with OECD Guideline No. 408, 21 September 1998.

See Section 5.4 for additional details.
Details on dosing and sampling:
Three treated groups of 10 male and 10 female Sprague-Dawley rats received the test item, Resorcinol (A011), (batch No. 706030517), daily by gavage at 40, 80 or 250 mg/kg/day for 13 weeks. An additional group of 10 males and 10 females received only the vehicle (purified water) and acted as a control group. At 0 and 250 mg/kg/day (groups 1 and 4), six animals of each sex were treated for 13 weeks and then kept for a 4-week treatment-free period. Six animals of each sex in groups 2, 3 and 4 were used for toxicokinetic investigations; blood samples were taken from the animals on day 1 and in week 13 at the following time-points: 0.5, 1, 2, 4, 8 and 24 hours post-dosing, and each animal was sampled on three occasions. 

Blood samples were taken from the animals on day 1 and in week 13 at the following time-points: . 0.5, 1, 2, 4, 8 and 24 hours post-dosing. For each time-point, three animals/sex/group were sampled (groups 2, 3 and 4), and each animal was sampled on three occasions.  Venous blood (approximately 0.5 mL) was taken from the orbital sinus of the animals under light isoflurane anesthesia into a tube containing lithium heparin. The blood was centrifuged, and the plasma was kept frozen in individual tubes at -20°C until analysis after the development and validation of the analytical method. 
Statistics:
The toxicokinetic parameters were calculated, according to standard non-compartmental methods, using Excel 2000 software installed on a personal computer. The following parameters were determined: Cmax, maximal plasma concentration measured, tmax, time of occurrence of this maximal plasma concentration, AUCx-t, Area under the concentration-time curve (calculated according to the linear trapezoidal rule) from time 0 to the last quantifiable data-point. 

Statistical analysis were peformed using the followng tests when appropriate:  Kolmogorov-Lilliefors test, Dunn test, Mann-Whitney/Wilcoxon test, Student test, Bartlet test and Fischer test

Results and discussion

Toxicokinetic / pharmacokinetic studies

Toxicokinetic parametersopen allclose all
Test no.:
#1
Toxicokinetic parameters:
AUC: Day 1: at 40 mg/kg/day the AUC for males is 24 and females 25.7 (ug*h/mL).
Test no.:
#1
Toxicokinetic parameters:
Cmax: Day 1: at 40 mg/kg/day the Cmax in males is 1.45 ug/mL and 1.31 ug/mL in females.
Test no.:
#1
Toxicokinetic parameters:
Tmax: Day 1: The tmax for males is 1 and females 24 hours. The trend towards a plateau level, as several peaks may be noted at different time points from 0.5 to 24 hours.
Test no.:
#2
Toxicokinetic parameters:
AUC: Day 1: at 80 mg/kg/day the AUC in males is 6.25 ug*h/mL and 18 ug*h/mL in females.
Test no.:
#2
Toxicokinetic parameters:
Cmax: Day 1: at 80 mg/kg/day the Cmax in males is 1.13 ug/mL and 1.07 ug/mL in females.
Test no.:
#2
Toxicokinetic parameters:
Tmax: Day 1: The tmax for males is 2 and females 24 hours. The trend towards a plateau level, as several peaks may be noted at different time points from 0.5 to 24 hours.
Test no.:
#3
Toxicokinetic parameters:
AUC: Day 1: at 250 mg/kg/day the AUC in males is 6.12 ug*h/mL and 31.8 ug*h/mL in females.
Test no.:
#3
Toxicokinetic parameters:
Cmax: Day 1: at 250 mg/kg/day the Cmax in males is 2.37 ug/mL and 9.29 ug/mL in females.
Test no.:
#3
Toxicokinetic parameters:
Tmax: Day 1: The tmax for males is 0.5 and females 0.5 hours.
Test no.:
#4
Toxicokinetic parameters:
AUC: Week 13: at 40 mg/kg/day the AUC in males is NC and 0.15 ug*h/mL in females.
Test no.:
#4
Toxicokinetic parameters:
Cmax: Week 13: at 40 mg/kg/day the Cmax in males is NC and 0.59 ug/mL in females.
Test no.:
#4
Toxicokinetic parameters:
Tmax: Week 13: at 40 mg/kg/day, the tmax for males is NC and females 0.5 hours.
Test no.:
#5
Toxicokinetic parameters:
AUC: Week 13: at 80 mg/kg/day the AUC in males is 1.31 ug*h/mL and 3.61 ug*h/mL in females.
Test no.:
#5
Toxicokinetic parameters:
Cmax: Week 13: at 80 mg/kg/day the Cmax in males is 2.28 ug/mL and 4.48 ug/mL in females.
Test no.:
#5
Toxicokinetic parameters:
Tmax: Week 13: at 80 mg/kg/day, the tmax for males is 0.5 hours and females 0.5 hours.
Test no.:
#6
Toxicokinetic parameters:
AUC: Week 13: at 250 mg/kg/day the AUC in males is 10.9 ug*h/mL and 27.5 ug*h/mL in females.
Test no.:
#6
Toxicokinetic parameters:
Cmax: Week 13: at 250 mg/kg/day the Cmax in males is 17.9 ug/mL and 13.8 ug/mL in females.
Test no.:
#6
Toxicokinetic parameters:
Tmax: Week 13: at 250 mg/kg/day, the tmax for males is 0.5 hours and females 0.5 hours.

