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EC number: 701-118-1 | CAS number: 2156592-54-8
- 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:
- short-term repeated dose toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 1995-05-08 to 1995-11-06
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: Guideline study, well-performed and well-documented
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 995
- Report date:
- 1995
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
Test material
- Reference substance name:
- 6-(3-tetrapropenyl-2,5-dioxopyrrolidin-1-yl)hexanoic acid
- EC Number:
- 800-770-5
- Cas Number:
- 1424148-99-1
- Molecular formula:
- C22H39NO4
- IUPAC Name:
- 6-(3-tetrapropenyl-2,5-dioxopyrrolidin-1-yl)hexanoic acid
- Test material form:
- liquid: viscous
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Crj: CD(SD)
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Japan Charles River Company, Ltd.
- Age at study initiation: 15 weeks
- Weight at study initiation: 122.6 to 142.0 g in males and 100.9 to 118.3 g in females
- Fasting period before study:
- Housing: individually in cages with stainless steel wire net flooring in a barrier system rearing room
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period:
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23 ± 2
- Humidity (%): 55 ± 10
- Air changes (per hr): 10-15
- Photoperiod (hrs dark / hrs light): 13
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- CMC (carboxymethyl cellulose)
- Analytical verification of doses or concentrations:
- no
- Duration of treatment / exposure:
- 28 days
- Frequency of treatment:
- once daily, morning
Doses / concentrations
- Remarks:
- Doses / Concentrations:
8, 40, 200, 1000 mg/kg bw/day
Basis:
actual ingested
- No. of animals per sex per dose:
- 6
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- The study included recovery groups for doses of 200 and 1000 mg/kg bw
Examinations
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: one or more times a day
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: one or more times a day
BODY WEIGHT: Yes
- Time schedule for examinations: day -2 before administration , days 1 (administration), 3, 5, 8, 10, 12, 15, 17, 19, 22, 24, 26 and 28 during the administration period and on days 1(recovery) 3, 5, 8, 10, 12 and 14 during the recovery period.
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined once before administration and two times a week during the administration and recovery periods.
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: Yes
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No
HAEMATOLOGY: Yes
- Time schedule for collection of blood: when the administrat.ion period was concluded and when the recovery period was concluded after one night of fasting (16 to 20 hours) .
- Anaesthetic used for blood collection: Yes (ether anesthesia)
- Animals fasted: Yes
- How many animals: all
- Parameters: RBC, WBC, Hb, Ht, MCV, MCH, MCHC, Platelet count, Reticulo, PT, APTT, Differential leukocyte count
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: when the administrat.ion period was concluded and when the recovery period was concluded after one night of fasting (16 to 20 hours) .
- Animals fasted: Yes
- How many animals: all
- Parameters: GOT, GPT, ALP, ChE, T-Cho, TG, glucose, T-protein, Albumin, A/G ratio, BUN, Creatinine, T-Bil, Ca, IP, Na, K, Cl
URINALYSIS: Yes
- Time schedule for collection of urine: once during the administration period (day, 28) and once during the recovery period (day 14 (recovery).
- Metabolism cages used for collection of urine: Yes
- Animals fasted: No data
- Parameters: volume, color tone, pH, protein, ketone bodies, bilirubin, occult blood, sugar, urobilinogen
NEUROBEHAVIOURAL EXAMINATION: No - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
Test period:
Solvent control and 100 mg/kg group: liver, spleen, kidneys, heart, stomachm intestines, testes, adrenals
200 mg/kg group: Liver, kidneys (males only), stomach (males only), testes
40 mg/kg group :Liver (females only), kidneys (males only)
8 mg/kg group: Kidneys (males only)
Recovery period:
Solvent control group, 1000 mg/kg group: Liver, kidneys (males only), stomach (males only), testes
200 mg/kg group: Liver, kidneys (males only) testes - Other examinations:
- Organ weight determinations: brain, liver, spleen, kidney, adrenals, testes (or overies)
- Statistics:
- The findings for body weight, feed consumption, hematological tests, blood biochemistry tests, urine volume and organ weights were subjected to homoscedastic analysis by Bartlett's test. When equal variance at a 5% level of significance was found, tests between the solvent control group and each administration group were performed by Dunnett'smet.hod when the number of cases in each group were equal and by Scheffe's method when they were not equal.
