Registration Dossier

Toxicological information

Dermal absorption

Currently viewing:

Administrative data

Endpoint:
dermal absorption in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
no data
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Acceptable, reasonably well-documented publication which meets basic scientific principles. Study not on the substance defined in Section 1.
Justification for type of information:
No toxicokinetic studies have been conducted on Santicizer 278, however read-across information available for the structurally related, high molecular weight phthalates DIDP (European Chemicals Bureau, 2003a), DINP (European Chemicals Bureau, 2003b), and butyl benzyl phthalate (BBP) provides useful supporting information.
Cross-reference
Reason / purpose for cross-reference:
read-across: supporting information
Reference
Endpoint:
dermal absorption in vivo
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
no data
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Acceptable, reasonably well-documented publication which meets basic scientific principles. Study not on the substance defined in Section 1.
Justification for type of information:
No toxicokinetic studies have been conducted on Santicizer 278, however read-across information available for the structurally related, high molecular weight phthalates DIDP (European Chemicals Bureau, 2003a), DINP (European Chemicals Bureau, 2003b), and butyl benzyl phthalate (BBP) provides useful supporting information.
Reason / purpose for cross-reference:
read-across source
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 427 (Skin Absorption: In Vivo Method)
Deviations:
yes
Remarks:
(only 3 animals tested (guideline recommends 4); only 1.3 cm2 skin area of application (guideline recommends 10 cm2); expired air not collected; some omissions in reporting but no indication whether or not these related to omissions in practice)
GLP compliance:
not specified
Radiolabelling:
yes
Species:
rat
Strain:
Fischer 344
Sex:
male
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Division of Animal Resources of the University of Arizona Health Sciences Center
- Age at study initiation: no data
- Weight at study initiation: 180-220 g
- Fasting period before study: no data
- Housing: no data
- Individual metabolism cages: yes
- Diet (e.g. ad libitum): Purina Lab Chow, ad lib
- Water (e.g. ad libitum): ad lib
- Acclimation period: no data

ENVIRONMENTAL CONDITIONS
- Temperature (°C): no data
- Humidity (%): no data
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12 / 12

IN-LIFE DATES: no data
Type of coverage:
semiocclusive
Vehicle:
ethanol
Duration of exposure:
7 days
Doses:
- Nominal doses: 157 µmol/kg bw (49 mg/kg bw ) at 40 µCi/kg bw
- Actual doses: 7.7 mg/cm2
- Actual doses calculated as follows: applied to a circular area of 1.3 cm internal diameter, i.e. area of 1.3 cm2; at a body weight of 200 g, total dose ~10 mg; 10/1.3 = 7.7 mg/cm2
- Dose volume: no data
- Rationale for dose selection: 0.01x oral/intraperitoneal LD50
No. of animals per group:
3
Control animals:
no
Details on study design:
DOSE PREPARATION
- Method for preparation of dose suspensions: no data
- Method of storage: no data

APPLICATION OF DOSE:

VEHICLE
- Justification for use and choice of vehicle (if other than water): no data
- Amount(s) applied (volume or weight with unit): no data
- Concentration (if solution): no data
- Lot/batch no. (if required): no data
- Purity: USP grade

TEST SITE
- Preparation of test site: middle of back clipped using electric clipper 1 hour prior to application of test material
- Area of exposure: 1.3 cm2
- % coverage: no data
- Type of cover / wrap if used: no dressing or wrap (but see 'site protection' below)
- Time intervals for shavings or clipplings: once, single application

SITE PROTECTION / USE OF RESTRAINERS FOR PREVENTING INGESTION: yes
- site protection: skin covered by circular plastic cap with an internal diameter of 1.8 cm, perforated with 10 needle holes to allow aeration, secured with Krazy-Glue cyanoacrylate glue
- restrainers: thick-walled rubber tubing wrapped around chest behind front legs and around abdomen in front of hind legs; held in place with wire placed through centre of tubing; animal could walk freely and access food and water, but could not twist its body or wipe or lick its back

REMOVAL OF TEST SUBSTANCE
- Removal of protecting device: 7 days
- Washing procedures and type of cleansing agent: not required
- Time after start of exposure: 7 days

SAMPLE COLLECTION
- Collection of blood: at study termination only
- Collection of urine and faeces: yes
- Collection of expired air: no
- Terminal procedure: necropsy
- Analysis of organs: brain, spinal cord, lung, liver, spleen, intestine, kidney, testis, fat, muscle, skin (from area of application and a distant site)

