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EC number: 278-636-5 | CAS number: 77182-82-2
- 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
Repeated dose toxicity: oral
Administrative data
- Endpoint:
- chronic toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- May 1983 - Jun 1984
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 984
- Report date:
- 1984
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 452 (Chronic Toxicity Studies)
- Version / remarks:
- May 12, 1981
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- Ammonium 2-amino-4-(hydroxymethylphosphinyl)butyrate
- EC Number:
- 278-636-5
- EC Name:
- Ammonium 2-amino-4-(hydroxymethylphosphinyl)butyrate
- Cas Number:
- 77182-82-2
- Molecular formula:
- C5H12NO4P.H3N
- IUPAC Name:
- ammonium 2-amino-4-[hydroxy(methyl)phosphoryl]butanoate
Constituent 1
Test animals
- Species:
- dog
- Strain:
- Beagle
- Details on species / strain selection:
- This system has been selected as an internationally recognized standard non-rodent species.
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: KFM, Kleintierfarm Madoerin AG, 4414 Fuellinsdorf / Switzerland
- Age at study initiation: 4 - 6 months
- Weight at study initiation: 4.2 - 8.0 kg (males), 3.6 - 6.5 kg (females)
- Housing: individually
- Diet (e.g. ad libitum): each dog was provided with 300 grams of repelleted standard Kliba no. 335 dog maintenance diet for 3 hours daily
- Water (e.g. ad libitum): tap water, ad libitum
- Acclimation period: 17 days under test conditions, after veterinary examination
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 +/- 2 °C
- Humidity (%): 55 +/- 10 %
- Air changes (per hr): 20
- Photoperiod (hrs dark / hrs light): 12 h / 12 h
Administration / exposure
- Route of administration:
- oral: feed
- Details on route of administration:
- Peroral ingestion (feeding) was considered the most appropriate route for testing systemic effects of the test article. Therefore, each dog received daily 300 grams of the appropriate test article / diet mixture for the duration of the study. The animals of group 1 (controls) received similar diet without the test article. The feed was available daily for approximately 3 hours. Any remaining feed was weighed to calculate the daily food consumption.
- Vehicle:
- unchanged (no vehicle)
- Details on oral exposure:
- DIET PREPARATION
- Rate of preparation of diet (frequency): twice monthly
- Mixing appropriate amounts with (Type of food): standard Kliba no. 335 dog maintenance diet
- Storage temperature of food: room temperature - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- The stability of the test substance was tested before starting the study. The homogeneity and concentration of the test article in the diet preparations were determined every three months in the analytical laboratory of RCC.
- Duration of treatment / exposure:
- 12 months
- Frequency of treatment:
- daily
Doses / concentrationsopen allclose all
- Dose / conc.:
- 2 mg/kg bw/day (nominal)
- Dose / conc.:
- 5 mg/kg bw/day (nominal)
- Dose / conc.:
- 8.5 mg/kg bw/day (nominal)
- No. of animals per sex per dose:
- 8
- Control animals:
- yes, plain diet
- Details on study design:
- - Dose selection rationale: The dietary route administration was selected in accordance with regulatory requirements for the registration of pesticides to define human health risk.