When equal variance was not found,the Kruskall-Wallis test was performed. When significant differendes were found, tests between the solvent control group and each administration group were performed by Dunnet's method when the number of cases in each group was equal and by Scheffe's nonparametric method when they were not equal.
Results and discussion
Results of examinations
- Clinical signs:
- effects observed, treatment-related
- Mortality:
- mortality observed, treatment-related
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Food efficiency:
- no effects observed
- Water consumption and compound intake (if drinking water study):
- not specified
- Ophthalmological findings:
- not specified
- Haematological findings:
- effects observed, treatment-related
- Clinical biochemistry findings:
- effects observed, treatment-related
- Urinalysis findings:
- no effects observed
- Behaviour (functional findings):
- effects observed, treatment-related
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Gross pathological findings:
- effects observed, treatment-related
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Histopathological findings: neoplastic:
- not specified
- Details on results:
- CLINICAL SIGNS AND MORTALITY
at the time administration was concluded:
- no death occurred.
- salivation in males and females in groups given 200 mg/kg and higher
- decrease in spontaneous movement and decrease in respiratory rate in males in the 200 mg/kg group
- decrease in spontaneous movement, decrease in respiratory rate, soiling around the nose and mouth, hunchback posture, soiling around the anus and depilation in the lower neck region in males and females in the 1000 mg/kg group
- soft stool, reddish tears, reddish tear traces and ptosis in males in the 1000 mg/kg group
at the time recovery was concluded:
- No significant effect.
BODY WEIGHT AND WEIGHT GAIN
No effects
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
No effects
HAEMATOLOGY
at the time administration was concluded:
-decrease in hemoglobin concentration and in hematocrit values in males and females in the 1000 mg/kg group
- decreases in erythrocyte counts in males in the 1000 mg/kg group
- prolongation of activated partial thromboplastin time and decreases in erythrocyte counts were seen in females in the 1000 mg/kg group
- increases in leukocyte counts in males in groups given 200 mg/kg and higher
- increase in the rod neutrophil ratio in males in the 1000 mg/kg group.
at the time recovery was concluded
- no effects in males
-decreases in erythrocyte counts and homoglobin concentrations and increases in platelet counts in females in 1000 mg/kg bw.
CLINICAL CHEMISTRY
at the time administration was concluded:
- decrease in blood sugar in males in groups given 200 mg/kg and higher
- increase in total bilirubin in males in the 1000 mg/kg group
- decrease in chlorine in females in groups given200 mg/kg and higher
- increase in triglycerides and decrease in creatinine in females in the 1000 mg/kg group
at the ime recovery was concluded
-decrease in creatinine and increase in total bilirubin in males in 200 mg/kg bw and higher.
- no effects in females
ORGAN WEIGHTS
at the time administration was concluded:
-increases in the liver weight in females in groups given 200 mg/kg and higher and in males in the 1000 mg/kg group
at the time recovery was concluded:
-increase in the relative weights of the liver and kidneys in males in the 1000 mg/kg bw group
-increase in the relative weight of the liver in females in the 1000 mg/kg bw group
- increase in the relative weight of the kidneys in females in the 200 mg/kg bw
GROSS PATHOLOGY
at the time administration was concluded:
- apparent surface spotting of the kidneys in males in the 1000 mg/kg group;
- roughening of the mucosa of the glandular stomach in males in the 1000 mg/kg group
- no effect in females
at the time recovery was concluded:
- black spots on the mocosa of the glandular stomach in males in the 200 mg/kg bw group.
