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EC number: 245-524-2 | CAS number: 23251-72-1
- 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
Endpoint summary
Administrative data
Description of key information
No relevant data are available on DEA acetate, but reliable 28-day oral gavage studies have been carried out on structurally-related read-across compounds. NOAELs of 150 and 1000 mg/kg bw/day were reported for RA1 and RA2, respectively.
Key value for chemical safety assessment
Repeated dose toxicity: via oral route - systemic effects
Link to relevant study records
- Endpoint:
- short-term repeated dose toxicity: oral
- Type of information:
- migrated information: read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- weight of evidence
- Study period:
- 1999-08-11 to 1999-09-15
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: The study is the result of a structural analogue substance used as read-across substance. Study is conducted according to Guidelines in a GLP certified laboratory.
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- EU Method B.7 (Repeated Dose (28 Days) Toxicity (Oral))
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
- Species:
- rat
- Strain:
- Wistar
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: RCC Ltd, Biotechnology & Animal Breeding Division CH-4414 Fullinsdorf/Switzerland
- Age at study initiation: 7 Weeks (6 weeks old on delivery, 1 week of Acclimatization)
- Weight at study initiation: At Acclimatization (Males = 122 - 158 grams (Mean 137 grams)) (Females = 102 - 127 grams (Mean 114 grams))
- Fasting period before study: None
- Housing: In groups of five in Makrolon type-4 cages with wire mesh tops and standardised softwood bedding.
- Diet: Pelleted standard Provimi Kliba 3433 rat maintenance diet was available ad libitum. The feed batch was analysed for contaminants
- Water: Community tap water from Itingen was avaible ad libitum in water bottles
- Acclimation period: Under test conditions after health examination. Only animals without any visible signs of illness were used for the study.
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3 ºC
- Humidity (%): 40 - 70 %
- Air changes (per hr): 10 - 15 air changes per hour
- Photoperiod (hrs dark / hrs light): 12 hours fluorescent light / 12 hours dark
IN-LIFE DATES: From: 11th August 1999 To: 15 September 1999 - Route of administration:
- oral: gavage
- Vehicle:
- water
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS:
The test article formulations were prepared weekly.
RA1 was weighed into a tared glass beaker on a Mettler balance and the vehicle assed (weight:volume). The mixtures were then prepared using a magnetic stirrer and stored at room temperature (17 – 23ºC).
Homogeneity of the test article in the vehicle was maintained during the daily administration period using a magnetic stirrer.
DIET PREPARATION
- Rate of preparation of diet: Prepared weekly
- Mixing appropriate amounts with: Pelleted standard Provimi Kliba 3433 rat maintenance diet
- Storage temperature of food: Room temperature 17 - 23ºC
VEHICLE
- Concentration in vehicle: The test substance was administered to groups 1-4 at dose levels of 0, 30, 150 and 750 mg/kg body weight, respectively.
- Amount of vehicle (if gavage): 10 ml/kg body weight - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Concentration, homogeneity and stability (after 2 hours and 7 days) of the dose formulations were determined in samples taken during acclimatisation. Concentration and homogeneity of the dose formulations were determined in samples taken during week 3 of the treatment. The analyses were performed using a GC method.
- Duration of treatment / exposure:
- 28 days
- Frequency of treatment:
- Dose was administered every day
- Remarks:
- Doses / Concentrations:
0, 30, 150 and 750 mg/kg/day
Basis:
nominal in water - No. of animals per sex per dose:
- 5 males and 5 females were in each group
Group 1 (Control): 0 mg/kg/day
Group 2: 30 mg/kg/day
Group 3: 150 mg/kg/day
Group 4: 750 mg/kg/day - Control animals:
- yes
- Details on study design:
- The purpose of this oral toxicity study was to assess the cumulative toxicity of RA1 when administered daily to rats by gavage for a period of 28 days. This study should provide a rational basis for toxicological risk assessment in man. The results of this study should indicate potential target organs and should identify chemicals with neurotoxic potential.
Dose selection rationale:
Basd upon the results of a non-GLP 5 day dose range-finding study in which RA1 was administered by gavage to 2 rats per group and sex. Animals showed marked organ weight changes (spleen) at 600 mg/kg bw/day (males only) and 1000 mg/kg bw/day (both sexes). - Positive control:
- Not required.
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: The animals were observed for mortality/morbidity twice daily. The animals were observed for clinical signs once before commencement of administration, twice daily on days 1-3 (ca. 1 and 3 hours after administration), as well as once daily on days 4-28 (ca. 1 hour after administration).