SAMPLE PREPARATION
- Storage procedure: no data
- Preparation details:
- Urine: pH adjusted to 4.5-5.5 using glacial acetic acid
- Faeces: digested in 0.5 N NaOH, sample air dried and combusted in a sample oxidizer
- Tissues: samples air dried for 24 hours and combusted
- Skin from area of application: digested in 2 M KOH/methanol; aliquot adjusted to pH 4.5-5.5 with glacial acetic acid
- Plastic cap: washed with 95% ethanol

ANALYSIS
- Method type(s) for identification: Liquid scintillation counting
- Liquid scintillation counting results (cpm) converted to dpm as follows: no data (radioactivity presented as 14C-equivalents)
- Validation of analytical procedure: no data
- Limits of detection and quantification: no data

OTHER:
- Data analysis: one-way analysis of variance, Student's t-test, level of significance p<0.05
Signs and symptoms of toxicity:
not specified
Dermal irritation:
not specified
Absorption in different matrices:
Mean (+- SD) % of dose in 14C-equivalents 7 days after application to the skin:
- Non-occlusive cover + enclosure rinse: 6.3 (+- 0.8) %
- Skin wash: not done
- Skin test site: 44.9 (+- 6.2) %
- Skin, untreated site: 0.08 (+- 0.03) %
- Blood: no separate data (see 'other tissues' below)
- Carcass: no data
- Urine: no separate data; urine and faeces combined: 30% excreted by 7 days
- Cage wash + cage wipe: not done
- Faeces: see urine
- Expired air (if applicable): not done
- Serial non-detects in excreta at termination: no data
- Other:
- adipose tissue: 0.17 (+- 0.08) %
- muscle: 4.6 (+- 3.7) %
- 'other tissues' (summation of brain, lung, liver, spleen, small intestine, kidney, testis, spinal cord and blood): <0.5%
Total recovery:
- Total recovery: 86 (+- 2) % (sum of percentage dose found in urine, faeces, tissues and plastic cap in 7 days)
- Recovery of applied dose acceptable: no data
- Results adjusted for incomplete recovery of the applied dose: no data
- Limit of detection (LOD): no data
- Quantification of values below LOD or LOQ: no data
Dose:
49 mg/kg bw (7.7 mg/cm2)
Parameter:
percentage
Absorption:
ca. 35 %
Remarks on result:
other: 7 days
Remarks:
30% of dose excreted in urine and faeces, 4.6% recovered from muscle, 0.17% from adipose tissue, <0.5% from brain, spinal cord and testis, and 0.08% from skin distant from the application site.
Conversion factor human vs. animal skin:
no data
Conclusions:
No dermal absorption data are available on S278. Covered application of the structurally related compound butyl benzyl phthalate (as 14C-BBP) on the shaved skin of rats (to an area of 1.3 cm2) at 49 mg/kg bw (7.7 mg/cm2) for 7 days resulted in approximately 35% dermal absorption over this period, equivalent to 5% per day.
Executive summary:

No dermal absorption data are available on S278. In a reliable dermal absorption study on the structurally related compound, butyl benzyl phthalate (BBP), 14C-labelled BBP

was applied to the shaved skin of three male rats at a dose of 49 mg/kg bw on an area of 1.3 cm2. The application was semi-occluded for 7 days during which time urine and faeces were collected. At study termination, samples of a number of tissues were taken. Radioactivity was determined in all these tissues and excreta.

The proportion of the administered dose found in the tissues and excreta after 7 days was

30% in urine and faeces, 4.6% in muscle, <0.5% in brain, spinal cord and testis, 0.17% in adipose tissue and

0.08% in skin distant from the application site, making a total of about 35%. Total recovery (including site of application and covering) was 86%.

Covered application of 14C-BBP on the shaved skin of rats (to an area of 1.3 cm2) at 49 mg/kg bw (7.7 mg/cm2) for 7 days resulted in approximately 35% dermal absorption over this period, equivalent to 5% per day.