HISTOPATHOLOGY
at the time administration was concluded:
- increase in eosinophilic bodies in the kidneys in males in the group given 200 mg/kg and higher
- swelling of hepatocytes in males and females in the 1000 mg/kg group
- granulation tissue accompanied by calcification in the liver in males in the 1000 mg/kg bw
- mucosal degeneration of the proventriculus [forestomach] in males in the 1000 mg/kg group.
at the time recovery was concluded:
- increase in eosinophilic bodies in the liver in males in the 1000 mg/kg bw
-necrosis of the mucosa of the glandular stomach in males in the 200 mg/kg bw
Effect levels
- Key result
- Dose descriptor:
- NOEL
- Effect level:
- 40 mg/kg bw/day (nominal)
- Sex:
- male/female
- Basis for effect level:
- histopathology: non-neoplastic
- organ weights and organ / body weight ratios
Target system / organ toxicity
- Critical effects observed:
- not specified
Any other information on results incl. tables
Table: Reversibility of major findings; histopathology not included |
|||||||
|
At the time administration was concluded |
At the time recovery was concluded |
|||||
Vehicle control |
200 mg/kg bw |
1000 mg/kg bw |
Vehicle control |
200 mg/kg bw |
1000 mg/kg bw |
||
Hematology |
|||||||
RBC [x104/mm3] |
Males |
786 ± 14 |
751 ± 32 |
716 ** ± 38 |
829 ± 47 |
809 ± 19 |
781 ± 42 |
females |
738 ± 22 |
731 ± 36 |
707 ± 33 |
794 ± 24 |
772 ± 21 |
743 ** ± 23 |
|
WBC [x102/mm3] |
Males |
74 ± 12 |
108** ± 13 |
107 ** ±19 |
117 ± 13 |
93 ±20 |
112 ±17 |
females |
71 ± 18 |
77 ± 10 |
82 ± 21 |
75 ± 30 |
57 ± 8 |
73 ± 11 |
|
Hb [g/dt] |
Males |
15.5 ± 0.6 |
15.0 ± 0.4 |
14.1 ** ± 0.4 |
15.6 ± 0.5 |
15.2 ± 0.7 |
15.3 ± 0.3 |
females |
15.1 ± 0.6 |
14.8 ± 0.6 |
13.9 ** ± 0.5 |
15.6 ± 0.4 |
15.1 ± 0.3 |
15.0 * 0.5 |
|
Ht [%] |
Males |
44.5 ±1.4 |
44.0 ± 1.0 |
41.2 ** ± 1.0 |
45.0 ± 2.0 |
43.7 ± 1.6 |
44.1 ± 1.4 |
females |
42.1 ± 1.4 |
41.0 ± 2.5 |
38.9 * ± 1.5 |
43.3 ± 0.8 |
41.9 ± 0.8 |
42.0 ± 1.5 |
|
Platelet [x104/mm3] |
Males |
121.6 ± 10.9 |
130.2 ± 15.6 |
136.4 ± 16.5 |
115.5 ± 9.9 |
116.7 ± 10.4 |
110.6 ± 11.2 |
females |
129.1 ± 11.6 |
132.5 16.7 |
120.2 ± 6.3 |
120.6 ± 9.4 |
124.4 ± 11.6 |
135.7 * ± 6.1 |
|
PT [sec] |
Males |
16.6 ± 3.9 |
14.9 ± 2.1 |
17.8 ± 0.9 |
14.1 ± 1.5 |
14.5 ± 2.1 |
15.7 ± 2.5 |
females |
12.0 ± 0.7 |
