Dimethyl phosphonate

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Acceptable, well documented publication which meets basic scientific principles. Adopted according to OECD SIDS (public available peer reviewed source). The original source is available and has been reviewed.

Cross-reference

Reason / purpose for cross-reference:

reference to same study

Data source

Reference

Reference 1

Reference Type:

publication

Title:

Metabolism and disposition of dimethyl hydrogen phosphite in rats and mice

Author:

Nomeir AA, and Matthews HB

Year:

1997

Bibliographic source:

J Toxicol Environ Health 51: 489-501

Reference 2

Reference Type:

secondary source

Title:

Unnamed

Year:

2004

Materials and methods

Objective of study:

absorption

distribution

excretion

metabolism

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

Fischer 344 rats were administered once orally 10 - 200 mg/kg 14C-labelled dimethyl phosphonate by gavage. Furthermore, rats were treated repeatedly for 5 days with an oral dose of 200 mg/kg bw 14C-labelled dimethyl phosphonate.

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

Dimethyl phosphonate

EC Number:

212-783-8

EC Name:

Dimethyl phosphonate

Cas Number:

868-85-9

Molecular formula:

C2H7O3P

IUPAC Name:

dimethyl phosphonate

Details on test material:

Name of test material (as cited in study report): dimethyl hydrogen phosphite (DMHP).
- Analytical purity: > 99%
- Radiochemical purity (if radiolabelling): 97%

Radiolabelling:

yes

Remarks:

[14C]DMHP (dimethyl hydrogen phosphite)

Test animals

Species:

rat

Strain:

Fischer 344

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Breeding Laboratories (Kingston, NY).
- Age at study initiation: 8-10 weeks old.
- Weight at study initiation: 180-220 g.
- Housing: Following dosing, the animals were housed in individual all-glass metabolism cages that allowed separate collection of urine, faeces, and exhaled radioactivity.
- Diet (e.g. ad libitum): food pellet ad libitum.
- Water (e.g. ad libitum): ad libitum.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21-22
- Humidity (%): 50 ± 10
- Photoperiod (hrs dark / hrs light): 12 / 12 hrs

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on exposure:

PREPARATION OF DOSING SOLUTIONS: Dosing solutions were prepared by dissolving the 14C-labeled and unlabeled DMHP in corn oil.

The animals received a dosing volume of 4 mL/kg of body weight containing doses ranging from 10 to 200 mg/kg.

Duration and frequency of treatment / exposure:

24 hours for single administration; 10 days after repeated administration.

Doses / concentrations

Remarks:

Doses / Concentrations:
Males: 10, 20, 200 mg/kg bw (single administration) and 200 mg/kg bw for 5d (repeated administration).

No. of animals per sex per dose / concentration:

Males: 3

Control animals:

no

Positive control reference chemical:

Not necessary

Details on study design:

No data

Details on dosing and sampling:

Expired air passed through two consecutive traps; the first contained 200 mL ethanol to collect volatile organics, and the second contained 200 mL of a mixture of ethanolamine and ethylene glycol monomethyl ether (3:7) to collect 14CO2. Urine, faeces, and trap contents were collected at selected time intervals. After preset time intervals (1-10 d), the animals were anesthetized by intraperitoneal injection of pentobarbital (80 mg/kg) and blood was collected by heart puncture. The animals were terminated by exsanguination. Radioactivity in urine and the ethanol and CO2 trap contents were determined by liquid scintillation counting using a Beckman model LS 9800 counter. Tissues were analyzed for total radioactivity by oxygen combustion of triplicate 100 mg samples to 14CO2 in Packard Tri-Carb sample oxidizer. Radioactivity was determined by liquid scintillation counting.
Faeces were extracted with methanol and the residue was air-dried, weighed, and ground to a fine powder. The extracts were counted directly. Triplicate 50 mg samples of the faecal powder were combusted.
Recovery of radioactivity from the samples oxidizer was 95-98%, while the counting efficiency was 70% for the oxidized samples and 91% for nonoxidized samples.
Calculation of the percentages of dose in each tissue was based on the actual weight of the organ and the following estimates of tissue volumes: blood, 8%, muscle, 50%, fat, 11%; and skin 16% of body weight.

