Dimethyl phosphonate

Repeated dose toxicity: inhalation

Administrative data

Endpoint:

short-term repeated dose toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

other information

Reliability:

3 (not reliable)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

Several relevant methodological deficiencies: at the commencement of the study the weights variation of animals used exceeded ± 20 per cent of the mean weight (21% in males and 33% in females); only vehicle control used; the lowest concentration showed evidence of toxicity; analytical purity was not reported; test material administration was conducted in different ways in different test groups; exposure atmospheric sampling was not conducted properly; temperature at which the test is performed was between 24-27 °C; on test day 16, four male rats of group treated with 483.1 mg/m³ were not loaded into the chamber and did not receive exposure to the test material, due to a technician error. However, according to OECD SIDS a reliability of 1 was given.

Data source

Reference

Reference 1

Reference Type:

other company data

Title:

Unnamed

Year:

1982

Reference 2

Reference Type:

secondary source

Title:

Unnamed

Year:

2004

Materials and methods

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

In a 4-week study, male and female Sprague-Dawley rats (20/sex per group) inhaled 48.7, 142.1, 483.1, and 803.9 mg/m³ (12, 35, 119, and 198 ppm) dimethyl phosphonate vapour for 6 hours/day on 5 days/week.

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 phosphonate
- Physical state: liquid
- Analytical purity: not reported

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: 28 days
- Weight at study initiation: males: 349-437g (mean 397 g); females: 187-278 (mean 239 g).

Administration / exposure

Route of administration:

inhalation

Type of inhalation exposure:

not specified

Vehicle:

other: nitrogen

Details on inhalation exposure:

- Interim sacrifices: Five male and five female rats from each group were sacrificed 2, 4 and 6 week after commencement of exposure (exceptions: in the 119 ppm group only 8 animals were necropsied after 6 weeks; in the 198 ppm group no animals were necropsied after 4 and after 6 weeks each).
- Determination of chamber concentration: a calibration curve relating concentration to the absorption at this wavelength was prepared (calibration was carried out with dry air). One to two samples were taken daily from each exposure chamber. The exposure concentration was calculated by comparing the infrared absorption of the sample to the standard curve.

Analytical verification of doses or concentrations:

yes

Duration of treatment / exposure:

4 weeks

Frequency of treatment:

6 hours/day, 5 days/week

Doses / concentrations

Remarks:

Doses / Concentrations:
target concentration: 0, 10 (40.6), 30 (121.8), 100 (406), 300 (1218) ppm (mg/m³) (effective inhaled concentration: 0, 12 (48. 7), 35 (142.1), 119 (483.14), 198 (803.88) ppm(mg/m³)).
Basis:

No. of animals per sex per dose:

20

Control animals:

yes, concurrent vehicle

Details on study design:

Post-exposure period: 4 weeks

Positive control:

No

Examinations

Observations and examinations performed and frequency:

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Clinical signs were performed daily; full recorded physical assessment was performed weekly.

BODY WEIGHT: Yes
- Time schedule for examinations: daily

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: every two weeks (in a pre-exposure ophthalmoscopic examination those animals that showed ocular abnomalities were discarded from study).

HAEMATOLOGY: Yes
- Time schedule for collection of blood: once in week 4.
- The following parameters were examined: haemoglobin, hematocrit, erythrocyte count, leukocyte count (total and differential), clotting time.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: once in week 4.
- The following parameters were examined: blood urea nitrogen, serum glutamic pyruvic transaminase, serum alkaline phosphatase, glucose.

URINALYSIS: Yes
- Time schedule for collection of urine: once in week 4.
- The following parameters were examined: appearance, specific gravity, occult blood, pH, protein, bilirubin, ketones, glucose.

-ORGAN WEIGHT: brain, gonads (ovary or testicle paired), heart, kidneys (right and left separately), liver, lungs, pituitary, spleen.

Sacrifice and pathology:

GROSS PATHOLOGY: Yes; all animals died during the study or were killed in extremis and at scheduled sacrifice respectively.
HISTOPATHOLOGY: Yes.

Other examinations:

The reversibility of cataract formation was studied in detail.

Statistics:

Body weights, haematology, clinical chemistry parameters, organ weights, and organ/body weight ratios were statistically evaluated according to Snedecor, G.W. and Cochran, W.G., Statistical Methods, 6th Edition, Iowa State Univ. Press (1967), Hollander and Wolfe, Nonparametric Statistical Methods, John Wiley and Sons, New York (1973); Dunnett, C.W. J. Am. Sta. Assn., Vol. 50 (1955), Biometrics, Vol. 20 (1964).