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Weekly
The animals were observed in their home cages, outside their home cages in a standard arena and in the hand. These observations were performed in random sequence once before commencement of administration and once weekly thereafter.
BODY WEIGHT: Body weights were recorded weekly during pretest, treatment and before necropsy, using an on-line electronic recording system consisting of a Mettler balance connected to the RCC computer. Please see Table 6 and 7
- Time schedule for examinations: Weekly
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg bw/day: The food consumption was recorded once during the pretest period and weekly thereafter, using an on-line electronic recording system consisting of a Mettler balance connected to a computer. Please see Tables 4 and 5
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No
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
OPHTHALMOSCOPIC EXAMINATION: No
HAEMATOLOGY: Yes
- Time schedule for collection of blood: Blood samples were collected early in the working day to reduce biological variation caused by circadian rhythms. Blood samples were drawn from the retro-orbital plexus using a micro-hematocrit glass capillary tube
- Anaesthetic used for blood collection: Yes Blood samples for hematology were collected from all animals under light ether anesthesia.
- Animals fasted: Yes the animals were fasted for approximately 18 hours before blood sampling but allowed access to water ad libitum.
- How many animals: All 20 animals
- Parameters checked in table [No.?] were examined.
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: Blood samples were collected early in the working day to reduce biological variation caused by circadian rhythms. Blood samples were drawn from the retro-orbital plexus using a micro-hematocrit glass capillary tube
- Animals fasted: Yes the animals were fasted for approximately 18 hours before blood sampling but allowed access to water ad libitum.
- How many animals: All 20 animals
- Parameters checked in table [No.?] were examined.
URINALYSIS: No .
FUNCTIONAL OBSERVATIONAL BATTERY:
During week 4, relevant parameters from a modified Irwin screen test were evalueated in all animals. Forelimb and hind limb grip strength measurements were performed using a push-pull strain gauge. The animals were placed with the forepaws inside a triangular grsaping ring and with the hind paws outside a triangular grasping ring. Using one hand, the animals were held towards the base of the tail and steadily pulled away or towards the ring until the grip was broken. Each measurement was repeated three times.
Locomotor activity was measured quantitatively with Activity Monitor AM 1052 system. Animals were randomised and monitored during the fourth treatment week for a 60 minute period and the total activity of this time period was recorded.
- Sacrifice and pathology:
- GROSS PATHOLOGY: Yes After 4 weeks all animals were weighed and necropsied. Descriptions of all macroscopic abnormalities were recorded. Necropsies were performed by experienced prosectors supervised by an experienced veterinary pathologist. All animals were anesthetized by intraperitoneal injection of sodium pentobarbitone and killed by exsanguinations. Samples of the following tissues and organs were collected at necropsy and fixed in neutral phosphate buffered 4 % formaldehyde solution: adrenal glands, aorta, bone (sternum, femur), bone marrow (femur), brain (cerebrum, cerebellum, pons), cecum, colon, duodenum, epididymides, eyes with optic nerve, Harderian gland, heart, ileum (with Peyer's patches), jejunum with Peyer's patches, kidneys, larynx, lacrimal gland (exorbital), liver, lungs, lymph nodes (mesenteric, mandibular), mammary gland are, nasal cavity, oesophagus, ovaries, pancreas, pituitary, prostate gland, rectum, salivary glands, sciatic nerve, seminal vesicles, skeletal muscle, skin spinal cord, spleen, stomach, testes, thymus, thyroid, tongue, trachea, urinary bladder, uterus, vagina and gross lesions.
HISTOPATHOLOGY: Slides of the following organs and tissues were processed, embedded and slides at 2 to 4 micrometers, stained with H&E, and were examined by a pathologist: adrenal glands, bone marrow (femur), brain (cerebrum, cerebellum, pons), cecum, colon, duodenum, epididymides, heart, ileum (with Peyer's patches), jejunum with Peyer's patches, kidneys, liver, lungs, lymph nodes (mesenteric, mandibular), ovaries, prostate gland, rectum, sciatic nerve, seminal vesicles, spinal cord, spleen, stomach, testes, thymus, thyroid, trachea, urinary bladder, uterus, vagina and gross lesions.
