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EC number: 212-052-3 | CAS number: 756-79-6
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Carcinogenicity
Administrative data
- Endpoint:
- carcinogenicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- supporting study
- Reliability:
- 3 (not reliable)
- Rationale for reliability incl. deficiencies:
- other: Survival rate too low
Data source
Reference
- Reference Type:
- publication
- Title:
- Unnamed
- Year:
- 1 987
Materials and methods
Test guideline
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 451 (Carcinogenicity Studies)
- Principles of method if other than guideline:
- Evaluation of test substance carcinogenic potential after 2 years oral administration to test animals
- GLP compliance:
- no
- Remarks:
- well documented study peer reviewed study
Test material
- 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): Dimethyl methylphosphonate; Synonyms: Fyrol DMMP; Methyl phosphonic acid, dimethyl ester; DMMP; Methanephosphonic acid dimethyl ester; Dimethyl methanephosphonate
- Molecular formula (if other than submission substance): C3H9O3P
- Molecular weight (if other than submission substance): 124.1
- Analytical purity: ~98% for lot No. 4182-2, ~99% - > 99% for lots No. L120381, 1114L-6-l or 1114L-2-1
- Composition of test material, percentage of components: 0.04% - 0.06water and 0.47-1.1% total impurities
- Lot/batch No.: 4182-2; L120381; 1114L-6-l; 1114L-2-1
- Stability under test conditions and storage condition of test material: stability studies with the gas chromatographic indicated that dimethyl methylphosphonate was stable as a bulk chemical when kept for 2 weeks at temperatures of up to 60° C. The test substance at 0.6% in corn oil was stable when stored at room temperature for up to 7 days. A subsequent stability study performed at the study laboratory indicated that dimethyl methylphosphonate/corn oil mixtures are stable for 14 days under refrigeration. In the 2-year studies, dose mixtures were stored at 4° C for no longer than 13 days.
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Fischer 344
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: the male and female F344/N rats used in these studies were produced under strict barrier conditions at Frederick Cancer Research Center under a contract to the Carcinogenesis Program. Breeding stock for the foundation colonies at the production facility originated at the National Institutes of Health Repository. Animals shipped for study were progeny of defined microflora-associated parents that were transferred from isolators to barrier-maintained rooms.
- Age at study initiation: 4-5 weeks (placed on study at 7-8 weeks age)
- Weight at study initiation: see Table 1
- Fasting period before study: none
- Housing: Polycarbonate (Lab Products, Inc., Garfield, NJ, and Hazleton Systems, Aberdeen, MD); 5 animals per cage
- Diet (e.g. ad libitum): NIH 07 Rat and Mouse Ration (Zeigler Bros., Inc., Gardners, PA)
- Water (e.g. ad libitum): Acidified to pH 2.5
- Acclimation period: 20 days; the animals were quarantined. Thereaft;er, a complete necropsy was performed on five animals of each sex and species to assess their health status.
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22.2-24.4°C
- Humidity (%): 30-70%
- Air changes (per hr): 12-15 room air change per hour
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- corn oil
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS:
dose volume 6.5 ml/kg; test substance was formulated with corn oil with a Polytron mixer and resuspended daily with a magnetic stirrer - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- During the 2-year studies, the dose preparations were analyzed at approximately 8-week intervals. The dose mixtures were prepared within specifications 94% of the time (within ±10% of the target concentration). Only 3/47 dose formulations were determined to be out of specifications (within ±13%). Referee analysis periodically performed by the analytical chemistry laboratory, found good agreement was found between the results at the two laboratories.