Results and discussion

Results of examinations

Details on results:

TOXIC RESPONSE/EFFECTS BY DOSE LEVEL
MORTALITY AND TIME TO DEATH
At 119 ppm the number of death in week 1-4: 0, 0, 1, 2 ; at 198 ppm the number of death in week 1-4: 0, 8, 5, 11, 3. Causes of deaths may have been necrosis and acute purulent inflammation of the skin.
At 483.1 and 803.9 mg/m³ the time of death varied betwwen 7 and 26 days.
TOXIC EFFECTS
At doses >= 12 ppm (48.7 mg/m³; males and females): EYES: irritation of superficial ocular structures (associated with inflammatory changes of intraocular structures in many rats) - mucosal irritation - keratitis; KIDNEY: increased absolute and relative kidney weights.
At doese >= 35 ppm: BODY WEIGHT: reduced body weight gain; EYES (males and females): lenticular opacities, progressed to cataract; SKIN (males and females): cutaneous and mucosal irritation (increased lacrimal, nasal or buccal secretions and/or erythema, edema, loss of elasticity, fissuring, necrosis or eschar formation of the skin); nasal and ocular responses disappeared within one week; cutaneous changes were not fully reversible during the observation period.
RESPIRATORY TRACT MALE AND FEMALE
Inflammation of the anterior nares (control: 4/39; 12 ppm: 4/38; 35 ppm: 6/39; 119 ppm: 7/39; 198 ppm: 9/36) seems to be an extension of the effect on the skin >=119 ppm.
MORTALITY MALE AND FEMALE
Increased mortality. Time of death: at 119 ppm: on days 14 (1, female) and 23 (1, male); 198 ppm: on days 7 to 26 included (13, male + 14, females); BODY WEIGHT MALE AND FEMALE
Body weight losses.
CLINICAL SIGNS MALE AND FEMALES
Neurological impairment (lack of coordination, lack of grip).
SKIN MALE AND FEMALE
Dermatitis (control 12, 35, ppm: 0/40; 119 ppm: 7/39; 198 ppm: 27/36)
RESPIRATORY TRACT MALES AND FEMALES
Irritation of the respiratory tract (dry or moist rales labored or irregular breathing); changes were reversible within one to two weeks.
Inflammation of the external nares (control, 12 and 35 ppm: 0/40, 119 ppm: 5/39, 198 ppm: 22/36). At 198 ppm: red discoloration of lungs and nasal turbinates; 9 rats (4 males and 5 females) had no discernible thymus tissue.
HAEMATOLOGY
male: hematocrit and haemoglobin reduced; male and female: neutrophils increased, increased total leukocyte numbers.
CLINICAL CHEMISTRY
male: increased SGPT; male and female: decreased glucose concentration.
FERTILITY MALE
Hypospermatogenesis (control, 12, 35 ppm: 0/20, 119 ppm:3/20, 198 ppm: 4/19). In each case the content of sperm in the epididymis was below normal.
SPLEEN
hematopoiesis in the spleen (control, 12, 35, 119 ppm: each 0/40, 198 ppm: 4/18).
PROSTATE
Acute prostatitis 4/18 (low incidence of prostatitis was seen in general).
FURTHER FINDINGS
Enlarged costochondral junction (control: 1/40; 12 and 35 ppm: 0/40, 119 ppm: 6/40, 198 ppm: 2/36). Treatment relation was not studied.
OTHER EXAMINATIONS
Cataract formation and cessation was studied in animals of the 119 ppm group. Cataract formation had stopped after two weeks post-exposure and at four weeks post-exposure the formation of normal lens fibers had recommenced.

Effect levels

Dose descriptor:

LOAEC

Effect level:

12 ppm

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: eye effects and kidney weights; 12 ppm=48.7 mg/m³

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Executive summary:

Mobil Oil Corporation (1992)

In a 4-week study, male and female Sprague-Dawley rats (20/sex per group) inhaled 48.7, 142.1, 483.1, and 803.9 mg/m³ (12, 35, 119, and 198 ppm) dimethyl phosphonate vapour for 6 hours/day on 5 days/week.

At all concentrations increased kidney weights were observed in male and female rats. Irritation of superficial ocular structures, mucosal irritation and keratitis were shown in all dose groups and in both sexes. The eye changes progressed to cataracts in dose groups of 142.1 mg/m³. At 142.1 mg/m³ cutaneous irritation was observed, the skin effects progressed to dermatitis at 483.1 mg/m³, and at 803.9 mg/m³ necrosis and acute purulent inflammation of the skin were main causes of deaths. At 142.1 mg/m³ inflammation of the anterior nares was visible in male and female rats. At 483.1 mg/m³ the external nares were affected, and at 803.9 mg/m³ red discoloration of the lungs and the nasal turbinates were observed in both sexes.

In male rats reduced body weight gains were observed at 142.1 mg/m³. In the next higher dosage (483.1 mg/m³) body weight losses and increased mortality was shown in male and female rats.

Time to death varied between 7 and 26 days at 483.1 and 803.9 mg/m³. Hypospermatogenesis was observed in male rats at lethal doses of = 483.1 mg/m³. Hematopoiesis in the spleen occurred in 4/18 female rats at 803.9 mg/m³ only and was not observed in the controls or the lower doses. No historical control data were provided.

The LOAEC derived for this study is 48.7 mg/m³ (12 ppm).

No NOAEL was achieved in this study.

This study is not reliable because several relevant methodological deficiencies: at the commencement of the study the weights variation of animals used exceeded ± 20% of the mean weight (21% in males and 33% in females); only vehicle control used; the lowest concentration should evidence of toxicity; analytical purity was not reported; test material administration was conducted in different ways in different test groups; exposure atmospheric sampling was not conducted properly; temperature at which the test is performed was between 24-27 °C; on test day 16 four male rats of group treated with 483.1 mg/m³, were not loaded into the chamber and did not receive exposure to the test material, due to a technician error.