Metabolite characterisation studies

Metabolites identified:
not measured

Any other information on results incl. tables

When measured on day 1, for groups 2, 3 and 4, which received the test item at 40, 80 and 250 mg/kg/day, plasma
levels of Resorcinol (A011) were quantifiable at least for two animals at all time-points (except for group 2 males at
8 hours, for group 3 males at 24 hours and females at 4 hours, and for group 4 males at 24 hours). In contrast, in
week 13, plasma levels of the test item were generally below the limit of quantification (0.5µg/mL) at all time-points
for group 2, and only quantifiable at 0.5 to 2 hours for groups 3 and 4. 

For all treated groups, plasma levels of the test item generally increased quickly from the first quantifiable
time-point at 0.5 hours on day 1 to reach a (first) maximum Cmax at 0.5-2 hours. In some cases, a second Cmax was seen
at 8/24 hours. For groups 2 and 3 females, the second Cmax noted at 24 hours actually was the highest observed plasma
level. The exposure on day 1, as measured by the Cmax and by AUC0-t, showed no clear increase with test item dose-level.
The mean concentration of Resorcinol (A011) remained stable over the 24 hour-period at 40 and 80 mg/kg/day, which may
suggest enterohepatic recycling of the test item. At 250 mg/kg/day, the Cmax was reached from 0.5 hour and plasma
levels gradually decreased thereafter. 

In week 13, the first quantifiable time-point at 0.5 hours was the maximal concentration. The exposure in week 13 (as
measured by the Cmax and by AUC0-t) increased with dose-level in a supra linear manner. 

Resorcinol (A011) plasma levels were characterized by a low to moderate interanimal variability. 


SAMPLING PERIOD:  Day 1
                                 40 mg/kg/day
                                 Male        Female
Kinetic parameter:                 
C(max) (µg/mL):            1.45         1.31
t(max) (h):                        1(p)         24(p)
AUC(0-t) (µg*h/mL):       24.0         25.7
Ratio, C(max)/dose:       0.036        0.0327
Ratio, AUC/dose             0.600        0.643

                                 80 mg/kg/day
                                 Male         Female
Kinetic parameter:                 
C(max) (µg/mL):        1.13         1.07
t(max) (h):                    2(p)         24(p)
AUC(0-t) (µg*h/mL):      6.25         18.0
Ratio, C(max)/dose:      0.014         0.013
Ratio, AUC/dose            0.078         0.225

                                 250 mg/kg/day
                                 Male         Female
Kinetic parameter:                 
C(max) (µg/mL):               2.37         9.29
t(max) (h):                         0.5         0.5
AUC(0-t) (µg*h/mL):         6.12         31.8
Ratio, C(max)/dose:         0.009         0.037
Ratio, AUC/dose               0.024         0.127

where: p = trend towards a plateau level, as several peaks may be noted  at different time-points from 05. to 24 hours.


SAMPLING PERIOD:  Week 13
                                 40 mg/kg/day
                                 Male         Female
Kinetic parameter:                 
C(max) (µg/mL):              nc         0.59
t(max) (h):                         nc         0.5
AUC(0-t) (µg*h/mL):       nc         0.15
Ratio, C(max)/dose:       nc         0.015
Ratio, AUC/dose             nc         0.004

                                 80 mg/kg/day
                                 Male        Female
Kinetic parameter:                 
C(max) (µg/mL):             2.28        4.48
t(max) (h):                        0.5         0.5
AUC(0-t) (µg*h/mL):       1.31        3.61
Ratio, C(max)/dose:      0.029      0.056
Ratio, AUC/dose            0.016      0.0451

                                 250 mg/kg/day
                                 Male        Female
Kinetic parameter:                 
C(max) (µg/mL):                17.9         13.8
t(max) (h):                         0.5         0.5
AUC(0-t) (µg*h/mL):          10.9         27.5
Ratio, C(max)/dose:          0.072         0.055
Ratio, AUC/dose                0.044         0.110


See Section 5.4 for additional details.

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): other:
No clear conclusions were drawn by the authors regarding the dose, sex and time related observations, however, the rapid peaking of blood levels demonstrated rapid absorption after an oral dose, and the differences in blood levels at day 1 and week 13 suggest that the rats had adapted the way in which they handled resorcinol.