During the study, deaths occurred in April 1983 in low dose (male mice dosed in parallel). Special analyses were therefore performed on the contents of the dosing containers and their corresponding archive samples. The concentrations in the archive samples were within the specified limits, whereas that of the high-dose sample taken in the animal room was high (134% of target), and the low-dose sample taken in the animal room was low (79% of target). Because the archive samples were determined to be within specifications, it would appear that a dosing accident or misdosing due to improper handling or re-suspending of the dose mixture occurred in the animal room on these days. - Duration of treatment / exposure:
- 103 weeks
- Frequency of treatment:
- 5 days per week
Doses / concentrations
- Remarks:
- Doses / Concentrations:
0, 500 and 1000 mg/kg bw per day
Basis:
actual ingested
gavage
- No. of animals per sex per dose:
- 50
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: based on the results of the 13-week study
- Positive control:
- none
Examinations
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: all animals were observed two times per day and palpated once each 4 weeks
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: clinical signs were recorded once per week (also see above
DERMAL IRRITATION (if dermal study): No
BODY WEIGHT: Yes
- Time schedule for examinations: body weights by cage were recorded once per week for the first 13 weeks of the studies and once per month thereafter. Mean body weights were calculated for each group.
FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No data
FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No data
WATER CONSUMPTION AND: No data
OPHTHALMOSCOPIC EXAMINATION: No data
HAEMATOLOGY: No (also see pathology)
CLINICAL CHEMISTRY: No
URINALYSIS: No
NEUROBEHAVIOURAL EXAMINATION: No - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes; animals found moribund and those surviving to the end of the studies were humanely killed. A necropsy was performed on all animals including those found dead, unless they were excessively autolyzed, cannibalized, missexed, or found missing. Thus, the number of animals from which particular organs or tissues were examined microscopically varies and is not necessarily equal to the number of animals that were placed on study. During necropsy, all organs and tissues were examined for grossly visible lesions.
HISTOPATHOLOGY: Yes; tissues were preserved in 10% neutral buffered formalin, embedded in paraffin, sectioned, and stained with hematoxylin and eosin. Tissues examined microscopically are: cecum, colon, costochondral junction, duodenum, esophagus, eyes, gallbladder (mice), gross lesions and tissue masses, heart, ileum, jejunum, kidneys, larynx, liver, lungs and mainstem bronchi, mammary gland, mandibular and mesenteric lymph nodes, nasal cavity, pancreas, parathyroids, pituitary gland, prostate/testes/seminal vesicles or ovaries/uterus, rectum, regional lymph nodes, salivary glands, sciatic nerve, skin, spinal cord, spleen, sternum including marrow, stomach, thyroid gland, thigh muscle, thymus, trachea, and urinary bladder. - Other examinations:
- None
- Statistics:
- see below
Results and discussion
Results of examinations
- Details on results:
- CLINICAL SIGNS
No compound-related clinical signs were recorded.
MORTALITY
Estimates of the probabilities of survival for male and female rats administered test substance at the doses used in these studies and for vehicle controls are shown in Table 1. In male rats, the number of survivors in both the low dose group (after week 88) and the high dose group (after week 82) was significantly lower than that in the vehicle controls (Tables 1&2). The survival of high dose female rats was significantly lower than that of the vehicle controls after week 63 (P<0.05; P<0.01 between weeks 76 and 101). Survival of low dose female rats was comparable to that of the vehicle controls.
BODY WEIGHT AND WEIGHT GAIN
Mean body weights of high dose male rats were 5%-10% lower than those of the vehicle controls between weeks 28 and 76 and 10%-24% lower between weeks 80 and 104 (Table 2). Mean body weights of high dose female rats were 8%-12% lower than those of the vehicle controls after week 80. Mean body weights of low dose male and female rats were comparable to those of the vehicle controls throughout most of the studies.
GROSS PATHOLOGY AND HISTOPATHOLOGY
- Renal effects: administration of test substance to male rats increased the average severity of nephropathy and caused mineralization (calcification) of the collecting tubules in the renal papilla (overall incidences of 12/50; 41/50; 36/49, respectively for the vehicle control, low dose and high dose group), hyperplasia of the transitional epithelium lining the renal pelvis and overlying the renal papilla (0/50; 23/50; 21/49), and focal hyperplasia of the renal tubular epithelium (0/50; 8/50; 9/49).