OTHER: The following organ weights were recorded on the scheduled date of necropsy: brain, heart, liver, thymus, kidneys, adrenals, spleen, testes, epididymides. The organ to terminal body weight ratios as well as organ to brain weight ratios were determined. The determination of the terminal body weight was performed immediately prior to necropsy. - Statistics:
- The following statistical methods were used to analyse the cody weights, organs, and all ratios as well as clinical laboratory data:
If the variables could be assumed to follow a normal distribution, the Dunnett-test (many to one-t-test) based on a pool variance estimate was applied for the comparison between the treated groups and the control groups for each sex.
The Steel-test (many-one rank test) was applied when the data could not be assumed to follow a normal distribution.
The Fisher's exact test was applied to macroscopial findings.
T-test was applied to grip strength and locomotor activity - Clinical signs:
- no effects observed
- Mortality:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- no effects observed
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not specified
- Ophthalmological findings:
- not specified
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- effects observed, treatment-related
- Description (incidence and severity):
- The total cholesterol and phospholipid levels were marginally lower in males and females treated at 750 mg/kg bw/day when compared with those of the controls. Plasma sodium and chloride levels were slightly raised in females in the 750 mg/kg bw/day group
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- effects observed, treatment-related
- Description (incidence and severity):
- Locomotor Activity: A test article-related reduction in mean locomotor activity was noted in males (-9.3 %) and females (-30.7 %) treated with 750 mg/kg/day when compared with that of the control females.
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- Marginally higher relative kidney weights were noted in females treated at 750 mg/kg bw/day
- Gross pathological findings:
- no effects observed
- Histopathological findings: non-neoplastic:
- no effects observed
- Histopathological findings: neoplastic:
- no effects observed
- Details on results:
- CLINICAL SIGNS AND MORTALITY:
No effects (All animals survived the study period. There were no clinical signs in any dose group.)
BODY WEIGHT AND WEIGHT GAIN:
No effects (body weight was unaffected by treatment with the test article)
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
No effects
FOOD EFFICIENCY
Not examined
HAEMATOLOGY:
No effects
CLINICAL CHEMISTRY:
The total cholesterol and phospholipids levels were marginally lower in the males and females treated at 750 mg/kg/day when compared with those of the controls. These findings were considered to be indicative of minor changes in lipid metabolism.
The plasma sodium and chloride levels were slightly elevated in females treated with 750 mg/kg/day when compared with the control females. Although these findings were not seen in males, a relationship with treatment could not be excluded.
All other clinical biochemistry parameters of test article-treated animals were similar to those of the controls.
URINALYSIS
Not examined
FUNCTIONAL OBSERVATIONAL BATTERY:
No clinical signs or abnormal behaviour were evident in any animals during treatment week 4.
Grip Strength: The mean grip strength of the test article-treated animals compared favourably with those of the control animals.
Locomotor Activity: A test article-related reduction in mean locomotor activity was noted in males (-9.3 %) and females (-30.7 %) treated with 750 mg/kg/day when compared with that of the control females. Marginally, lower locomotor activity (-4.6 %) was noted in the females treated with 150 mg/kg/day, but these differences were considered to be within the range of normal variation and unrelated to the treatment with the test article.
ORGAN WEIGHTS:
The slightly higher (and statistically significant when compared to control females, p<0.05) kidney to body weight ratio of females treated at 750 mg/kg/day was considered to be a test article-related change.
The remaining organ weights were considered to be unaffected by treatment when compared with the control values.
GROSS PATHOLOGY:
There were no macroscopic findings which were considered to distinguish treated rats from control rats.
HISTOPATHOLOGY: NON-NEOPLASTIC:
A number of findings were noted in the organs/tissues examined. They were comparable to those occurring spontaneously in rats of the same strain and age, and their incidence, severity and morphologic appearance did not distinguish treated rats from control rats. - Dose descriptor:
- NOAEL
- Effect level:
- ca. 150 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: see 'Remark'
- Critical effects observed:
- not specified
- Conclusions:
- Based on the results of this 28-day gavage study in rats, 150 mg/kg bw/day of RA1 was established as the study no-observed-adverse-effect level (NOAEL).
- Executive summary:
In this sub-acute toxicity study, RA1 was administered daily by oral gavage to SPF-bred Wistar rats of both sexes at dose levels of 30, 150 and 750 mg/kg bw/day for a period of 28 days. A control group was treated concurrently with the vehicle only.
The groups comprised 5 animals per sex which were sacrificed after 28 days of treatment.
Clinical signs, outside cage observation, food consumption and body weights were recorded periodically during pre-test and treatment periods. Functional observational battery, locomotor activity and grip strength were performed during week 4.
