2,2-bis(bromomethyl)propane-1,3-diol

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Well performed study, study design similar to guidelines.

Data source

Reference

Reference Type:

publication

Title:

Unnamed

Year:

2009

Materials and methods

Objective of study:

absorption

distribution

excretion

metabolism

Test guideline

Test guideline 1

Qualifier:

no guideline followed

Test guideline 2

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 417 (Toxicokinetics)

Principles of method if other than guideline:

The absorption, distribution, metabolism, and elimination and the pharmacokinetics of [14C] BMP was explored after a single oral or intravenous administration to male F-344 rats. Additional studies were designed to determine whether repeated oral administration (5 or 10 days) of BMP alters its disposition profile.

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

2,2-bis(bromomethyl)-1,3-propanediol

IUPAC Name:

2,2-bis(bromomethyl)-1,3-propanediol

Details on test material:

U-14C labeled BMP, in absolute ethanol (1mCi/ml) was obtained from Midwest Research Institute (Kansas City, MO). The radiochemical purity of BMP
was determined by reverse-phase HPLC-UV/visible-radiometric analysis to be 97.3%. The specific activity was reported to be 65.1mCi/mmol (247uCi/mg). Non radiolabeled BMP was obtained from Sigma-Aldrich (St. Louis, MO). Chemical purity of the unlabeled was 98%.

Radiolabelling:

yes

Remarks:

U- [14C] BMP

Test animals

Species:

rat

Strain:

Fischer 344

Sex:

male

Details on test animals or test system and environmental conditions:

Male F-344 rats, 8-9 weeks of age (182-236g), without surgical alteration (conventional) or with an indwelling jugular vein cannula (JVC) were obtained form Harlan (Indianapolis, IN). Animals were housed in the University of Arizona Animal care facility, which is accredited by the Association for Assessment and Accredation of Laboratory Animal Care. The animals were maintained in a temperature-controlled (25o) room under a 12-h light/dark cycle. Conventional animal were acclimated for 5-7 days after receipt. Animals with surgically implanted JVCs were acclimated only for one day after arrival to ensure patency of the cannula. Animals were allowed food and water ad libitum except for a 12 hours fasting period before a single administration of BMP. Animals used for the repeated oral administration studies were not fasted. Animals were placed in Nalgene metabolism cages 24 hours before administration of BMP. Food was provided as a powder to reduce contamination of fecal matter.

Administration / exposure

Route of administration:

other: Either oral gavage or intravenous administartion

Vehicle:

ethanol

Duration and frequency of treatment / exposure:

1. A single oral administration of [14C](10 or 100mg/kg) 2,2-Bis(bromomethyl)-1,3-propanediol (BMP) to male Fischer- 344 rats.
2. Repeated daily oral doses for 5 or 10 days.

Doses / concentrations

Remarks:

Doses / Concentrations:
Subtoxic doses of 10, 100, 150, 300, and 600mg/kg were chosen to assess the effect of dose on the rate and route of excretion after oral gavage. For the repated dose studies 100/mg/kg was administered daily by oral gavage, for 5, 10, or 10 days. Doses provided 25 to 200uCi/kg [14C] BMP .

No. of animals per sex per dose / concentration:

n=4

Control animals:

no

Positive control reference chemical:

No.

Details on dosing and sampling:

Sample collection and preparation:
In single dose studies:
Urine was collected at 6, 12, 24, 36, 48, 72 h.
Feces were collected at 12, 24, 36, 48, 72 h.

In the repeated dose studies:
Urine was collected at 6, 12, 24h after each dose.
Feces were collected at 12, 24h after each administration.

The metabolism cages were rinsed with methanol after after the collection of urine. Radioactivity recovered in cage rinses was added to that of determined in urine.

At the end of each study, animals were euthanized by CO2 inhalation. Blood was collected and animals were subjected to necropsy.
Tissues collected: adipose, brain, cecum, cecumcontents, heart,intestine, intestinal contents, kidneys, liver, lung, muscle, spleen, stomach, stomch contents, skin, testes.

Results and discussion

Main ADME results

Main ADME results 1

Type:

absorption

Results:

After a single oral administration of [14C]BMP (10 or 100 mg/kg) >80% of the low dose and 48% of the high dose were excreted by 12 h in the urine

Main ADME results 2

Type:

distribution

Results:

the total percentage of radioactivity remaining in tissues at 72h after was less than 1%.. Adipose tissues, liver, kidneys, muscle, and skin contained 0.2, 0.7, 0.1, 0.3, and 0.3% of dose, respectively.