Statistics:

No data

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:

DMHP was readily and near completely absorbed from the gastrointestinal tracts of rats.

Details on distribution in tissues:

Liver and kidneys, followed by forestomach, spleen, and lungs, contained the highest of DMHP concentration by radioactivity, while the lowest concentrations were in brain, adipose tissue, muscle, and testes. The concentrations of DMHP-derived radioactivity in tissues were approximately proportional to the dose.

Details on excretion:

At the doses studied, 28-38 % and 49-57% of dose were excreted in urine and as CO2 in the expired air within 24 h following administration, respectively. Elimination of labelled dose as 14CO2 continued up to approximately 12 hours following dosing. Elimination in urine continued in an almost linear fashion for up to 24 hours following dosing. Radioactivity collected in the ethanol trap and that excreted in faeces accounted for approximately 1 and 2% of dose hours, respectively, at all doses studied.
There appeared to be little or no effect of dose on the rate or route of metabolism and elimination in the dose range studied.
The effects of repeat exposure of rats to DMHP indicate that repeat administration had a little effect on metabolism to CO2 or elimination in urine.

Metabolite characterisation studies

Metabolites identified:

yes

Details on metabolites:

The main metabolic pathway in rodents is demethylation to monomethyl hydrogen phosphite (MMP) and further oxidation to CO2.

Any other information on results incl. tables

Table.1 Concentrations of [14C] DMHP equivalent in tissues of male rats (as µg/g wet tissue) at 24 h following a single oral dose of 10, 100, or 200 mg/kg.

	Number of daily [14C]DMHP doses
Tissue	1	2	5
Blood	36 ± 0.1	13 ± 1.4	36 ± 8
Liver	8.5 ± 1.0	64 ± 6.4	165 ± 25
Kidney	6.8 ± 1.3	59 ± 9.6	175 ± 40
Spleen	3.9 ± 0.5	37 ± 3.6	81 ± 10
Lung	3.5  ± 0.3	26  ± 2.7	70 ± 18
Heart	2.1  ± 0.1	15  ± 1.3	45  ± 10
Skin	1.6  ± 0.0	11  ± 3.3	42  ± 4
Skeletal muscle	1.0  ± 0.1	6.0 ± 2.5	22  ± 4
Adipose tissue	1.5  ± 0.1	7.0  ± 3.0	32  ± 7
Testes	1.5  ± 0.2	12 ± 1.3	29 ± 3
Brain	0.9  ± 0.2	7.0 ± 1.5	17 ± 3
Forestomach	4.5 ± 0.7	40 ± 7.2	76 ± 7
Glandular stomach	3.4  ± 0.1	23  ± 1.2	65  ± 9
Small intestine	5.7  ± 0.6	54  ± 2.0	154  ± 31
Large intestine	6.5  ± 4.6	34 ± 5.5	87  ± 17

Values are mean  ± standard deviation of data from three rats

Table 2. Concentrations of [14C] DMHP equivalents in tissues of male rats (as µg/g wet/tissue) at interavals following a sinlge oral dose of 200 mg/kg.