At the end of the dosing period, blood samples were withdrawn for haematology and plasma chemistry analyses. All animals were killed, necropsied and examined post mortem. Histological examinations were performed on organs and tissues (including those of the reproductive system) from all control and high dose animals, and all gross lesions from all animals.
The results are summarised as follows:
Mortality
All animals survived the study period
Clinical signs
No clinical signs were observed
Food consumption
There were no effects of the test substance on food consumption
Organ weights, gross pathology and histopathology
No treatment-reated effects observed
Clinical laboratory investigations
There were no effects of the test substance on the haematology parameters measured.
In a clinical chemistry examination, the total cholesterol and phospholipids levels were found to be marginally lower in the males and females treated at 750 mg/kg bw/day when compared with those of the controls. These findings were considered to be indicative of minor changes in lipid metabolism. The plasma sodium and chloride levels were slightly elevated in females treated with 750 mg/kg/day when compared with the control females. Although these findings were not seen in males, a relationship with treatment could not be excluded.
All other clinical biochemistry parameters of test article-treated animals were similar to those of the controls.
Functional observations
A test article-related reduction in mean locomotor activity was noted in males (-9.3 %) and females (-30.7 %) treated with 750 mg/kg bw/day when compared with that of the control females. Marginally, lower locomotor activity (-4.6 %) was noted in the females treated with 150 mg/kg bw/day, but these differences were considered to be within the range of normal variation and unrelated to the treatment with the test article.
Based on the results of this study, 150 mg/kg bw/day of RA1 was etablished as the NOAEL.
Reference
Table 3: Organ Weights (gram) in Males
|
|
Group 1 |
Group 2 |
Group 3 |
Group 4 |
|
|
0 mg/kg |
30 mg/kg |
150 mg/kg |
750 mg/kg |
Body Weight |
Mean |
263.402 |
268.082 |
255.076 |
278.118 |
|
St. Dev. |
35.699 |
25.657 |
21.763 |
35.638 |
Brain |
Mean |
1.90 |
1.91 |
1.88 |
1.92 |
|
St. Dev. |
0.15 |
0.09 |
0.05 |
0.08 |
Heart |
Mean |
0.920 |
0.887 |
0.861 |
0.949 |
|
St. Dev. |
0.163 |
0.056 |
0.086 |
0.114 |
Liver |
Mean |
7.87 |
7.38 |
7.28 |
7.79 |
|
St. Dev. |
1.85 |
1.15 |
1.17 |
1.21 |
Thymus |
Mean |
0.41 |
0.42 |
0.37 |
0.43 |
|
St. Dev. |
0.10 |
0.06 |
0.11 |
0.12 |
Kidneys |
Mean |
1.91 |
1.97 |
1.87 |
2.14 |
|
St. Dev. |
0.27 |
0.31 |
0.22 |
0.20 |
Adrenals |
Mean |
0.057 |
0.064 |
0.058 |
0.061 |
|
St. Dev. |
0.008 |
0.010 |
0.006 |
0.009 |
Spleen |
Mean |
0.662 |
0.663 |
0.603 |
0.723 |
|
St. Dev. |
0.134 |
0.140 |
0.080 |
0.126 |
Testes |
Mean |
3.41 |
3.31 |
3.16 |
3.11 |
|
St. Dev. |
0.40 |
0.20 |
0.20 |
0.21 |
Epididymides |
Mean |
1.008 |
0.996 |
0.935 |
0.953 |
|
St. Dev. |
0.172 |
0.104 |
0.029 |
0.116 |
Table 4: Organ Weights (gram) in Females
|
|
Group 1 |
Group 2 |
Group 3 |
Group 4 |
|
|
0 mg/kg |
30 mg/kg |
150 mg/kg |
750 mg/kg |
Body Weight |
Mean |
180.652 |
169.402 |
178.032 |
137.322 |
|
St. Dev. |
15.551 |
9.966 |
13.310 |
16.676 |
Brain |
Mean |
1.78 |
1.80 |
1.86 |
1.86 |
|
St. Dev. |
0.05 |
0.09 |
0.09 |
0.04 |
Heart |
Mean |
0.695 |