Examinations
- Observations and examinations performed and frequency:
- MORTALITY / VIABILITY: Yes
- Time schedule: at least twice daily
CLINICAL OBSERVATIONS: Yes
- Time schedule: at least twice daily
BODY WEIGHT: Yes
- Time schedule for examinations: weekly
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- Time schedule: daily
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No
OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: at pretest and after 3, 6, 9 and 12 months
- Dose groups that were examined: all animals
HAEMATOLOGY: Yes
- Time schedule for collection of blood: at pretest and after 1, 3, 6 and 12 months of treatment
- Anaesthetic used for blood collection: No
- Animals fasted: Not specified
- How many animals: all animals
- Parameters examined: erythrocyte count, hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, platelet count, reticulocyte count, nucleated erythrocytes - normoblasts, total leukocyte count, differential leukocyte count, red cell morphology, thromboplastin time, partial thromboplastin time, thrombin time
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at pretest and after 1, 3, 6 and 12 months of treatment
- Animals fasted: Not specified
- How many animals: all animals
- Parameters examined: glucose, urea, creatinine, uric acid, total bilirubin, direct bilirubin, total cholesterol, aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, creatine kinase, alkaline phosphatase, gamma-glutamyl-transferase, ornithine carbamyl-transferase, calcium, phosphorus, sodium, potassium, chloride, total protein, protein electrophoresis, bromosulfophthalein, phenolsulfonphthalein
URINALYSIS: Yes
- Time schedule for collection of urine: at pretest and after 1, 3, 6 and 12 months of treatment
- Metabolism cages used for collection of urine: No
- Animals fasted: Not specified
- Parameters examined: specific gravity, color, appearance, pH, protein, glucose, ketone, bilirubin, blood, nitrite, urobilinogen, urine sediment
NEUROBEHAVIOURAL EXAMINATION: No
IMMUNOLOGY: No
OTHER:
- Hearing Tests: at pretest and after 3, 6, 9 and 12 months
- Examinations of the teeth and mucous membranes: at pretest and after 3, 6, 9 and 12 months
- Electrocardiograms: at pretest, after 6 months and after 12 months
- Bone marrow examinations - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes - Statistics:
- The following statistical methods were used to analyze body weights, food consumption, organ weights and clinical laboratory data:
- Univariate one-way analysis of variance was used to assess the significance of intergroup differences if the variables could be assumed to follow a normal distribution. Student's t-test, based on a pooled variance estimate, was used for intergroup comparisons (i.e. single treatment groups against the control group).
- William's test was used to determine the lowest dose group significantly different from the control group, if a monotone (increasing or decreasing) dose-response relationship existed.
- The difference of the overall mean of the treated groups to the control group was tested for significance if some evidence existed for differences between the treatment groups and the control group, and a monotone dose-response relationship and significant t-test were absent. This is referred to as "significance as a whole" in the results section.
- The median test was used to assess the significance of intergroup differences if the variables were defined on a discrete scale.
- Fisher's exact test for 2 x 2 tables was applied if the variables could be dichotomized without loss of information.
The adjustment for multiple testing was not performed in a formal way (i.e. Bonferoni inequality and subsequently lowering the test level), but rather informally by comparing the expected and observed number of significant results obtained.
Individual values, means, standard deviations and t-statistics were rounded off before printing. For example, t-tests were calculated on the basis of exact values for means and pooled variances and then rounded off to two decimal places. Therefore, two groups may display the same printed means for a given parameter, yet display different t-statistic values with respect to the control group.
Results and discussion
Results of examinations
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- Clinical symptoms were noted in three animals, manifested by trismus, salivation, hyperactivity followed by somnolence and hypoactivity, as well as stereotypic stiff gait, tremor, ataxia, whining, urinating, tonic-clonic spasms, paddling movements, opisthotonus and lateral recombency. These symptoms were observed in male No. 28 on days 9 - 12 and 14, and in females No. 61 on days 9 - 10 and in No. 63 on day 9. Generally, symptoms were noted from 0 - 2 hours after administration. However, in male No. 28, these symptoms were seen 23 hours after the administration on days 11 and 12. Convulsive movements, when observed, persisted for 1 to 5 minutes. Three hours prior to death, male No. 28 showed increased heart rate (> 200 beats/min), dyspnea, decreased body temperature (36.4 degrees centrigrade), reduced corneal reflexes and severe apathy.
In dog No. 47 of group 2, slightly hyperemic areas were noted on the skin of the axillary and abdominal regions, and on the skin of the stifle during weeks 15 - 21. Several times during that seven weeks, the hyperemia observed in the axillary region was more pronounced.
Dog No. 49 of group 3 revealed local alopecia on the ear lobes and alopecia as well as hyperemic skin on all paws from sixth months onwards. After 12 months, alopecia on the paws were widened, and additionally, new areas of slight alopecia were discerned: eye periphery, mandible and thoracic region, the latter also with hyperemic skin.
Both regular and sporadic incidents of soft feces, slight to marked in degree, were observed in all groups. In the males, a reversed dose-related severity was noted (greatest severity in group 1). In the females, the severity was similar in all groups. The feces of some animals from all treated and control groups were observed to contain occasionally traces of mucous and / or blood, but no differences between any group were noted. Sporadic vomiting was noted in some dogs of each group. - Mortality:
- mortality observed, treatment-related
- Description (incidence):
- In group 4, male No. 28 died on day 14, and female No. 63 was found dead on the morning of day 10.
