Dimethyl phosphonate

Toxicity to reproduction: other studies

Administrative data

Endpoint:

toxicity to reproduction: other studies

Remarks:

OECD 408 (repeated 90 day oral toxicity in rodents)

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remarks'

Remarks:

Comparable to guideline study (No organ weight determination, no haematological/biochemical examinations, no data on statistics). 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:

Toxicology and carcinogenesis studies of dimethyl hydrogen phosphite (CAS No. 868-85-9) in F344/N rats and B6C3F1 mice (gavage studies)

Author:

National Toxicology Program

Year:

1985

Bibliographic source:

Technical Report Series No. 287, NIH Publication No. 86-2543: 1 - 179

Reference 2

Reference Type:

review article or handbook

Title:

Dimethyl phosphonate - CAS No: 868-85-9 - SIDS Initial Assessment Report.

Author:

OECD

Year:

2004

Bibliographic source:

UNEP Publications

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

other: OECD 408 (repeated 90 day oral toxicity in rodents)

Deviations:

yes

Remarks:

No organ weight determination, no haematological/biochemical examinations, no data on statistics.

Principles of method if other than guideline:

Necropsy performed on all animals; the following tissues from vehicle control and all but the 95 mg/kg bw dosed group of mice were microscopically examined: gross lesions, skin , parathyroids, colon, esophagus, brain, sternebrae (including marrow), liver, lung and mainstem bronchi, stomach, thymus, pancreas, kidney, urinary bladder, eyes, mandibular lymph node, saliva glands, thyroid gland, small intestine, ovaries/ uterus or prostate / testes, heart, trachea, spleen, adrenal glands, pituitary gland, gallbladder, mammary gland. Only heart, liver, and kidney examined for the 95 mg/kg group of mice.

GLP compliance:

not specified

Type of method:

in vivo

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
- Analytical purity: ca 96%
- Lot/batch No.: DM 113077
- Stability under test conditions: stable when stored in sealed containers at temperature up to 60°C for 2 weeks. Gas chromatography was used to monitor stability.
- Storage condition of test material: the testing laboratory stored several portions at -20°C as reference samples and the remainder at room temperature. Solutions prepared 1 x wk.

Test animals

Species:

mouse

Strain:

B6C3F1

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Breeding Laboratories (Portage, MI, USA).
- Age at study initiation: 6-8 weeks old.
- Weight at study initiation: 23-25 g (male), 18-19 g (female).
- Housing: 5 animals per cage (polycarbonate).
- Diet (e.g. ad libitum): Purina Lab Chow meal (St. Louis, MO); available ad libitum.
- Water (e.g. ad libitum): Acidified with HCl (pH 2.5) tap water; available ad libitum.
- Acclimation period: 2 weeks.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22-24 (max 28).
- Humidity (%): 30-70
- Air changes (per hr): 12-15 room air changes/h.
- Photoperiod (hrs dark / hrs light): 12 / 12

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:
Appropriate amounts of dimethyl hydrogen phosphite were mixed with corn oil. Mixtures were resuspended before dosing.

VEHICLE
- Justification for use and choice of vehicle (if other than water): corn oil was chosen because of the potential for chemical hydrolysis in water.
- Concentration in vehicle: 0, 28.53, 57.06, 112.61, 225.22, 450.45 mg/mL
- Amount of vehicle (if gavage): 3.33 mL/kg.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Analytical verification of doses or concentrations: Analyses for dimethyl hydrogen phosphite in corn oil were performed on every eighth dose mixture to confirm that the correct concentrations were administered to the test animals. The method of analysis involved a methanolic extraction as a purification step and a gas chromatographic assay as a quantification step.

Duration of treatment / exposure:

13 weeks

Frequency of treatment:

5 days

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 95, 190, 375, 750, 1500 mg/kg/day
Basis:
actual ingested

No. of animals per sex per dose:

10

Control animals:

yes, concurrent vehicle

Details on study design:

CLINICAL OBSERVATIONS AND FREQUENCY:
- Clinical signs: yes (observed twice per day)
- Mortality: yes (observed twice per day)

- Body weight: yes (weeklyl)

- Organ weight: no

- Food consumption: no

- Water consumption: no

- Haematology: no

- Biochemistry: no

- Urinalysis: no

Necropsy performed on all animals; the following tissues from vehicle control and all but the 95 mg/kg bw dosed group of mice were microscopically examined: gross lesions, skin , parathyroids, colon, esophagus, brain, sternebrae (including marrow), liver, lung and mainstem bronchi, stomach, thymus, pancreas, kidney, urinary bladder, eyes, mandibular lymph node, saliva glands, thyroid gland, small intestine, ovaries/ uterus or prostate / testes, heart, trachea, spleen, adrenal glands, pituitary gland, gallbladder, mammary gland. Only heart, liver, and kidney examined for the 95 mg/kg group of mice.

Results and discussion

Effect levels

1

Dose descriptor:

NOAEL

Remarks:

Reproduction Toxicity

Effect level:

190 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

2

Dose descriptor:

LOAEL

Remarks:

Reproduction Toxicity

Effect level:

375 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male

Basis for effect level:

other: Testicular atrophy, characterized by hypospermatogenesis with the formation of large giant spermatids and syncytial cells, was seen in male mice at 375, 750, and 1500 mg/kg. These effects were probably secondary to the general toxicity.