0.695 |
0.684 |
0.643 |
|
St. Dev. |
0.036 |
0.090 |
0.059 |
0.065 |
Liver |
Mean |
5.36 |
5.25 |
5.45 |
5.67 |
|
St. Dev. |
0.40 |
0.36 |
0.57 |
0.65 |
Thymus |
Mean |
0.47 |
0.35 |
0.41 |
0.40 |
|
St. Dev. |
0.07 |
0.07 |
0.17 |
0.07 |
Kidneys |
Mean |
1.38 |
1.35 |
1.44 |
1.50 |
|
St. Dev. |
0.07 |
0.11 |
0.14 |
0.15 |
Adrenals |
Mean |
0.079 |
0.079 |
0.085 |
0.084 |
|
St. Dev. |
0.009 |
0.014 |
0.017 |
0.011 |
Spleen |
Mean |
0.497 |
0.455 |
0.484 |
0.517 |
|
St. Dev. |
0.137 |
0.071 |
0.54 |
0.023 |
Table 5: Summary of male and female food consumption (g/animal/day)
Day of study |
Group 1 control |
Group 2 30 mg/kg |
Group 3 150 mg/kg |
Group 4 750 mg/kg |
||||
Male |
Female |
Male |
Female |
Male |
Female |
Male |
Female |
|
1-8 |
21.9 |
14.7 |
20.9 |
14.1 |
22.3 |
15.1 |
21.9 |
15.4 |
8-15 |
22.7 |
17.1 |
21.6 |
15.8 |
22.9 |
16.5 |
23.1 |
16.3 |
15-22 |
22.7 |
17.8 |
22.1 |
15.9 |
22.5 |
17.2 |
24.1 |
16.4 |
22-28 |
23.2 |
18.2 |
23.3 |
17.5 |
24.6 |
17.5 |
24.3 |
17.0 |
Table 7: Summary of haematology
Parameter |
Group 1 control |
Group 2 30 mg/kg |
Group 3 150 mg/kg |
Group 4 750 mg/kg |
||||
Male |
Female |
Male |
Female |
Male |
Female |
Male |
Female |
|
RBC (T/L) |
8.83 |
8.36 |
8.99 |
8.30 |
9.12 |
8.53 |
8.82 |
8.11 |
Haemoglobin (mmol/L) |
9.97 |
9.58 |
10.12 |
9.51 |
10.15 |
9.73 |
10.10 |
9.22 |
Haematocrit (L/L) |
0.48 |
0.46 |
0.49 |
0.46 |
0.49 |
0.47 |
0.48 |
0.45 |
MCV (fL) |
54.6 |
55.5 |
54.2 |
55.1 |
53.3 |
54.9 |
54.5 |
55.9 |
MCH (fmol) |
1.13 |
1.15 |
1.13 |
1.15 |
1.11 |
1.14 |
1.15 |
1.14 |
MCHC (mmol/L) |
20.8 |
20.7 |
20.8 |
20.9 |
20.9 |
20.8 |
21.1 |
20.4 |
Platelets (g/L) |
885 |
1018 |
981 |
972 |
1016 |
1019 |
887 |
969 |
Reticulocytes (%) |
2.75 |
2.54 |
2.62 |
3.08 |
2.80 |
2.46 |
2.81 |
2.74 |
Reticulocytes (T/L) |
0.2376 |
0.2093 |
0.2298 |
0.2504 |
0.2421 |
0.2004 |
0.2397 |
0.2135 |
Heinz bodies |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
Methaemoglobin (%) |
0.8 |
0.9 |
0.8 |
0.9 |
0.7 |
0.7 |
0.9 |
0.9 |
WBC (g/L) |
7.1 |
6.6 |
6.4 |
5.8 |
7.6 |
6.0 |
8.1 |
6.3 |
Table 8: Summary of clinical biochemistry
Parameter |
Group 1 control |
Group 2 30 mg/kg |
Group 3 150 mg/kg |
Group 4 750 mg/kg |
||||
Male |
Female |
Male |
Female |
Male |
Female |
Male |
Female |
|
Glucose (mmol/L) |
5.54 |
4.59 |
5.35 |
4.83 |
5.63 |
4.67 |
5.58 |
4.45 |
Urea (mmol/L) |
6.38 |
7.20 |
6.15 |
7.69 |
5.40 |
6.56 |
6.93 |
7.10 |
Creatinine (µmol/L) |
47.5 |
53.8 |
47.4 |
54.9 |
47.9 |
49.7 |
48.6 |
54.0 |
Uric acid (µmol/L) |
37.8 |
50.2 |
28.4 |
35.6 |
45.6 |
37.0 |
41.6 |
50.6 |
Bilirubin total (µmol/L) |
2.12 |
2.30 |
2.16 |
2.03 |
1.95 |
1.99 |
2.41 |
2.31 |
Cholesterol total (mmol/L) |
1.95 |
1.60 |
1.96 |
1.52 |
1.88 |
1.57 |
1.52 |
1.15 |
Triglycerides (mmol/L) |
0.65 |
0.36 |
0.83 |
0.34 |
0.92 |
0.39 |
0.75 |
0.33 |
Phospholipids (mmol/L) |
1.76 |
1.58 |
1.80 |
1.61 |
1.76 |
1.68 |
1.43 |
1.33 |
ASAT (µkat/L) |
1.20 |
1.17 |
1.18 |
1.20 |
1.30 |
1.13 |
1.20 |
1.26 |
ALAT (µkat/L) |
0.53 |
0.46 |
0.61 |
0.44 |
0.56 |
0.42 |
0.53 |
0.38 |
Creatine kinase (µkat/L) |
4.01 |
3.72 |
3.21 |
3.95 |
4.42 |
3.01 |
3.53 |
4.85 |
Calcium (mmol/L) |
2.73 |
2.71 |
2.72 |
2.59 |
2.72 |
2.72 |
2.71 |
2.78 |
Phosphorous (mmol/L) |
2.41 |
2.12 |
2.18 |
1.93 |
2.17 |
1.97 |
2.42 |
1.95 |
Sodium (mmol/L) |
144.4 |
144.8 |
145.4 |
145.9 |
145.4 |
145.2 |
145.4 |
146.8* |
Chloride (mmol/L) |