For the two and one days preceding the spontaneous deaths of these animals, respectively, they were observed to have consumed rapidly the entire 300 gram daily feed ration, resulting in abruptly increased test article consumption, whereas they consumed considerably less food during the first 11 or 8 days of treatment, respectively. It is this rapid food (and therefore test article) consumption that is considered to be the cause of the symptoms described below. In dog No. 61 which survived, similar symptoms were observed prior to offering diet but the animal showed almost no food consumption on the day which symptoms were noted and highly decreased food consumption in the days following, although it increased slightly each day. After the initial observation of symptoms on day 9, no further symptoms were noted.
These findings indicate that these animals show individual sensitivity to the high doses of the test article, which seems to demonstrate a narrow dose-response relationship.
All other dogs survived the duration of the study. - Body weight and weight changes:
- effects observed, non-treatment-related
- Description (incidence and severity):
- The mean body weight gains of the treated males, especially group 4, was slightly reduced during the first six months of treatment, when compared with those of the control group.
The abrupt decline of body weight seen in four group 3 male dogs at week 11 was inexplicable, but because of its transient nature, it was considered not to be related to treatment. After 27 weeks of study all male groups and the females of groups 1 and 2 showed an abrupt decline. This was due to the slightly lower body weights of the remaining animals after interim sacrifice. In the females, the mean body weight gains of group 4 was slightly increased when compared with those of the control. - Food consumption and compound intake (if feeding study):
- effects observed, non-treatment-related
- Description (incidence and severity):
- With the exception of the group 4 males during week 1, the mean food consumption of the treated males was comparable to that of the controls. In the females, the mean food consumption of group 2 was decreased, whereas groups 3 and 4 were increased when compared with the control group.
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Somer superficial ocular abnormalities such as small opaque spots, reddened conjunctivae and watery and / or purulent discharge were noted in animals of all groups. These findings were considered to be spontaneous in nature as they are commonly observed in animals of this breed and age.
- Haematological findings:
- no effects observed
- Description (incidence and severity):
- The assessment of hematological data indicated no changes of toxicological significance after 1, 3, 6 and 12 months of treatment.
All differences in the results were considered incidental and of normal biological variation. - Clinical biochemistry findings:
- no effects observed
- Description (incidence and severity):
- The assessment of clinical biochemistry data indicated no changes of toxicological significance after 1, 3, 6 and 12 months of treatment.
All differences in the results were considered incidental and of normal biological variation. - Urinalysis findings:
- no effects observed
- Description (incidence and severity):
- The assessment of urinalysis data indicated no changes of toxicological significance after 1, 3, 6 and 12 months of treatment.
All differences in the results were considered incidental and of normal biological variation. - Behaviour (functional findings):
- not examined
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Description (incidence and severity):
- With the exception of a few statistically significant changes in organ weights and organ weight ratios which were considered to be incidental and of no toxicological relevance, there were no changes in absolute and relative organ weights.
- Gross pathological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- In the male that died spontaneously, the main gross lesions were increased fluid in the pericardium and subendocardial hemorrhages in the right heart.
In the female that died spontaneously, the main gross findings were numerous gray-green foci in the lung; the lung was not collapsed.
In the dogs killed on schedule, a number of gross lesions were observed at a random incidence in various organs. - Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- Heart
In both dogs that died during the study, multifocal myocardial necrosis was noted. This necrosis was marked and multi-cellular in the male dog (No. 28), with beginning granulocytic infiltration, and it was accompanied by hemorrhages and diffuse microvesicular lipid deposition. In the female (No. 63), the necrosis was slight and mainly unicellular without granulocytic reaction.
Lungs
Marked aspiration of diet material with beginning inflammatory reaction was noted in the female dog (No. 63) that died during the study. Bronchi and bronchioli were markedly filled with foreign material, and the bronchial epithelium was completely desquamated and necrotic.
Stomach
In the female (No. 63) that died during the study, a small acute ulcer was seen in the pyloric mucosa. This lesion corresponded to the red focus described at necropsy.
Other organs / tissues
After the 6-month and the 12-month administration period, a number of common findings were noted in various organs. The type, incidence, and severity of these lesions were similar in the treated dogs and in the controls. - Other effects:
- no effects observed
- Description (incidence and severity):
- - Hearing tests: No change of the auditory perception was noted.