Observed effects

TOXIC RESPONSE/EFFECTS BY DOSE LEVEL:
All the mice of each sex that received 750 or 1500 mg/kg died during the first 4 weeks. Two of 10 males and 5 of 10 females that received 375 mg/kg also died. Mice that received 375 mg/kg or more had tremors and decreased activity. Final weights of surviving dosed and vehicle control mice were comparable. Lung congestion in males and females, cardiac mineralization in males, and hepatocellular vacuolization in females were probably compound related. Pulmonary congestion was observed in animals that died during the studies. Testicular atrophy, characterized by hypospermatogenesis with the formation of large giant spermatids and syncytial cells, was seen in male mice at 375, 750, and 1500 mg/kg.
These effects were probably secondary to the general toxicity.

Any other information on results incl. tables

Table1. Survival and mean body weights of mice in the thirteen-week gavage studies of dimethyl hydrogen phosphite.

		Mean Body Weights (a) (grams)
Dose (mg/kg)	Survival (b)	Initial	Final	Change (c)	Final Weight Relative to Vehicle Controls (percent)
MALE
0	10/10	24	29	+ 5	--
95	10/10	24	30	+ 6	103.4
190	10/10	25	31	+ 6	106.9
375	(d) 8/10	24	28	+ 4	96.6
750	(e) 0/10	25	(f)	(f)	(f)
1500	(g) 0/10	23	(f)	(f)	(f)
FEMALE
0	10/10	18	23	+5	--
95	10/10	18	23	+5	100.0
190	10/10	18	22	+4	95.7
375	(f) 5/10	19	24	+5	104.3
750	(g) 0/10	18	(f)	(f)	(f)
1500	(h) 0/10	18	(f)	(f)	(f)

(a) Only group weights were taken by laboratory; no individual animal weight data are available.

(b) Number surviving /number in group.

(c) Mean weight change of the group.

(d) Week of death: 11, 12

(e) Week of death : 1, 3, 3, 3, 4, 4, 4, 4, 4, 4

(f) No results are reported due to the 100% mortality in this group.

(g) Week of death: 1, 1, 1, 1, 1, 2, 2, 2, 4, 4

(h) Week of death: 5, 10, 11, 12, 12

(i) Week of death: 3, 4, 4, 4, 4, 4, 4, 4, 4, 4

(j) Week of death: 1, 1, 1, 1, 1, 1 ,1, 1, 3, 4

Table 2. Histopathologic lesions observed in mice in the thirteen-week gavage studies of dimethyl hydrogen phosphite.

Dose (mg/kg)	Hepatocellular Vacuolization (a)	Cardiac Mineralization (minimal severity)	Testicular Atrophy	Lung Congestions
MALE
0	1/10	0/10	0/10	0/10
95	(b) 1/10	0/10	0/10	0/10
190	1/10	9/10	0/10	0/10
375	2/10	3/10	3/10	1/10
(c) 750	2/9	0/10	9/10	7/10
(c) 1500	1/10	1/10	2/10	7/10
FEMALE
0	0/10	1/10	-	0/10
95	0/10	0/10	-	0/10
190	5/10	1/10	-	0/10
375	5/10	2/10	-	4/10
(c) 750	0/9	0/9	-	7/10
(c) 1500	2/7	0/10	-	9/10

(a) Male: diffuse or focal: diffuse.

(b) Observed by quality assurance pathologist.

(c) Most animals in these groups died early.

Applicant's summary and conclusion

Executive summary:

A repeated dose toxicity study equivalent or similar to OECD 408 (repeated 90 day oral toxicity in rodents) was conducted. AnNecropsy performed on all animals. The following tissues from vehicle control and all but the 95 mg/kg bw dosed group of mice were microscopically examined: gross lesions, skin , parathyroids, colon, esophagus, brain, sternebrae (including marrow), liver, lung and mainstem bronchi, stomach, thymus, pancreas, kidney, urinary bladder, eyes, mandibular lymph node, saliva glands, thyroid gland, small intestine, ovaries/ uterus or prostate / testes, heart, trachea, spleen, adrenal glands, pituitary gland, gallbladder, mammary gland. Only heart, liver, and kidney examined for the 95 mg/kg group of mice.

TOXIC RESPONSE/EFFECTS BY DOSE LEVEL:  

All the mice of each sex that received 750 or 1500 mg/kg died during the first 4 weeks. Two of 10 males and 5 of 10 females that received 375 mg/kg also died. Mice that received 375 mg/kg or more had tremors and decreased activity. Final weights of surviving dosed and vehicle control mice were comparable. Lung congestion in males and females, cardiac mineralization in males, and hepatocellular vacuolization in females were probably compound related. Pulmonary congestion was observed in animals that died during the studies. Testicular atrophy, characterized by hypospermatogenesis with the formation of large giant spermatids and syncytial cells, was seen in male mice at 375, 750, and 1500 mg/kg.

These effects were probably secondary to the general toxicity.