100.6 |
101.6 |
100.9 |
102.9 |
100.8 |
101.6 |
100.4 |
103.8** |
Albumin (g/L) |
31.7 |
34.0 |
32.0 |
34.2 |
32.5 |
34.7 |
31.8 |
36.1 |
Total protein (g/L) |
67.5 |
68.1 |
67.6 |
67.8 |
68.6 |
69.5 |
66.5 |
71.7 |
*/** Dunnett t-test based on pooled variance significant at 5 % or 1 % level, respectively.
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 150 mg/kg bw/day
- Study duration:
- subacute
- Species:
- rat
- Quality of whole database:
- No repeated dose studies were available on DEA acetate, but two good-quality, reliable, GLP-compliant, OECD-guideline studies on the structurally-related compounds RA1 (Braun et al. 2000) and RA2 (Allard & Becker, 1997) meet the REACH tonnage-driven data requirements.
Repeated dose toxicity: inhalation - systemic effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Repeated dose toxicity: inhalation - local effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Repeated dose toxicity: dermal - systemic effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Repeated dose toxicity: dermal - local effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Additional information
No studies are available on the repeated dose toxicity of DEA acetate, but oral studies have been conducted on structurally-related read-across compounds.
In a 28-day study, RA1 was administered via daily oral gavage to SPF-bred Wistar rats (5/sex) at up to 750 mg/kg bw/day. Slightly elevated plasma sodium and chloride levels were seen in high-dose females. High-dose males and females demonstrated significant treatment-related reductions in locomotor activity. The no-observed-adverse-effect level (NOAEL) was determined to be 150 mg/kg bw/day (Braun et al. 2000). A 28-day study on Sprague-Dawley rats (5/sex) given RA2 by daily oral gavage at up to 1000 mg/kg bw/day. No treatment-related significant adverse effects were seen in treated animals (NOAEL 1000 mg/kg bw/day), although no neurobehaviour assessment was conducted (Allard and Becker, 1997).
As neurobehavioural effects (reductions in locomotor activity) were seen with RA1 in high dose animals, and such affects were not assessed in detail in the RA2 study, a health-precautionary NOAEL of 150 mg/kg bw/day is considered critical.
According to Annex VIII of Regulation (EC) No 1907/2006 REACH Regulation, repeated dose toxicity studies only need to be conducted on one species taking into consideration the most appropriate route of administration regarding human exposure. As the oral route of exposure is most appropriate for DEA acetate, repeated dose toxicity studies were not carried out for the dermal or inhalation routes.
Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
GLP, OECD guideline study (reliability 2).
Repeated dose toxicity: via oral route - systemic effects (target organ) neurologic: behaviour
Justification for classification or non-classification
Oral repeated dose toxicity studies in rats with RA2 and RA1 yielded NOAELs of 1000 and 150 mg/kg bw/day respectively (Allard & Becker, 1997; Braun et al. 2000). According to Regulation (EC) No. 1272/2008, classification is applicable when significant toxic effects are seen to occur at 300 mg/kg bw/day or less for an oral 28-day rat study. As such, the results of these studies indicate that classification of DEA acetate is not required.
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