- Examinations of teeth and mucous membranes: No change in the teeth or mucous membranes was noted.
- Electrocardiogram: All findings observed in this study were spontaneous in nature, except for P pulmonale in male No. 26 (group 4) which was possibly test article-related. The cause of the P pulmonale after 12 months treatment in animal No. 26 can not be determined, whether it is test article-related or spontaneous. There were, however, no similar findings in any other animal of this group, so that the P pulmonale could be considered spontaneous (developing tricuspid dysplasia) rather than test article-related. The heart rhythm changes, such as atrioventricular blocks (first and second degree) caused by excessive vagal activity during the respiratory arrhythmia, as well as sinus tachycardia - the most common primary heart arrhythmia - caused by excitation, are findings which occur frequently in clinically healthy Beagle dogs. Two dogs of group 4 which died suddenly on day 10 and 14, were not electrocardiographically examined prior to death. A slight decrease in heart rate within the normal range was observed in groups 2 and 3, more distinct in group 4 after six months of treatment. After 12 months of treatment, no dose related changes in the heart rate could be seen. Statistically significant differences between pretest and 6 or 12 months values in some ECG parameters were of limited biological relevance, because they occurred in control and treated groups. Based on these findings there was no indication of cardiotoxic effects.
- Bone Marrow Examination: The cells of the erythro-, granulo- and thrombopoietic system and the other cells of the animals sacrificed at 6 and 12 months showed no relevant test article-related quantitative or qualitative changes. No biologically relevant differences were noted between the control group and group 4.
Effect levels
open allclose all
- Dose descriptor:
- NOEL
- Effect level:
- 4.5 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: absence of effects
- Dose descriptor:
- NOAEL
- Effect level:
- 8.4 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: neurological signs, circulatory failure in 2 animals
Target system / organ toxicity
- Critical effects observed:
- not specified
Any other information on results incl. tables
Table 1: Food Consumption (g/animal/day) Treatment / Males
|
Group 1 |
Group 2 |
Group 3 |
Group 4 |
Week 1 |
266 |
253 |
249 |
218 |
Week 2 |
284 |
271 |
275 |
245 |
Week 3 |
290 |
276 |
287 |
285 |
Week 4 |
291 |
284 |
289 |
286 |
Week 5 |
278 |
279 |
289 |
279 |
Week 6 |
294 |
292 |
291 |
280 |
Week 7 |
295 |
299 |
300 |
289 |
Week 8 |
297 |
298 |
298 |
285 |
Week 9 |
300 |
300 |
300 |
289 |
Week 10 |