Administration of test substance to male rats was also associated with the occurrence of rare renal tubular cell adenocarcinomas (0/50; 2/50; 3/49) and papillomas of the transitional epithelium lining the renal pelvis (0/50; 7/50; 3/49); a transitional cell carcinoma occurred in a low dose male rat. There were no tubular cells or transitional cell neoplasms of the kidney in female rats.
- Hematopoietic system effects: The incidence of mononuclear cell leukemia was increased in high dose male rats (10/50; 11/50; 17/50).
- Thyroid gland effects: C-Cell carcinomas, considered a nonfatal tumor, occurred in male rats with a significant positive trend (1/49, 4/50, 4/49); the incidence in the high dose group was significantly greater than that in the vehicle controls, but the incidences of C-cell adenomas (3/49, 0/50, 1/49) or carcinomas (combined; 4/49, 4/50, 5/49) in dosed male rats were not significantly different from that in the vehicle controls by the incidental tumor test.
The incidences of follicular cell adenomas or carcinomas (combined; 0/49, 1/50, 0/49) in dosed male rats were increased by the life table trend test but only marginally by the incidental tumor trend test, the latter being the more appropriate test for nonfatal tumors. The incidences of thyroid gland tumors were not increased in female rats.
- Multiple organs effects: Mesotheliomas in the tunica vaginalis in male rats (0/50, 4/50, 6/50) occurred with a significant, positive trend; however, the incidence of total mesotheliomas at all sites was only marginally increased (2/50, 5/50, 6/50; historical control: 20/250) when analyzed by the incidental, tumor trend, test, and the incidence-of mesotheliomas (all sites) in dosed animals was not greater than the vehicle control incidence in pairwise comparisons with the vehicle controls by the life table test.
- Nasolacrimal duct effects: Chronic inflammation was observed at an increased incidence in high dose male rats (male: vehicle control, 1/50; low dose, 1/50; high dose, 8/50); this lesion was not notably increased in dosed females (0/50; 0/50; 2/50).
Effect levels
open allclose all
- Dose descriptor:
- NOAEL
- Effect level:
- 500 mg/kg bw/day (actual dose received)
- Sex:
- female
- Basis for effect level:
- other: no evidence of carcinogenic activity of test substance was observed for female F344/N rats given doses of 500 or 1000 mg/kg
- Remarks on result:
- other: Effect type: carcinogenicity (migrated information)
- Dose descriptor:
- LOAEL
- Effect level:
- 500 mg/kg bw/day (actual dose received)
- Sex:
- male
- Basis for effect level:
- other: see 'Remark'
- Remarks on result:
- other: Effect type: carcinogenicity (migrated information)
Any other information on results incl. tables
Table 1: Survival of rats in the 2-year gavage study
Sex |
|
0 mg/kg |
500 mg/kg |
1000 mg/kg |
Male |
Animals initially in study |
50 |
50 |
50 |
Non-accidental deaths before termination (a) |
22 |
33 |
45 |
|
Accidentally killed |
1 |
0 |
1 |
|
Killed at termination |
26 |
17 |
4 |
|
Died during termination period |
