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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
other information
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Comparable to guideline study with deviations (No organ weight determination, no haematological/biochemical examinations, no urinalysis, 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:
reference to same study

Data source

Referenceopen allclose all

Reference Type:
publication
Title:
Unnamed
Year:
1985
Reference Type:
secondary source
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:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents)
Deviations:
yes
Remarks:
No organ weight determination, no haematological/biochemical examinations, no urinalysis, no data on statistics
Principles of method if other than guideline:
13-week studies were conducted to evaluate the cumulative toxic effects of repeated administration of dimethyl hydrogen phosphite and to determine the doses in the 2-year studies.
GLP compliance:
not specified
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
other: liquid
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:
rat
Strain:
other: F344/N
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories (Portage, MI, USA).
- Age at study initiation: 6-7 weeks old.
- Weight at study initiation: 184-194 g (male), 136-138g (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 oral 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, 7.50, 15.01. 30.03, 60.06, 120.01 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:
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/week
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 25, 50, 100, 200, 400 mg/kg bw/day
Basis:
actual ingested
No. of animals per sex per dose:
10
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: fifteen-day repeated administration studies were conducted to determine doses for the 13-week studies.
Based on the mortality data and on the clinical signs, the high dose selected for the 13-week studies was 400 mg/kg.
Positive control:
No

Examinations

Observations and examinations performed and frequency:
CLINICAL OBSERVATIONS AND FREQUENCY: 
- Clinical signs: yes (observed twice per day).
- Mortality: yes (observed twice per day).

- Body weight: yes (recorded weekly).

- Organ weight: no

- Food consumption: no

- Water consumption: no

- Haematology: no

- Biochemistry: no

- Urinalysis: no

Sacrifice and pathology:
ORGANS EXAMINED AT NECROPSY (MACROSCOPIC AND MICROSCOPIC): Necropsy performed on all animals; the following tissues from vehicle control and 400 mg/kg group of rats: gross lesions, parathyroids, colon, esophagus, brain, sternebrae (including marrow), liver, lung and mainstem bronchi, stomach, thymus, pancreas, kidney, urinary bladder, eyes, mandibular lymph node, salivary glands, thyroid gland, small intestine, ovaries/ uterus or testis, trachea, spleen, adrenal glands, pituitary gland, mammary gland.
Eyes of vehicle control and 200 mg/kg groups of rats were examined.
Other examinations:
No further data
Statistics:
Not performed

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
effects observed, treatment-related
Description (incidence and severity):
observed in male and female rats that received 400 mg/kg bw.
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
no effects observed
Details on results:
TOXIC RESPONSE/EFFECTS BY DOSE LEVEL:
MORTALITY
-100 mg/kg bw, f: 2/10
-200 mg/kg bw, m: 1/10; f: 2/10
-400 mg/kg bw, m: increased mortality in male and female animals; 9/10; f: 8/10.
3/5 deaths that occurred in the 100 and 200 mg/kg groups may be due to the accidental introduction of gavage solutions into the lungs.


BODY WEIGHTS
Final mean body weights of males and females that received 400 mg/kg were depressed 46% and 39% relative to those of the vehicle control. The final mean body weight of females that received 200 mg/kg was depresses 14% relative to that of the vehicle controls.

OTHER EFFECTS
Degeneration of the lens was observed in the eyes of 4/9 females and 1/7 males that received 400 mg/kg. Acute diffuse inflammation of the cornea was observed in 1/9 females that received 400 mg/kg. The eyes of the next lower dose group (200 mg/kg) were examined histologically; eye lesions were not seen in either males (0/10) or females (0/9) (Eyes from all animals were not available for analysis to autolysis). Urinary bladder calculi were observed in 2/10 male rats that received 400 mg/kg.

Lesions were observed in the lungs of vehicle controls and all dosed groups.
Blood taken at the end of the studies was found to be positive by hemagglutination inhibition assay for pneumonia virus and by the complement fixation assay Sendai virus in 5/5 vehicle control females and 5/5 vehicle control males




Effect levels

open allclose all
Dose descriptor:
NOAEL
Effect level:
200 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male
Dose descriptor:
LOAEL
Effect level:
400 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male
Basis for effect level:
other: Body weight decrease, increased urinary bladder calculi, eye changes, increased lung lesions, and increased mortality at 400 mg/kg bw
Dose descriptor:
NOAEL
Effect level:
100 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
female
Dose descriptor:
LOAEL
Effect level:
200 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: Body weight decrease at 200 mg/kg bw

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

Table 1. Survival and mean body weights of rats in the thirteen-week gavage studies of dimethly hydrogen phosphite

           Mean Body Weights (a)  
 Dose (mg/kg)  Survival (b)  Initial  Final  Change (c)  Final Weight Relative to Vehicle Controls (percent)
 MALE          
 0  10/10  186  308  +122  --
 25  10/10  185  290  +105  94.2
 50  10/10  188  266  + 78   86.4
 100   10/10  194  314 +120  101.9
 200  (d) 9/10  184  298  +114   96.8
 400  (e) 1/10  184  168  - 16   54.5
 FEMALE          
 0  10/10  136  193  +57  --
 25  10/10  137  195  +58  101.0
 50  10/10  136  191  +55   99.0
 100  (f) 8/10  138  185  +47   95.9
 200  (g) 8/10  137  167  +30   86.5
 400  (h) 2/10  135  117  -18   60.6

(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: 10

(e) Week of death : 3, 4, 4, 5, 5, 7, 8, 9

(f) Week of death: 7, 11

(g) Week of death: 9, 12

(h) Week of death: 2, 3, 3, 3, 3, 4, 5, 8, 10

Table 2. Numbers of rats with histopathologic lesions in the eye and lung in hte 13 -week gavage studies of dimethyl hydrogen phosphite

    Vehicle Control  100 mg/kg

  200 mg/kg  

    400 mg/kg

Lesion  Male  Female  Female  Male  Female  Male  Female
Eye      
No.animals examined microscopically  --  -- -- 10  9  7
Degeneration, lens  --  --  --  --  --  1   4
Inflammation, chronic, diffuse cornea   --  --  -- -- --  --   1
Lung            
 No.animals examined microscopically  10  10   2   1   2  10  10
 Inflammation, chronic, focal   4   1  --  --  --  --  --
 Inflammation, chronic, diffuse   3   2  --  --   1   5   6
Congestion  --  --   2   1 1  --   1
Congestion, diffuse  --  --  --  --   --   3   1
Congestion, acute  --  --  --  --   --   1   --
 Histiocytosis  --  --  --  --  --   5   --

Applicant's summary and conclusion

Executive summary:

NTP (1985) reported that in a sub-chronic investigation male and female Fischer 344 rats were administered 0, 25, 50, 100, 200, 400 mg/kg bw/d dimethyl phosphonate for 5 days/week for 13 weeks via gavage, with a method similar to OECD guideline 408 with restrictions (No organ weight determination, no haematological/biochemical examinations, no urinalysis, no data on statistics). A decreased body weight gain was observed in female rats at 200 mg/kg bw/d and above and for male rats at 400 mg/kg bw/d. Mortality was increased at 400 mg/kg bw/d for both sexes. Eye changes (degeneration of the lens, acute diffuse inflammation of the cornea) and increased lung lesions (inflammation, congestion, histiocytosis) were found in male and female rats at 400 mg/kg bw/d. In male rats increased urinary bladder calculi were observed at 400 mg/kg bw/d. The NOAEL is 100 mg/kg bw/d for female and 200 mg/kg bw/d for male rats.