Reaction mass of dimethyl phosphonate and methyl hydrogenphosphonate and phosphonic acid

Repeated dose toxicity: inhalation

Administrative data

Endpoint:

short-term repeated dose toxicity: inhalation

Adequacy of study:

other information

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Reliability judgement is given by OECD-ICCA-SIDS

Data source

Reference

Reference Type:

secondary source

Title:

Dimethylphosphonate: Mobil Oil Cooperation (1982) Dimethy hydrogen phosphite: Four week inhalation toxicity study of MCTR-242-79 in the rat with pathology report and cover letter dated 122281, Old Doc. 8"HQ-0182-0366 Bio dynamic Inc. 26.5.80.

Author:

OECD-HPV-SIDS

Year:

2006

Bibliographic source:

UNEP

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 412 (Subacute Inhalation Toxicity: 28-Day Study)

GLP compliance:

not specified

Limit test:

no

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

Test material form:

other: liquid

Details on test material:

colorless liquid, not further specified

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ORGANISMS
- Age: 28 days
- Weight at study initiation: m: 349-437 g (mean 397 g), f:
187-278 g (mean 239 g)
- Number of animals: 200 (20/sex/group)

Administration / exposure

Route of administration:

inhalation: vapour

Type of inhalation exposure:

not specified

Vehicle:

other: nitrogen

Remarks on MMAD:

MMAD / GSD: no data

Details on inhalation exposure:

ADMINISTRATION / 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)

Analytical verification of doses or concentrations:

not specified

Details on analytical verification of doses or concentrations:

- 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.

Duration of treatment / exposure:

6 hours/day , 5 days,/week, 4 weeks

Frequency of treatment:

6 hours/day , 5 days,/week, 4 weeks

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 10, 30, 100, 300 ppm (approximately: 0, 40.6, 121.8, 406, 1218 mg/m³)
Basis:

No. of animals per sex per dose:

20/sex/group

Control animals:

yes

Details on study design:

according to the respective guideline
interim sacrifice: 5 male and 5 female rats from each group were sacrificed 2, 4, 6 week after commencement of the 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)

Positive control:

no

Examinations

Observations and examinations performed and frequency:

CLINICAL OBSERVATIONS AND FREQUENCY:
- Clinical signs: observed daily; full recorded physical
assessment was performed weekly
- Mortality: observed daily
- Body weight: weekly during exposure and post-exposure
period
-
- Food consumption: no
- Water consumption: no
- Ophthalmoscopic examination: every two weeks (in a
pre-exposure ophthalmoscopic examination those animals were
discarded from study who showed ocular abnomalities)
- Haematology: once in week 4; parameter evaluated:
hemoglobin, hematocrit, erythrocyte count, leukocyte count
(total and differential), clotting time
- Biochemistry: once in week 4; parameter evaluated: blood
urea nitrogen, serum glutamic pyruvic transaminase, serum
alkaline phosphatase, glucose
- Urinalysis: once in week 4; parameter evaluated:
appearance, specific gravity, occult blood, pH, protein,
bilirubin, ketones, glucose

Sacrifice and pathology:

EXAMINED AT NECROPSY (MACROSCOPIC AND MICROSCOPIC):
Organ weight: brain, gonads (ovary or testicle paired),
heart, kidneys (right and left separately), liver, lungs,
pituitary, spleen
- macroscopic: yes; all animals died during study or killed
in extremis and at scheduled sacrifice respectively
- microscopic: tissues fixed and exposed to histopathology
according to OECD guideline 407

Statistics:

STATISTICAL METHODS: Body weights, hematology, clinical
chemistry paramethers, organ weights, and organ/body weight
ratios were statistically evaluated; References: 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:
119 ppm (number of deaths in week 1-4): 0, 0, 1, 2
198 ppm (number of deaths in week 1-5): 0, 8, 5, 11, 3
(Causes of deaths may have been necrosis and acute purulent
inflammation of the skin)
Time to death varied between 7 and 26 days at 483.1 and
803.9 mg/m3.

>= 12 ppm (= 48.7 mg/m³; m and f):
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

>= 35 ppm
Body weight m:
- reduced body weight gain
Eyes m and f:
- lenticular opacities, progressed to cataracts
Skin m and f:
- 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 m and f:
- 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, m and f:
- increased mortality;
Time of death
- 119 ppm: on days 14(1,f) and 23(1,m)
- 198 ppm: on days 7 to 26 incl. (13,m + 14,f)
Body weight m and f:
- body weight losses
Clinical signs, m and f:
- neurological impairment (lack of coordination, lack of
grip)
Skin m and f:
- Dermatitis (control, 12, 35 ppm: 0/40, 119 ppm: 7/39, 198
ppm: 27/36)
Respiratory tract m and f:
- 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)
Haematology:
- m: hematocrit and hemoglobin reduced
- m and f: neutrophils increased, increased total leukocyte
numbers
Clinical chemistry:
- m: increased SGPT
- m and f: decreased glucose concentration
Fertility m:
- 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.

198 ppm m and f:
Respiratory tract:
- red discoloration of lungs and nasal turbinates; 9 rats (4
m and 5 f) had no discernible thymus tissue
Haematology:
- hemoglobin reduced
Clinical chemistry:
- increased SGPT, alkaline phophatase and urea levels
Spleen:
- hematopoiesis in the spleen (control, 12, 35, 119 ppm:
each 0/40, 198 ppm: 4/18)
Prostate m:
- 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.



OTHER EXAMINATION: The reversibility of cataract formation
was studied in detail

Effect levels

1

Dose descriptor:

NOAEC

Remarks on result:

not determinable

Remarks:

no NOAEC identified

2

Dose descriptor:

LOAEC

Effect level:

12 ppm

Sex:

male/female

Basis for effect level:

other: approx. 49 mg/m³: based on increased kidney weights and keratitis in both sexes down to the lowest tested concentration (UNEP 2006)

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

OECD-ICCA_SIDS (published by UNEP 2006) reported that 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) DMP vapor for 6 hours/day on 5 days/week

(Mobil Oil Corporation, 1982).

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 (details see chapter 3.1.8). 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 LOAEL derived for this study is 48.7 mg/m3 (12 ppm; corresponds to about 10 mg/kg bw/d).

No NOAEL was achieved in this study.

Applicant's summary and conclusion

Executive summary:

Mobil Oil Corporation, 1982).cited by OECD-ICCA_SIDS published by UNEP 2006:

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) DMP vapor for 6 hours/day on 5 days/week. No NOAEC was achieved in this study.

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