	Days following administration
Tissue	1	2	5	10
Blood	36 ± 8	22 ± 0.4	17 ± 1	13 ± 1
Liver	165 ± 25	116 ± 8	69 ± 5	36 ± 6
Kidney	175 ± 40	99 ± 5	74 ± 15	31 ± 2
Spleen	81 ± 10	59 ± 3	47 ± 2	23 ± 1
Lung	70 ± 18	52 ± 3	38 ± 1	22 ± 5
Heart	45 ± 10	37 ± 3	33 ± 2	25 ± 4
Skin	42 ± 4	28 ± 0	16 ± 10	15 ±1
Skeletal muscle	22 ± 4	15 ± 2	17 ± 3	14 ± 2
Adipose tissue	32 ± 7	16 ± 3	17 ± 4	9 ± 1
Testes	29 ± 3	27 ± 1	25 ± 1	19 ± 1
Brain	17 ± 3	13 ± 1	16 ± 1	13 ±1
Forestomach	76 ± 7	69 ± 12	31 ± 7	17 ± 1
Glandular stomach	65 ± 9	53 ± 3	32 ± 3	19 ± 1
Small intestine	154 ± 31	82 ± 1	38 ± 6	19 ± 2
Large intestine	87 ± 17	60 ± 4	36 ± 3	16 ± 2

Values are mean ± standard deviation of data from three rats.

Table 3. Concentrations of DMHP equivalents (µg/g wet tissue) in tissue of male rats following oral administration of 1, 2, or 5 daily doses of 200 mg/kg/d of [14C]DMHP.

	Number of daily [14C] DMHP doses
Tissue	1	2	5
Blood	36 ± 8	69 ± 11	93 ± 4
Liver	165 ± 25	243 ± 22	443 ± 29
Kidney	175 ± 40	207 ± 63	343 ± 18
Spleen	81 ± 10	121 ± 11	237 ± 19
Lung	70 ± 18	107 ± 11	212 ± 5
Heart	45 ± 4	70 ± 5	143 ± 14
Skin	42 ± 4	69 ± 12	137 ± 38
Skeletal muscle	22 ± 4	31 ± 1	65 ±1
Adipose tissue	32 ± 7	54 ± 17	58 ± 11
Testes	29 ± 3	48 ± 8	111 ± 10
Brain	17 ± 3	28 ± 6	54 ± 4
Forestomach	76 ± 7	119 ± 14	259 ± 47
Glandular stomach	65 ± 9	99 ± 9	204 ± 7
Small intestine	154 ± 31	188 ± 3	255 ± 12
Large intestine	87 ± 17	119 ± 23	210 ± 25

Data are mean ± standard deviation of data from 3 rats at 24 hours after the last dose.

Applicant's summary and conclusion

Conclusions:

Interpretation of results: low bioaccumulation potential based on study results.

Executive summary:

The current study evaluates the metabolism and disposition of [14C]-dimethyl hydrogen phosphite ([14C]DMHP) in rats.

DMHP was administered by single oral dose at 10, 100, or 200 mg/kg bw and by repeated administration at 200 mg/kg bw/day for 5 days. Rats were dosed by gastric intubation. At least three animals were used for each time point

DMHP administered at a range dose of 10-200 mg/kg was readily and near completely adsorbed from the gastrointestinal tracts of rats.

DMHP-derived radioactivity was widely distributed in tissues of rats. Liver and kidneys, followed by forestomach, spleen, and lungs, contained the highest concentration by radioactivity, while the lowest concentrations were in brain, adipose tissue, muscle, and testes. The concentrations of DMHP-derived radioactivity in tissues were approximately proportional to the dose.

At the doses studied, 28-38 % and 49-57% of dose were excreted in urine and as CO₂ in the expired air within 24 h following administration, respectively. Elimination of labelled dose as ¹⁴CO₂ continued up to approximately 12 hours following dosing. Elimination in urine continued in an almost linear fashion for up to 24 hours following dosing. Radioactivity collected in the ethanol trap and that excreted in faeces accounted for approximately 1 and 2% of dose hours, respectively, at all doses studied.

There appeared to be little or no effect of dose on the rate or route of metabolism and elimination in the dose range studied.

The effects of repeat exposure of rats to DMHP indicate that repeat administration had little effect on metabolism to

CO₂ or elimination in urine.

The main metabolic pathway in rodents is demethylation to monomethyl hydrogen phosphite (MMP) and further oxidation to CO₂.