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Link to relevant study record(s)

Reference
Endpoint:
basic toxicokinetics
Type of information:
experimental study
Adequacy of study:
key study
Study period:
March 1988 - July 1991
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP study, following equivalent or similar method to OECD study guideline
Reason / purpose:
reference to same study
Reason / purpose:
reference to other study
Objective of study:
toxicokinetics
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 417 (Toxicokinetics)
Principles of method if other than guideline:
none
GLP compliance:
yes
Radiolabelling:
yes
Remarks:
14 C
Species:
rat
Strain:
Fischer 344
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Raleigh, NC
- Age at study initiation: n/a
- Weight at study initiation: 200-230 g bw
- Fasting period before study: 12 hours before testing
- Housing: according to standard operating procedures
- Individual metabolism cages: yes
- Diet (e.g. ad libitum): ad libitum except 12 h before dosing
- Water (e.g. ad libitum): ad libitum
- Acclimation period: at least a week of acclimation upon arrival. 3-4 days acclimation period in metabolism cages


ENVIRONMENTAL CONDITIONS
- Temperature (°C): according to standard operation procedure
- Humidity (%): according to standard operation procedure
- Air changes (per hr): n/a
- Photoperiod (hrs dark / hrs light): 12 h/12 h

Route of administration:
oral: gavage
Vehicle:
other: 1% methylcellulose
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
Dosing solutions containing 14C-DPnB were prepared by dissolving appropriate volumes of labeled and non-labeled DPnB in 1% methylcellulose in water.

Each animal received a volume of approximately 3.0 ml targeted to deliver a dose of either 0.4 or 4.4 mmol of DPnB/kg bw.
VEHICLE
- Concentration in vehicle: adjusted by body weight to give doses of 0.4 or 4.4 mmol DPnB/kg BW.
- Amount of vehicle (if gavage): 3.0 ml
- Lot/batch no. (if required): Lot#105F-0100
- Purity: n/a

HOMOGENEITY AND STABILITY OF TEST MATERIAL:
Prior to the start of the study, homogeneity of DPnB in a sample dose solution preparation was examined. Aliquots taken from the top, middle and bottom of the sample dose solution confirmed homogeneous distribution of DPnB in the vehicle.
Duration and frequency of treatment / exposure:
Animals were sacrificed 48 hs after dosing.
Remarks:
Doses / Concentrations:
0.4 and 4.4 mmol DPnB/kg BW.
No. of animals per sex per dose:
4 rats/dose
Control animals:
yes
Positive control:
none
Details on study design:
- Dose selection rationale: The high dose (4.4 mmol/kg bw) was chosen as maximum tolerated dose. The low dose (0.4 mmol/kg bw) was chosen to assit in the toxicokinetic evaluation.
- Rationale for animal assignment (if not random): random
Details on dosing and sampling:
ADME STUDIES
- Tissues and body fluids sampled: urine, faeces, blood, CO2 trap, charcoal trap, tissues and carcass, cage wash.
- Time and frequency of sampling: 0.5, 1.0, 2.0, 4.0, 8.0, 12, 24, 48 h for blood; 12, 24, 36, 48 h for urine; 24 adn 48 h for faeces;

Statistics:
Descriptive statistics (mean and standard deviation) were calculated for appropriate data. Linear regression analysis of 14CO2, urinary 14C-activity and total 14C-activity in the blood versus time was done according to Steel and Torrie (1960) and Goldstein (1964). Estimation of elimination half-life for 14CO2, urinary 14C-activity and total 14C-activity in the blood was done according to Rowland and Tozer 91989).
Preliminary studies:
none
Details on absorption:
n/a
Details on distribution in tissues:
Tissues, carcass and skin retained 11% of the dose 48 hrs after 0.4 mmol DPnB/kg BW and 7% after 4.4 mmol DPnB/kg BW. Peak blood levels of 14C-activity occurred at 0.5 hrs after dosing with 0.4 mmol DPnB/kg BW and at 4.0 hrs after mmol DPnB/kg BW. The distribution of 14C-activity in tissues was similar between dose groups with liver, bone marrow and kidneys retaining the highest percentage. Peak blood levels of 14C-activity occurred at 0.5 hrs after dosing with 0.4 mmol DPnB/kg BW and at 4.0 hrs after 4.4 mmol DPnB/kg BW. Profiles of urinary 14C-activity were qualitatively similar between dose levels.
Details on excretion:
In 48 hrs, 42% of the dose was excreted in urine and 42% as 14CO2 at 0.4 mmol/kg BW; while the high dose rats excreted 51% in urine and 35% as 14CO2. Fecal excretion accounted for 4% of the dose at the low dose and 11% at the high dose. Less than 1% of the dose was eliminated as expired volatile organics at both dose levels.
Metabolites identified:
yes
Details on metabolites:
Metabolites identified were: the sulfate conjugate of DPnB, propylene glycol n-butul ether, dipropylene glycol, and propylene. Parent compound was also found in the urine.

none

Conclusions:
Interpretation of results: no bioaccumulation potential based on study results
The metabolism of DPnB has many similarities to that of PGME and DPGME suggestive of a common route of metabolism giving rise to the same general types of metabolites.
Executive summary:

'This study was conducted to determine the disposition and metabolism of 14C-DPnB (dipropylene glycol n-butyl ether) in male Fischer-344 rats after a single oral dose of 0.4 or 4.4 mmol DPnB/kg BW. Urine, faeces, expired air, blood and tissues were collected and analyzed for total 14C-activity. Urinary metabolites were identified structurally.