292 |
300 |
298 |
283 |
Week 11 |
288 |
300 |
299 |
287 |
Week 12 |
292 |
299 |
300 |
289 |
Week 13 |
298 |
300 |
300 |
285 |
Week 14 |
296 |
300 |
299 |
288 |
Week 15 |
298 |
298 |
300 |
290 |
Week 16 |
297 |
300 |
300 |
289 |
Week 17 |
297 |
299 |
300 |
290 |
Week 18 |
294 |
300 |
300 |
286 |
Week 19 |
295 |
300 |
300 |
291 |
Week 20 |
300 |
300 |
300 |
290 |
Week 21 |
296 |
299 |
300 |
288 |
Week 22 |
298 |
300 |
300 |
289 |
Week 23 |
297 |
300 |
300 |
292 |
Week 24 |
296 |
300 |
300 |
290 |
Week 25 |
292 |
297 |
300 |
284 |
Week 26 |
293 |
300 |
30 |
287 |
Week 27 |
286 |
297 |
300 |
289 |
Week 28 |
294 |
300 |
300 |
281 |
Week 29 |
293 |
300 |
300 |
282 |
Week 30 |
292 |
300 |
300 |
285 |
Week 31 |
293 |
300 |
300 |
276 |
Week 32 |
281 |
300 |
300 |
283 |
Week 33 |
289 |
300 |
300 |
282 |
Week 34 |
289 |
300 |
300 |
285 |
Week 35 |
283 |
300 |
300 |
274 |
Week 36 |
296 |
300 |
300 |
284 |
Week 37 |
286 |
300 |
300 |
287 |
Week 38 |
273 |
300 |
300 |
285 |
Week 39 |
283 |
300 |
300 |
279 |
Week 40 |
293 |
300 |
300 |
278 |
Week 41 |
284 |
300 |
300 |
282 |
Week 42 |
280 |
300 |
300 |
283 |
Week 43 |
290 |
300 |
300 |
281 |
Week 44 |
295 |
300 |
300 |
292 |
Week 45 |
293 |
300 |
300 |
279 |
Week 46 |
285 |
300 |
300 |
280 |
Week 47 |
284 |
300 |
300 |
275 |
Week 48 |
236 |
300 |
289 |
280 |
Week 49 |
268 |
300 |
300 |
281 |
Week 50 |
283 |
300 |
297 |
283 |
Week 51 |
271 |
300 |
300 |
278 |
Week 52 |
275 |
297 |
300 |
278 |
Week 53 |
289 |
300 |
300 |
277 |
Treatment mean |
288 |
297 |
297 |
282 |
Table 2: Food Consumption (g/animal/day) Treatment / Females
|
Group 1 |
Group 2 |
Group 3 |
Group 4 |
Week 1 |
238 |
208 |
243 |
212 |
Week 2 |
256 |
233 |
254 |
244 |
Week 3 |
251 |
236 |
269 |
273 |
Week 4 |
251 |
230 |
285 |
276 |
Week 5 |
253 |
211 |
281 |
268 |
Week 6 |
253 |
240 |
289 |
285 |
Week 7 |
278 |
247 |
288 |
291 |
Week 8 |
269 |
255 |
281 |
282 |
Week 9 |
272 |
268 |
283 |
290 |
Week 10 |
269 |
253 |
284 |
289 |
Week 11 |
281 |
256 |
289 |
286 |
Week 12 |
273 |
251 |
291 |
294 |
Week 13 |
271 |
249 |
288 |
287 |
Week 14 |
281 |
250 |
285 |
289 |
Week 15 |
283 |
260 |
285 |
287 |
Week 16 |
279 |
263 |
289 |
290 |
Week 17 |
280 |
257 |
288 |
291 |
Week 18 |
277 |
257 |
293 |
292 |
Week 19 |
284 |
264 |
292 |
294 |
Week 20 |
287 |
249 |
294 |
291 |
Week 21 |
270 |
241 |
288 |
287 |
Week 22 |
280 |
267 |
292 |
292 |
Week 23 |
284 |
262 |
291 |
298 |
Week 24 |
285 |
256 |
292 |
292 |
Week 25 |
279 |
241 |
283 |
287 |
Week 26 |
272 |
240 |
284 |
293 |
Week 27 |
255 |
233 |
287 |
284 |
Week 28 |
267 |
227 |
291 |
293 |
Week 29 |
260 |
226 |
299 |
294 |
Week 30 |
269 |
217 |
300 |
300 |
Week 31 |
262 |
207 |
300 |
300 |
Week 32 |
266 |
199 |
295 |
283 |
Week 33 |