1 |
0 |
0 |
|
Survival P values (b) |
<0.001 |
<0.031 |
<0.001 |
|
Female |
Animals initially in study |
50 |
50 |
50 |
Non-accidental deaths before termination (a) |
20 |
17 |
27 |
|
Killed at termination |
30 |
32 |
23 |
|
Died during termination period |
0 |
1 |
0 |
|
Survival P values (b) |
0.044 |
0.720 |
0.049 |
|
(a) Includes animals killed in a moribund condition; (b) The result of the life table trend test is in the vehicle control column, and the results of the life table pairwise comparisons with the vehicle controls are in the dosed columns. |
Table 2: Mean body weights and survival (only time period where deaths occurred are presented)
Week on study |
Mean body weights and number of animals still alive at indicated time period |
|||||||||||||||
Vehicle control (0 mg/kg) |
Low dose (500 mg/kg) |
High dose (1000 mg/kg) |
||||||||||||||
Mean BW (g) |
Survivors |
Mean BW (g) |
BW %of control |
Survivors |
Mean BW (g) |
BW %of control |
Survivors |
|||||||||
Male |
Female |
Male |
Female |
Male |
Female |
Male |
Female |
Male |
Female |
Male |
Female |
Male |
Female |
Male |
Female |
|
0 |
163 |
119 |
50 |
50 |
162 |
126 |
99 |
106 |
50 |
50 |
158 |
123 |
97 |
103 |
50 |
50 |
24 |
410 |
213 |
50 |
50 |
408 |
214 |
100 |
100 |
50 |
50 |
392 |
208 |
95 |
98 |
49 |
50 |
36 |
439 |
229 |
49 |
50 |
437 |
225 |
100 |
98 |
50 |
50 |
417 |
223 |
95 |
97 |
49 |
50 |
40 |
450 |
231 |
49 |
50 |
439 |
227 |
98 |
98 |
50 |
50 |
418 |
226 |
93 |
98 |
49 |
49 |
44 |
456 |
238 |
49 |
50 |
448 |
231 |
98 |
97 |
49 |
50 |
425 |
230 |
93 |
97 |
49 |
49 |
48 |
464 |
445 |
49 |
49 |
455 |
236 |
98 |
96 |
49 |
50 |
428 |
235 |
92 |
96 |
49 |
49 |
52 |
467 |
254 |
48 |
49 |
463 |
247 |
99 |
97 |
48 |
50 |
435 |
245 |
93 |
96 |
49 |
49 |
56 |
475 |
262 |
47 |
49 |
468 |
254 |
99 |
97 |
45 |
49 |
438 |
252 |
92 |
96 |
46 |
45 |
60 |
484 |
266 |
43 |
49 |
472 |
258 |
98 |
97 |
41 |
46 |
445 |
254 |
92 |
95 |
43 |
42 |
64 |
487 |
276 |
42 |
49 |
478 |
269 |
98 |
97 |
39 |
46 |
450 |
265 |
92 |
96 |
43 |
42 |
68 |
485 |
283 |
40 |
49 |
480 |
276 |
99 |
98 |
38 |
45 |
445 |
274 |
92 |
97 |
40 |
40 |
72 |
488 |
291 |
40 |
48 |
478 |
283 |
98 |
97 |
37 |
44 |
439 |
277 |
90 |
95 |
37 |
40 |
76 |
487 |
298 |
39 |
48 |
478 |
286 |
98 |
96 |
34 |
44 |
437 |
285 |
90 |
96 |
35 |
37 |
80 |
489 |
303 |
39 |
47 |
477 |
287 |
98 |
95 |
32 |
44 |
434 |
278 |
89 |
92 |
27 |
30 |
84 |
484 |
304 |
38 |
46 |
471 |
294 |
97 |
97 |
30 |
44 |
423 |
276 |
87 |
91 |
24 |
29 |
88 |
479 |
306 |
37 |
44 |
466 |
293 |
97 |
96 |
25 |
44 |
413 |
283 |
86 |
92 |
17 |
27 |
92 |
480 |
310 |
36 |
43 |
468 |
301 |
98 |
97 |
24 |
42 |
406 |
283 |
85 |
91 |
10 |
26 |
96 |
473 |
313 |
35 |
37 |
457 |
296 |
97 |
95 |
23 |
39 |
386 |
281 |
82 |
90 |
10 |
26 |
100 |
468 |
314 |
29 |
34 |
459 |
293 |
98 |
93 |
19 |
35 |
369 |
283 |
79 |
90 |
8 |
24 |
104 |
451 |
318 |
27 |
30 |
416 |
293 |
92 |
92 |
17 |
33 |
343 |
280 |
76 |
88 |
4 |
23 |
BW: body weight |
Applicant's summary and conclusion
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.