In 48 hours, 42% of the dose was excreted in urine and 42% as 14CO2 at 0.4 mmol/kg BW; while the high dose rats excreted 51% in urine and 35% as 14CO2. Faecal excretion accounted for 4% of the dose at the low dose and 11% at the high dose. Less than 1% of the dose was eliminated as expired volatile organics at both dose levels. Tissues, carcass and skin retained 11% of the dose 48 hours after 0.4 mmol DPnB/kg BW and 7% after 4.4 mmol DPnB/kg BW. The distribution of 14C-activity in tissues was similar between dose groups with liver, bone marrow and kidneys retaining the highest percentage. Peak blood levels of 14C-activity occurred at 0.5 hours after dosing with 0.4 mmol DPnB/kg BW and at 4.0 hours after 4.4 mmol DPnB/kg BW. Profiles of urinary 14C-activity were qualitatively similar between dose levels.

The following urinary metabolites were identified: the sulfate conjugate of DPnB, propylene glycol n-butyl ether, dipropylene glycol, and propylene. Also parent material was found in the urine.

The metabolism of DPnB has many similarities to that of PGME and DPGME suggestive of a common route of metabolism giving rise to the same general types of metabolites.'

This study was identified as key for this toxicity endpoint because of the methods followed (which were comprehensively documented in the report).  The report included GLP and Quality Assurance statements, signed by the Study Director and Head of the QA Unit, respectively.  

Although the study report did not specify that OECD Protocol 417: "Toxikokinetics" was followed, the study satisfied the methods stipulated in Protocol 417.  Specifically, the numbers and type of test animals used and their husbandry conditions were as prescribed in the guidance.  Test material characterization was adequate.  The dose level tested satisfied the appropriate OECD guidance, the length of the dosing (48 hours) was reasonable, and the disposition, metabolism and toxicokinetic endpoints monitored were typical for this type assay and adequately recorded.

Description of key information

Short description of key information on bioaccumulation potential result: 
A metabolism and disposition study, conducted under GLP and equivalent to OECD guideline 417, is available for dipropylene glycol butyl ether.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential
Absorption rate - oral (%):
100
Absorption rate - dermal (%):
20
Absorption rate - inhalation (%):
100

Additional information

Metabolism and disposition data is available for dipropylene glycol butyl ether (DPnB). DPnB was almost completely absorbed by animals dosed via oral route, and therefore the rate is set as 100%. Likewise, inhalation was also set as 100%. Dermal absorption rate was based on DPM data (see read-across justification document) and set at 20%, a conservative assumption. DPnB is mainly excreted via urine and as CO2 within 48 hours after oral administration to rats. The distribution of 14C-activity in tissues was similar between dose groups with liver, bone marrow and kidneys retaining the highest percentage. The following urinary metabolites were identified: the sulfate conjugate of DPnB, propylene glycol n-butyl ether, dipropylene glycol, and propylene. Also parent material was found in the urine. The metabolism of DPnB has many similarities to that of propylene glycol methyl ether (PGME) and dipropylene glycol methyl ether (DPGME) suggestive of a common route of metabolism giving rise to the same general types of metabolites.

Discussion on bioaccumulation potential result:

This study was conducted to determine the disposition and metabolism of 14C-DPnB (dipropylene glycol n-butyl ether) in male Fischer-344 rats after a single oral dose of 0.4 or 4.4 mmol DPnB/kg BW. Urine, faeces, expired air, blood and tissues were collected and analyzed for total 14C-activity. Urinary metabolites were identified structurally. In 48 hours, 42% of the dose was excreted in urine and 42% as 14CO2 at 0.4 mmol/kg BW; while the high dose rats excreted 51% in urine and 35% as 14CO2. Faecal excretion accounted for 4% of the dose at the low dose and 11% at the high dose. Less than 1% of the dose was eliminated as expired volatile organics at both dose levels. Tissues, carcass and skin retained 11% of the dose 48 hours after 0.4 mmol DPnB/kg BW and 7% after 4.4 mmol DPnB/kg BW. The distribution of 14C-activity in tissues was similar between dose groups with liver, bone marrow and kidneys retaining the highest percentage. Peak blood levels of 14C-activity occurred at 0.5 hours after dosing with 0.4 mmol DPnB/kg BW and at 4.0 hours after 4.4 mmol DPnB/kg BW. Profiles of urinary 14C-activity were qualitatively similar between dose levels.

The following urinary metabolites were identified: the sulfate conjugate of DPnB, propylene glycol n-butyl ether, dipropylene glycol, and propylene. Also parent material was found in the urine. The metabolism of DPnB has many similarities to that of propylene glycol methyl ether (PGME) and dipropylene glycol methyl ether (DPGME) suggestive of a common route of metabolism giving rise to the same general types of metabolites. This study was identified as key for this toxicity endpoint because of the methods followed (which were comprehensively documented in the report).