262 |
205 |
280 |
272 |
Week 34 |
245 |
216 |
282 |
272 |
Week 35 |
260 |
206 |
287 |
288 |
Week 36 |
275 |
225 |
294 |
293 |
Week 37 |
258 |
223 |
292 |
296 |
Week 38 |
264 |
243 |
292 |
298 |
Week 39 |
249 |
221 |
264 |
284 |
Week 40 |
247 |
244 |
288 |
300 |
Week 41 |
231 |
229 |
277 |
295 |
Week 42 |
251 |
230 |
276 |
300 |
Week 43 |
252 |
233 |
283 |
300 |
Week 44 |
259 |
245 |
299 |
300 |
Week 45 |
255 |
221 |
290 |
300 |
Week 46 |
257 |
226 |
289 |
300 |
Week 47 |
256 |
216 |
277 |
300 |
Week 48 |
252 |
218 |
280 |
300 |
Week 49 |
246 |
214 |
281 |
300 |
Week 50 |
245 |
222 |
288 |
300 |
Week 51 |
239 |
208 |
285 |
300 |
Week 52 |
248 |
199 |
271 |
300 |
Week 53 |
244 |
195 |
276 |
300 |
Treatment mean |
263 |
234 |
285 |
289 |
Table 3: Body Weights (gram) Treatment / Males
|
Group 1 |
Group 2 |
Group 3 |
Group 4 |
Day 3 Week 1 |
6842 |
6621 |
6532 |
6397 |
Day 10 Week 2 |
7118 |
6844 |
6641 |
6361 |
Day 17 Week 3 |
7418 |
7108 |
6961 |
6730 |
Day 24 Week 4 |
7705 |
7382 |
7222 |
6977 |
Day 31 Week 5 |
7814 |
7533 |
7495 |
7095 |
Day 38 Week 6 |
8014 |
7694 |
7637 |
7232 |
Day 45 Week 7 |
8210 |
7913 |
7769 |
7431 |
Day 52 Week 8 |
8294 |
8084 |
7953 |
7461 |
Day 59 Week 9 |
8479 |
8222 |
8149 |
7590 |
Day 66 Week 10 |
8415 |
8584 |
8317 |
7805 |
Day 73 Week 11 |
8712 |
8500 |
7780 |
7896 |
Day 80 Week 12 |
8923 |
8572 |
8559 |
8011 |
Day 87 Week 13 |
9118 |
8713 |
8807 |
8049 |
Day 94 Week 14 |
9209 |
8763 |
8789 |
8149 |
Day 101 Week 15 |
9352 |
8844 |
8856 |
8245 |
Day 108 Week 16 |
9452 |
8921 |
9026 |
8349 |
Day 115 Week 17 |
9551 |
9094 |
9082 |
8443 |
Day 122 Week 18 |
9659 |
9174 |
9203 |
8526 |
Day 129 Week 19 |
9729 |
9268 |
9263 |
8586 |
Day 136 Week 20 |
9842 |
9364 |
9343 |
8611 |
Day 143 Week 21 |
9987 |
9388 |
9381 |
8690 |
Day 150 Week 22 |
10026 |
9467 |
9401 |
8672 |
Day 157 Week 23 |
10055 |
9502 |
9505 |
8763 |
Day 164 Week 24 |
10133 |
9587 |
9596 |
8829 |
Day 171 Week 25 |
10102 |
9602 |
9682 |
8890 |
Day 178 Week 26 |
10229 |
9718 |
9690 |
8910 |
Day 185 Week 27 |
10159 |
9691 |
9661 |
8861 |
Day 192 Week 28 |
9671 |
9425 |
9309 |
8363 |
Day 199 Week 29 |
9767 |
9383 |
9306 |
8457 |
Day 206 Week 30 |
9795 |
9348 |
9322 |
8516 |
Day 213 Week 31 |
9845 |
9433 |
9411 |
8561 |
Day 220 Week 32 |
9876 |
9448 |
9485 |
8703 |
Day 227 Week 33 |
9928 |
9475 |
9453 |
8727 |
Day 234 Week 34 |
9961 |
9435 |
9368 |
8691 |
Day 241 Week 35 |
9929 |
9552 |
9377 |
8725 |
Day 248 Week 36 |
9982 |
9567 |
9419 |
8736 |
Day 255 Week 37 |
10086 |
9599 |
9444 |
8620 |
Day 262 Week 38 |
10036 |
9625 |
9516 |
8879 |
Day 269 Week 39 |
10091 |
9690 |
9575 |
8987 |
Day 276 Week 40 |
10287 |
9863 |
9801 |
9055 |
Day 283 Week 41 |
10281 |
9785 |
9839 |
9158 |
Day 290 Week 42 |