Main ADME results 3

Type:

metabolism

Results:

glucuronide metabolite. see details below

Main ADME results 4

Type:

excretion

Results:

After a single oral administration of [14C]BMP (10 or 100 mg/kg) >80% of the low dose and 48% of the high dose were excreted by 12 h in the urine

Toxicokinetic / pharmacokinetic studies

Details on absorption:

After a single oral administration of [14C]BMP (10 or 100 mg/kg) >80% of the low dose and 48% of the high dose were excreted by 12 h in the urine predominantly as a glucuronide metabolite.  After repeated daily oral doses for 5 or 10 days, route and rate of elimination were similar to those obtained after single administrations of BMP.  Parent BMP and BMP glucuronide were present in blood plasma after oral or i.v. dosing.  After an i.v. dose of BMP (15 mg/kg) the hepatic BMP glucuronide was primarily exported into the bile (>50% within 6 h), but it underwent enterohepatic recycling with subsequent elimination in the urine.  
Adipose tissues, liver, kidneys, muscle, and skin contained 0.2, 0.7, 0.1, 0.3, and 0.3% of dose, respectively. The majority of unexcreted 14C equivalents (11.9% of dose) were found in the contents of the intestine and cecum. Concentrations in nanomoles/ gram of tissues were and contents ranged from 2.2 to 10.

Details on distribution in tissues:

After a single oral administration of 100 mg/kg [14C] BMP to food deprived rats, the total percentage of radioactivity remaining in tissues at 72h after was less than 1%.. When the same dose of BMP was administered orally to nonfasted animals, 4.2% of the total radioactivity was recovered from tissues at 24h post dose. Parent BMP and BMP glucuronide were present in blood plasma after oral or i.v. dosing.  After an i.v. dose of BMP (15 mg/kg) the hepatic BMP glucuronide was primarily exported into the bile (>50% within 6 h), but it underwent enterohepatic recycling with subsequent elimination in the urine.  
Adipose tissues, liver, kidneys, muscle, and skin contained 0.2, 0.7, 0.1, 0.3, and 0.3% of dose, respectively.
The majority of unexcreted 14C equivalents (11.9% of dose) were found in the contents of the intestine and cecum. Concentrations in nanomoles/ gram of tissues were and contents ranged from 2.2 to 10.

After 5 or 10 days of repeated oral administration (100mg/kg/ day, not fasted), total tissue levels of 14C equivalents at 24h after the last dose were in the same range. The repeated daily dosing did not lead to retention of the test substance in tissues.
(similar to the single dosing), with the majority of the dose remaining in the gastrointestinal (GI) tract. Tissue disposition of BMP was not determined at the lower dose of 10mg/kg. Route and rate of elimination were similar to those obtained after single administration of BMP.

Details on excretion:

After intravenous administration, the radiolabel found in blood decreased rapidly.
Excretion profiles were similar to those after oral administration.
After an IV dose of BMP (15mg/kg), the hepatic BMP glucuronide was primarily exposed into the bile (>50% within 6h), but it underwent enterohepatic recycling with subsequent elimination in the urine.

The results for the cumulative excretion of BMP- derived 14C equivalents after intravenous and oral are summarized in Fig. 2. When [14C] BMP was administered intravenously (10mg/ kg), the predominant route of its elimination was urinary. The peak excretion in the urine occurred between 6 and 12 h, and the majority of the dose (>80%) was eliminated by 12 h, in the urine, predominantly as a glucuronide metabolite.. By 24 h, greater than 89% of the administered radioactivity had been recovered in the urine. Only trace amounts were excreted in the feces by 72 h (<4% of dose). After a single oral bolus dose (10mg/kg), the excretion BMP-derived 14C equivalents in the urine were similar to that after intravenous administration. The fecal elimination accounted for less than 10% of the dose at 72 h. Administration of 10-fold higher dose of BMP (100mg/ kg) resulted in a similar excretion profile, but urinary excretion was slower; within the first 12 h only 48% of the administered 14C equivalents were excreted. The urinary excretion rate at higher oral doses of BMP (150-160 mg/kg) paralleled those of 100mg/kg (data not shown).
After the rate and the route of elimination of BMP after a single oral administration were defined, the effects of repeated daily oral dosing of [14C] BMP on excretion of BMP-derived 14C equivalents were determined (Table 1). After 5 or 10 days of repeated daily dosing of 100mg/kg [14C] BMP, the elimination profile of BMP was not notably altered from that of a single dose. The average cumulative amounts of 14C equivalents found in the urine including cage rinses were 71 75, and 77% of dose, respectively. In addition, it was noted that the radioactivity recovered in feces at 24 h after administration was increased to 7-8% of dose in nonfasted rats compared with 4% in fasted animals (Fig. 2).



After a single oral administration of [14C]BMP (10 or 100 mg/kg) >80% of the low dose and 48% of the high dose were excreted by 12 h in the urine predominantly as a glucuronide metabolite.  After repeated daily oral doses for 5 or 10 days, route and rate of elimination were similar to those obtained after single administrations of BMP. In all studies, the radioactivity recovered in feces was low (<15%).  
The total amt. of radioactivity remaining in tissues at 72 h after a single oral administration of BMP (100 mg/kg) was less than 1% of the dose, and repeated daily dosing did not lead to retention in tissues.  After i.v. administration, the radiolabeled test material was found in blood decreased rapidly.  Excretion profiles were similar to those after oral administration.  Parent BMP and BMP glucuronide were present in blood plasma after oral or i.v. dosing.  After an i.v. dose of BMP (15 mg/kg) the hepatic BMP glucuronide was primarily exported into the bile (>50% within 6 h), but it underwent enterohepatic recycling with subsequent elimination in the urine.   These data indicate that the extensive excretion and rapid glucuronidation by the liver limits exposure of internal tissues to BMP by greatly reducing its systemic bioavailability after oral exposure.
 