Data source

Reference
Reference Type:
publication
Title:
Dermal absorption of phthalate diesters in rats
Author:
Elsisi AE, Carter DE & Sipes IG
Year:
1989
Bibliographic source:
Fundamental and Applied Toxicology, 12, 70-77

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 427 (Skin Absorption: In Vivo Method)
Deviations:
yes
Remarks:
(only 3 animals tested (guideline recommends 4); only 1.3 cm2 skin area of application (guideline recommends 10 cm2); expired air not collected; some omissions in reporting but no indication whether or not these related to omissions in practice)
GLP compliance:
not specified

Test material

Constituent 1
Reference substance name:
1,2-benzenedicarboxylic acid, butyl phenylmethyl ester
IUPAC Name:
1,2-benzenedicarboxylic acid, butyl phenylmethyl ester
Constituent 2
Chemical structure
Reference substance name:
Benzyl butyl phthalate
EC Number:
201-622-7
EC Name:
Benzyl butyl phthalate
Cas Number:
85-68-7
Molecular formula:
C19H20O4
Constituent 3
Reference substance name:
Butyl benzyl phthalate
IUPAC Name:
Butyl benzyl phthalate
Constituent 4
Reference substance name:
phthalic acid, benzyl butyl ester
IUPAC Name:
phthalic acid, benzyl butyl ester
Details on test material:
- Name of test material (as cited in study report): benzyl butyl phthalate (BBP)
- Molecular formula (if other than submission substance): C19-H20-O4
- Molecular weight (if other than submission substance):312.4
- Substance type: laboratory reagent
- Physical state: no data
- Analytical purity: no data
- Impurities (identity and concentrations): no data
- Composition of test material, percentage of components: no data
- Isomers composition: no data
- Purity test date: no data
- Lot/batch No.: no data; non-radioactive BBP obtained from Pfaltz and Bauer, Inc., Research Chemicals Division, Stamford, CN, USA; radioactive BBP obtained from Midwest Research Institute, Kansas City, KS, USA
- Expiration date of the lot/batch: no data
- Radiochemical purity (if radiolabelling): >96%
- Specific activity (if radiolabelling): no data
- Locations of the label (if radiolabelling): ring
- Expiration date of radiochemical substance (if radiolabelling): no data
- Stability under test conditions: no data
- Storage condition of test material: no data
- Other: no data
Radiolabelling:
yes

Test animals

Species:
rat
Strain:
Fischer 344
Sex:
male
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Division of Animal Resources of the University of Arizona Health Sciences Center
- Age at study initiation: no data
- Weight at study initiation: 180-220 g
- Fasting period before study: no data
- Housing: no data
- Individual metabolism cages: yes
- Diet (e.g. ad libitum): Purina Lab Chow, ad lib
- Water (e.g. ad libitum): ad lib
- Acclimation period: no data

ENVIRONMENTAL CONDITIONS
- Temperature (°C): no data
- Humidity (%): no data
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12 / 12

IN-LIFE DATES: no data

Administration / exposure

Type of coverage:
semiocclusive
Vehicle:
ethanol
Duration of exposure:
7 days
Doses:
- Nominal doses: 157 µmol/kg bw (49 mg/kg bw ) at 40 µCi/kg bw
- Actual doses: 7.7 mg/cm2
- Actual doses calculated as follows: applied to a circular area of 1.3 cm internal diameter, i.e. area of 1.3 cm2; at a body weight of 200 g, total dose ~10 mg; 10/1.3 = 7.7 mg/cm2
- Dose volume: no data
- Rationale for dose selection: 0.01x oral/intraperitoneal LD50
No. of animals per group:
3
Control animals:
no
Details on study design:
DOSE PREPARATION
- Method for preparation of dose suspensions: no data
- Method of storage: no data

APPLICATION OF DOSE:

VEHICLE
- Justification for use and choice of vehicle (if other than water): no data
- Amount(s) applied (volume or weight with unit): no data
- Concentration (if solution): no data
- Lot/batch no. (if required): no data
- Purity: USP grade

TEST SITE
- Preparation of test site: middle of back clipped using electric clipper 1 hour prior to application of test material
- Area of exposure: 1.3 cm2
- % coverage: no data
- Type of cover / wrap if used: no dressing or wrap (but see 'site protection' below)
- Time intervals for shavings or clipplings: once, single application

SITE PROTECTION / USE OF RESTRAINERS FOR PREVENTING INGESTION: yes
- site protection: skin covered by circular plastic cap with an internal diameter of 1.8 cm, perforated with 10 needle holes to allow aeration, secured with Krazy-Glue cyanoacrylate glue
- restrainers: thick-walled rubber tubing wrapped around chest behind front legs and around abdomen in front of hind legs; held in place with wire placed through centre of tubing; animal could walk freely and access food and water, but could not twist its body or wipe or lick its back