10239 |
9866 |
9997 |
9226 |
Day 297 Week 43 |
10332 |
9899 |
9917 |
9239 |
Day 304 Week 44 |
10244 |
9898 |
10004 |
9304 |
Day 311 Week 45 |
10310 |
9975 |
10002 |
9286 |
Day 318 Week 46 |
10376 |
9902 |
9960 |
9248 |
Day 325 Week 47 |
10497 |
10008 |
10204 |
9270 |
Day 332 Week 48 |
10361 |
10054 |
10100 |
9323 |
Day 339 Week 49 |
10262 |
10063 |
9927 |
9338 |
Day 346 Week 50 |
10130 |
10058 |
10045 |
9347 |
Day 353 Week 51 |
10202 |
10000 |
10074 |
9349 |
Day 360 Week 52 |
10124 |
10035 |
9989 |
9423 |
Day 367 Week 53 |
10138 |
9970 |
9929 |
9434 |
Table 4: Body Weights (gram) Treatment / Females
|
Group 1 |
Group 2 |
Group 3 |
Group 4 |
Day 3 Week 1 |
5214 |
5046 |
5345 |
5230 |
Day 10 Week 2 |
5520 |
5210 |
5538 |
5538 |
Day 17 Week 3 |
5734 |
5525 |
5779 |
5954 |
Day 24 Week 4 |
5893 |
5698 |
6066 |
6314 |
Day 31 Week 5 |
6060 |
5656 |
6268 |
6540 |
Day 38 Week 6 |
6119 |
5784 |
6445 |
6694 |
Day 45 Week 7 |
6416 |
5908 |
6726 |
7055 |
Day 52 Week 8 |
6553 |
6163 |
6788 |
7054 |
Day 59 Week 9 |
6608 |
6371 |
6943 |
7284 |
Day 66 Week 10 |
6718 |
6495 |
7035 |
7478 |
Day 73 Week 11 |
6902 |
6616 |
7141 |
7589 |
Day 80 Week 12 |
6984 |
6677 |
7253 |
7759 |
Day 87 Week 13 |
7077 |
6773 |
7423 |
7882 |
Day 94 Week 14 |
7203 |
6801 |
7446 |
7980 |
Day 101 Week 15 |
7171 |
6882 |
7508 |
8034 |
Day 108 Week 16 |
7375 |
6994 |
7609 |
8194 |
Day 115 Week 17 |
7458 |
7110 |
7650 |
8344 |
Day 122 Week 18 |
7468 |
7173 |
7780 |
8405 |
Day 129 Week 19 |
7602 |
7238 |
7802 |
8441 |
Day 136 Week 20 |
7645 |
7261 |
7853 |
8489 |
Day 143 Week 21 |
7735 |
7257 |
7906 |
8524 |
Day 150 Week 22 |
7785 |
7339 |
7907 |
8577 |
Day 157 Week 23 |
7863 |
7384 |
7976 |
8651 |
Day 164 Week 24 |
7877 |
7490 |
8076 |
8732 |
Day 171 Week 25 |
7967 |
7459 |
8105 |
8781 |
Day 178 Week 26 |
7980 |
7475 |
8157 |
8882 |
Day 185 Week 27 |
7900 |
7343 |
8210 |
8741 |
Day 192 Week 28 |
7312 |
6708 |
8277 |
9029 |
Day 199 Week 29 |
7388 |
6867 |
8332 |
9033 |
Day 206 Week 30 |
7430 |
6954 |
8286 |
9110 |
Day 213 Week 31 |
7490 |
6826 |
8395 |
9243 |
Day 220 Week 32 |
7559 |
6735 |
8413 |
9225 |
Day 227 Week 33 |
7723 |
6919 |
8422 |
9191 |
Day 234 Week 34 |
7566 |
6956 |
8434 |
9044 |
Day 241 Week 35 |
7580 |
6912 |
8435 |
9062 |
Day 248 Week 36 |
7712 |
7006 |
8467 |
9126 |
Day 255 Week 37 |
7785 |
7141 |
8540 |
9153 |
Day 262 Week 38 |
7782 |
7225 |
8532 |
9183 |
Day 269 Week 39 |
7862 |
7255 |
8489 |
9138 |
Day 276 Week 40 |
7976 |
7304 |
8613 |
9281 |
Day 283 Week 41 |
7844 |
7241 |
8531 |
9304 |
Day 290 Week 42 |
7909 |
7225 |
8508 |
9472 |
Day 297 Week 43 |
7912 |
7356 |
8460 |
9470 |
Day 304 Week 44 |
7906 |
7344 |
8562 |
9463 |
Day 311 Week 45 |
7869 |
7296 |
8509 |
9444 |
Day 318 Week 46 |
