Dimethyl methylphosphonate

Neurotoxicity

Administrative data

Endpoint:

neurotoxicity: acute oral

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Scientifically acceptable study (QC)

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1978

Report date:

1978

Materials and methods

Principles of method if other than guideline:

Evaluation of cholinesterase activity in blood plasma of rats animals after repeated oral administration (3 consecutive days) of the test substance

GLP compliance:

no

Remarks:

well documented study (QC)

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Dimethyl methylphosphonate

EC Number:

212-052-3

EC Name:

Dimethyl methylphosphonate

Cas Number:

756-79-6

Molecular formula:

C3H9O3P

IUPAC Name:

dimethyl methylphosphonate

Details on test material:

- Name of test material (as cited in study report): a liquid, labelled "FAT 80 021B"

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: derived rats bred on tlie premises
- Age at study initiation: 35-49 days
- Weight at study initiation: mean bw of 301 for males and 206 in females
- Diet (e.g. ad libitum): a commercial diet BP Nutrition UK Ltd. Rat and House No. 1 Expanded diet was fed
- Housing: housed in boxes of 5
- Water (e.g. ad libitum): drinking water

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21±2°C
no additional data

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

water

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:
The compound was mixed with tap water at the required concentrations and administered at a constant rate of 10 ml/kg. Control animals received the vehicle (tap water) only at the same rate. The concentration of the administered compoud in water was as follows: 0% in the control groups, 0.01% in the 1 mg/kg bw test group, 0.1% in the 10 mg/kg bw test group, 1.0% in the 100 mg/kg bw test group and 10.0% in the 1000 mg/kg bw test group.

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

the animals were given 3 consecutive daily doses

Frequency of treatment:

daily

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 1, 10, 100 and 1000 mg/kg bw per day
Basis:
actual ingested

No. of animals per sex per dose:

5 in each group (2 control groups and 4 test groups; the animals were treated and manipulated in two consecutive days with one control each times)

Control animals:

yes, concurrent vehicle

Details on study design:

Blood samples for plasma cholinesterase activity measurements were taken pretest and ½, 1, 2 and 4 hours after the third administration. Blood was obtained from the retro-orbital plexus under light anesthesia using ether/oxygen. No timed samples were obtained from one control male animal died under anesthetic at the ½ hour blood sampling on day 3.

Examinations

Observations and clinical examinations performed and frequency:

CLINICAL OBSERVATIONS
Following parameters were recorded daily: body weights, food consumption and clinical symptoms.

Specific biochemical examinations:

CHOLINESTERASE ACTIVITY
LKB Reaction Rate Analyser

Neurobehavioural examinations performed and frequency:

Not evaluated

Sacrifice and (histo)pathology:

All surviving rata were humanely killed after samples were completed. No autopsies were performed

Other examinations:

not applicable

Positive control:

none

Statistics:

Cholinesterase results were analyzed using Students' 't' test for independent variables, (Level of significance P<0.05)

Results and discussion

Results of examinations

Clinical signs:

effects observed, treatment-related

Mortality:

mortality observed, treatment-related

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Clinical biochemistry findings:

effects observed, treatment-related

Behaviour (functional findings):

not examined

Gross pathological findings:

not examined

Neuropathological findings:

not examined

Other effects:

not examined

Description (incidence and severity):

Migrated information from 'Further observations for developmental neurotoxicity study'



Details on results (for developmental neurotoxicity):- (migrated information)

Details on results:

MORTALITY
One animal died in the control group during blood sampling (see above)

BODY WEIGHT
No adverse effect observed (see Table 1)

FOOD CONSUMPTION
No adverse effect observed (see Table 2)

CHOLINESTERASE ACTIVITY
Plasma cholinesterase levels were depressed in the highest dose group only (1000 mg/kg; see Table 3). In males there was an approximate reduction of 30% over the 4 hour period when compared to control values taken at the same time, and in females there was a 40 – 50% reduction. There was no effect on plasma cholinesterase levels in the other groups.

Effect levels

Dose descriptor:

NOEL

Effect level:

100 mg/kg bw/day (actual dose received)

Sex:

male/female

Basis for effect level:

other: based on the significant reduced plasma cholinesterase activity at 1000 mg/kg bw

Remarks on result:

other: Generation: other: - null (migrated information)

Any other information on results incl. tables

Table 1: Mean daily body weights

Test groups	Mean body weight on day (g)
	1		2		3
	Males	Females	Males	Females	Males	Females
Control 1	300	206	306	209	310	211
Control 2	298	212	303	215	311	221
1 mg/kg bw	300	210	304	214	316	218
10 mg/kg bw	299	210	309	209	311	215
100 mg/kg bw	312	192	318	197	328	200
1000 mg/kg bw	298	207	306	212	310	213

Table 2: Daily food consumption

Test groups	Mean body weight on day (g/cage)
	1		2		3
	Males	Females	Males	Females	Males	Females
Control 1	26	17	26	19	17	10
Control 2	27	20	27	18	21	14
1 mg/kg bw	24	19	25	17	21	12
10 mg/kg bw	27	18	26	20	16	12
100 mg/kg bw	28	16	25	16	19	13
1000 mg/kg bw	26	16	25	17	16	10

Table 3: Mean plasma cholinesterase activity

Test groups	Mean cholinesterase activity (m units/ml plasma) after
	½ hour		1 hour		2 hours		4 hours
	Males	Females	Males	Females	Males	Females	Males	Females
Control 1	478	1158	464	1082	443	1023	465	1070
Control 2	414	956	460	974	428	932	413	894
1 mg/kg bw	474	1132	475	1193	445	1131	447	1075
10 mg/kg bw	451	1117	457	1095	451	998	454	1070
100 mg/kg bw	451	1222	468	1206	447	1100	432	1050
1000 mg/kg bw	334***	553**	322*	561**	323***	605*	341**	633**
*: P<0.05; **: P<0.01; ***: P<0.001