Metabolite characterisation studies

Metabolites identified:

yes

Details on metabolites:

After a single oral administration of [14C]BMP (10 or 100 mg/kg) >80% of the low dose and 48% of the high dose were excreted by 12 h in the urine predominantly as a glucuronide metabolite. Parent BMP and BMP glucuronide were present in blood plasma after oral or i.v. dosing.  After an i.v. dose of BMP (15 mg/kg) the hepatic BMP glucuronide was primarily exported into the bile (>50% within 6 h), but it underwent enterohepatic recycling with subsequent elimination in the urine.  

Any other information on results incl. tables

Identification of¹⁴C Radioactivity in Liver and Bile

Liver homogenates from rats treated intravenously or orally with [¹⁴C] BMP (10mg/kg) were extracted into ethyl acetate in the presence of glycine/HCl buffer at 30 min(intravenous) and 40 min (oral) postdose and analysed by HPLC with radiometric detection.

The¹⁴C radioactivity in these liver extracts consisted of parent BMP and the glucuronide conjugate. After intravenous administration of [¹⁴C] BMP (150mg/kg) to BDC rats, more than 50% of the dose was excreted in the bile within 6 h (data not shown). HPLC- radiometric analysis showed greater than 99% of the BMP- derived¹⁴C equivalents excreted in bile over time consisted of a single peak, identified by chromatography as the glucuronide conjugate of BMP detected in urine (data not shown).

 

Pharmacikinetics of BMP and Identification of 14C Radioactivity in blood 

Blood kinetics after a single intravenous administration of [¹⁴C] BMP (15mg/kg) indicated that parent BMP rapidly disappeared from the systemic circulation. The concentration- time profile of [¹⁴C] BMP in blood plasma after intravenous administration was best described in Fig. 5. After a rapid initial distribution of [¹⁴C] BMP, indicated by a short theoretical half-life of distribution (t_½a; 3.4min), a significantly slower elimination (t_½b; 2h) occurred. Blood plasma concentrations of BMP at times later than 30 min were very slow (1mg/ml).

[¹⁴C] BMP (10mg/kg) was administered orally and extracts obtained from small aliquots of whole blood (150ml per time point) and analyzed by LSC. The quantities of¹⁴C equivalents were close to or below the LOQ. Extracted BMP were quantifiable only at the first 4 time points (Fig.5). The area under the blood concentration- time curve for these 4 time points, compared with that after intravenous administration and adjusted for dose, suggests an oral bioavailability into the systemic circulation of less than 10%. The blood concentration- time profile after oral administration is presented for parent BMP at the quantifiable time points and for total [¹⁴C] BMP equivalents (Fig. 5.). After oral administration absorption was rapid with Cmax reached 40 min.¹⁴C equivalents were detected in the blood, although at very low levels, throughout to termination at 72h.

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): low bioaccumulation potential based on study results
The data indicate that the extensive extraction and rapid glucu-ronidaton by the liver limits exposure of internal tissues to 2,2-Bis(bromomethyl)-1,3-propanediol (BMP) by greatly reducing its systemic bioavailability after oral exposure.

Executive summary:

Hoehle et al. (2009) performed studies to characterize the dispositional and metabolic fate of Dibromoneopentyl glycol (BMP) after oral or intravenous administration to male F-344 rats. These studies report on the absorption, distribution, metabolism, and elimination of BMP and describe the pharmacokinetics of BMP. Additional studies were designed to determine whether repeated oral administration of BMP alters its disposition profile.

After a single oral administration of [¹⁴C]BMP (10 or 100 mg/kg) >80% of the low dose and 48% of the high dose were excreted by 12 h in the urine predominantly as a glucuronide metabolite.  After repeated daily oral doses for 5 or 10 days, route and rate of elimination were similar to those obtained after single administrations of BMP.  In all studies, the radioactivity recovered in feces was low (<15%).  The total amt. of radioactivity remaining in tissues at 72 h after a single oral administration of BMP (100 mg/kg) was less than 1% of the dose, and repeated daily dosing did not lead to retention in tissues.  After i.v. administration, the radiolabeled test material was found in blood decreased rapidly. Excretion profiles were similar to those after oral administration.  Parent BMP and BMP glucuronide were present in blood plasma after oral or i.v. dosing.  After an i.v. dose of BMP (15 mg/kg) the hepatic BMP glucuronide was primarily exported into the bile (>50% within 6 h), but it underwent enterohepatic recycling with subsequent elimination in the urine. These data indicate that the extensive excretion and rapid glucuronidation by the liver limits exposure of internal tissues to BMP by greatly reducing its systemic bioavailability after oral exposure.