7880 |
7405 |
8541 |
9494 |
Day 325 Week 47 |
7977 |
7324 |
8544 |
9513 |
Day 332 Week 48 |
7989 |
7415 |
8631 |
9542 |
Day 339 Week 49 |
7926 |
7382 |
8498 |
9564 |
Day 346 Week 50 |
7927 |
7538 |
8502 |
9589 |
Day 353 Week 51 |
7762 |
7316 |
8465 |
9611 |
Day 360 Week 52 |
7890 |
7392 |
8499 |
9646 |
Day 367 Week 53 |
7845 |
7305 |
8507 |
9743 |
Table 5: Organ Weights (gram) after 6 months / Males
|
Group 1 |
Group 2 |
Group 3 |
Group 4 |
Body weight |
10650 |
9908 |
9918 |
9433 |
Brain |
71.9 |
77.6 |
71.4 |
72.9 |
Heart |
91.1 |
84.5 |
82.2 |
81.7 |
Liver |
283.5 |
254.8 |
239.4 |
238.4 |
Lung |
94.9 |
81.3 |
79.6 |
82.8 |
Kidneys |
46.79 |
49.18 |
46.43 |
51.59 |
Spleen |
43.51 |
30.82 |
36.79 |
28.35 |
Testes |
15.61 |
14.90 |
14.23 |
13.71 |
Adrenals |
1.10 |
1.07 |
1.09 |
1.17 |
Pituitary |
0.064 |
0.058 |
0.051 |
0.065 |
Thyroid |
0.82 |
0.78 |
0.70 |
0.67 |
Thymus |
7.61 |
5.22 |
4.04 |
5.66 |
Table 6: Organ Weights (gram) after 6 months / Females
|
Group 1 |
Group 2 |
Group 3 |
Group 4 |
Body weight |
8015 |
7348 |
7810 |
7850 |
Brain |
66.8 |
63.9 |
66.4 |
69.6 |
Heart |
65.5 |
66.2 |
66.7 |
71.8 |
Liver |
258.9 |
222.8 |
252.9 |
233.8 |
Lung |
63.3 |
61.8 |
69.8 |
73.2 |
Kidneys |
33.93 |
31.97 |
34.73 |
34.43 |
Spleen |
28.72 |
20.41 |
22.94 |
28.01 |
Ovaries |
1.361 |
1.185 |
0.962 |
1.095 |
Adrenals |
1.09 |
1.12 |
1.02 |
0.97 |
Pituitary |
0.050 |
0.050 |
0.055 |
0.047 |
Thyroid |
0.67 |
0.50 |
0.65 |
0.55 |
Thymus |
5.98 |
5.04 |
6.19 |
4.39 |
Table 7: Organ Weights (gram) after 12 months / Males
|
Group 1 |
Group 2 |
Group 3 |
Group 4 |
Body weight |
9688 |
9300 |
9275 |
8913 |
Brain |
76.4 |
75.4 |
76.6 |
80.3 |
Heart |
94.7 |
90.1 |
87.7 |
87.1 |
Liver |
243.9 |
249.0 |
244.2 |
246.5 |
Lung |
76.6 |
87.3 |
79.4 |
71.1 |
Kidneys |
48.34 |
55.17 |
45.96 |
42.88 |
Spleen |
28.72 |
29.54 |
24.84 |
28.31 |
Testes |
13.05 |
14.86 |
14.27 |
14.25 |
Adrenals |
0.95 |
1.31 |
1.39 |
1.26 |
Pituitary |
0.060 |
0.067 |
0.057 |
0.053 |
Thyroid |
0.77 |
0.90 |
0.74 |
0.75 |
Thymus |
7.05 |
5.80 |
5.57 |
4.97 |
Table 8: Organ Weights (gram) after 12 months / Females
|
Group 1 |
Group 2 |
Group 3 |
Group 4 |
Body weight |
7310 |
6900 |
8000 |
9040 |
Brain |
66.2 |
67.1 |
72.4 |
74.1 |
Heart |
66.6 |
61.6 |
74.2 |
78.4 |
Liver |
219.9 |
199.3 |
227.3 |
290.6 |
Lung |
58.6 |
54.1 |
72.7 |
72.7 |
Kidneys |
35.31 |
31.48 |
36.40 |
43.03 |
Spleen |
35.34 |
26.59 |
26.99 |
30.24 |
Ovaries |
0.951 |
1.299 |
1.324 |
1.644 |
Adrenals |
1.19 |
1.15 |
1.47 |
1.22 |
Pituitary |
0.063 |
0.043 |
0.063 |
0.072 |
Thyroid |
0.63 |
0.62 |
0.61 |
0.80 |
Thymus |
4.88 |
4.48 |
4.98 |
7.00 |
Applicant's summary and conclusion
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