REMOVAL OF TEST SUBSTANCE
- Removal of protecting device: 7 days
- Washing procedures and type of cleansing agent: not required
- Time after start of exposure: 7 days

SAMPLE COLLECTION
- Collection of blood: at study termination only
- Collection of urine and faeces: yes
- Collection of expired air: no
- Terminal procedure: necropsy
- Analysis of organs: brain, spinal cord, lung, liver, spleen, intestine, kidney, testis, fat, muscle, skin (from area of application and a distant site)

SAMPLE PREPARATION
- Storage procedure: no data
- Preparation details:
- Urine: pH adjusted to 4.5-5.5 using glacial acetic acid
- Faeces: digested in 0.5 N NaOH, sample air dried and combusted in a sample oxidizer
- Tissues: samples air dried for 24 hours and combusted
- Skin from area of application: digested in 2 M KOH/methanol; aliquot adjusted to pH 4.5-5.5 with glacial acetic acid
- Plastic cap: washed with 95% ethanol

ANALYSIS
- Method type(s) for identification: Liquid scintillation counting
- Liquid scintillation counting results (cpm) converted to dpm as follows: no data (radioactivity presented as 14C-equivalents)
- Validation of analytical procedure: no data
- Limits of detection and quantification: no data

OTHER:
- Data analysis: one-way analysis of variance, Student's t-test, level of significance p<0.05

Results and discussion

Signs and symptoms of toxicity:
not specified
Dermal irritation:
not specified
Absorption in different matrices:
Mean (+- SD) % of dose in 14C-equivalents 7 days after application to the skin:
- Non-occlusive cover + enclosure rinse: 6.3 (+- 0.8) %
- Skin wash: not done
- Skin test site: 44.9 (+- 6.2) %
- Skin, untreated site: 0.08 (+- 0.03) %
- Blood: no separate data (see 'other tissues' below)
- Carcass: no data
- Urine: no separate data; urine and faeces combined: 30% excreted by 7 days
- Cage wash + cage wipe: not done
- Faeces: see urine
- Expired air (if applicable): not done
- Serial non-detects in excreta at termination: no data
- Other:
- adipose tissue: 0.17 (+- 0.08) %
- muscle: 4.6 (+- 3.7) %
- 'other tissues' (summation of brain, lung, liver, spleen, small intestine, kidney, testis, spinal cord and blood): <0.5%
Total recovery:
- Total recovery: 86 (+- 2) % (sum of percentage dose found in urine, faeces, tissues and plastic cap in 7 days)
- Recovery of applied dose acceptable: no data
- Results adjusted for incomplete recovery of the applied dose: no data
- Limit of detection (LOD): no data
- Quantification of values below LOD or LOQ: no data
Percutaneous absorption
Dose:
49 mg/kg bw (7.7 mg/cm2)
Parameter:
percentage
Absorption:
ca. 35 %
Remarks on result:
other: 7 days
Remarks:
30% of dose excreted in urine and faeces, 4.6% recovered from muscle, 0.17% from adipose tissue, <0.5% from brain, spinal cord and testis, and 0.08% from skin distant from the application site.
Conversion factor human vs. animal skin:
no data

Applicant's summary and conclusion

Conclusions:
No dermal absorption data are available on S278. Covered application of the structurally related compound butyl benzyl phthalate (as 14C-BBP) on the shaved skin of rats (to an area of 1.3 cm2) at 49 mg/kg bw (7.7 mg/cm2) for 7 days resulted in approximately 35% dermal absorption over this period, equivalent to 5% per day.
Executive summary:

No dermal absorption data are available on S278. In a reliable dermal absorption study on the structurally related compound, butyl benzyl phthalate (BBP), 14C-labelled BBP

was applied to the shaved skin of three male rats at a dose of 49 mg/kg bw on an area of 1.3 cm2. The application was semi-occluded for 7 days during which time urine and faeces were collected. At study termination, samples of a number of tissues were taken. Radioactivity was determined in all these tissues and excreta.

The proportion of the administered dose found in the tissues and excreta after 7 days was

30% in urine and faeces, 4.6% in muscle, <0.5% in brain, spinal cord and testis, 0.17% in adipose tissue and

0.08% in skin distant from the application site, making a total of about 35%. Total recovery (including site of application and covering) was 86%.

Covered application of 14C-BBP on the shaved skin of rats (to an area of 1.3 cm2) at 49 mg/kg bw (7.7 mg/cm2) for 7 days resulted in approximately 35% dermal absorption over this period, equivalent to 5% per day.