11.5 ± 0.5 |
11.7 ± 0.9 |
11.3 ± 0.5 |
11.0 ± 0.2 |
10.9 ± 0.3 |
|
APTT [sec] |
Males |
28.9 ± 3.1 |
30.7 ± 2.9 |
32.7 3.3 |
27.2 ± 3.8 |
24.1 ± 3.4 |
26.4 ± 1.9 |
females |
20.7 ± 0.8 |
22.1 ± 2.1 |
25.9 ** ± 3.6 |
21.8 ± 2.3 |
20.2 ± 3.9 |
20.2 ± 1.7 |
|
Clinical Chemistry |
|||||||
ALP [IU/l] |
Males |
512 ± 67 |
490 ± 57 |
476 ± 67 |
373 ± 43 |
336 ± 35 |
342 ± 40 |
females |
310 ± 34 |
265 ± 54 |
249 ± 31 |
200 ± 28 |
196 ± 42 |
171 ± 27 |
|
Glucose [mg/dl] |
Males |
133.1 ± 13.4 |
111.8* 13.8 |
108.3 * 12.6 |
150.8 ± 15.6 |
132.6 ± 16.2 |
129.7 ± 17.6 |
females |
116.5 ± 11.1 |
121.7 ± 14.0 |
103.8 ± 22.5 |
124.4 ±12.8 |
135.9 16.5 |
127.6 ±10.4 |
|
TG [mg/dl] |
Males |
51 ± 15 |
66 ±20 |
58 ±11 |
63 ± 11 |
61 ± 13 |
46 ± 16 |
females |
29 ± 4 |
31 ± 7 |
41 * ± 10 |
35 ± 11 |
33 ± 16 |
31 ± 6 |
|
Creatinine [mg/dl] |
Males |
0.45 ± 0.07 |
0.39 ± 0.03 |
0.40 ± 0.05 |
0.54 ± 0.03 |
0.47** ± 0.02 |
0.47 ** ± 0.04 |
females |
0.46 ± 0.03 |
0.43 ± 0.04 |
0.39* ± 0.04 |
0.50 ± 0.04 |
0.49 ± 0.05 |
0.49 ± 0.04 |
|
T-Bil [mg/dl] |
Males |
0.18 ± 0.03 |
0.22 ± 0.04 |
0.25 ** 0.04 |
0.15 ± 0.02 |
0.18 * ± 0.01 |
0.19 * ± 0.02 |
females |
0.18 ± 0.01 |
0.20 ± 0.02 |
0.21 ± 0.02 |
0.17 ± 0.03 |
0.19 ± 0.04 |
0.17 ± 0.02 |
|
Cl [mEq/l] |
Males |
106.2 ± 1.5 |
106.4 ± 1.3 |
106.0 ± 0.9 |
106.7 ± 2.0 |
107.2 ± 1.2 |
106.8 ± 1.9 |
females |
109.3 ± 1.0 |
106.7** ±1.3 |
106.8** ± 1.1 |
108.7 ± 1.5 |
108.4 ± 1.7 |
108.9 ± 2.6 |
|
Relative Organ weight |
|||||||
Liver [g/100g] |
Males |
3.05 ± 0.22 |
3.15 ± 0.14 |
3.81** ± 0.07 |
2.71 ± 0.05 |
2.74 ± 0.09 |
2.98** ± 0.09 |
females |
3.14 ± 0.18 |
3.47 * ± 0.17 |
4.25 ** ± 0.13 |
2.77 ± 0.12 |
3.05 ± 0.28 |
3.08* ± 0.16 |
Mean ± SD
*: significantly different from vehicle control at p < 0.05
Table: Reversibility of histopathological findings (number of animals affected out of six) |
||||||||
|
At the time administration was concluded |
At the time recovery was concluded |
||||||
Vehicle control |
200 mg/kg bw |
1000 mg/kg bw |
Vehicle control |
200 mg/kg bw |
1000 mg/kg bw |
|||
Liver |
||||||||
Swelling of hepatocytes |
Males |
0 |
0 |
3 |
0 |
0 |
0 |
|
females |
0 |
0 |
4 |
0 |
0 |
0 |
||
Kidney |
||||||||
Eosinophilic bodies |
males |
++ |
0 |
3 |
1 |
0 |
0 |
1 |
+++ |
0 |
0 |
3 |
0 |
0 |
0 |
||
++++ |
0 |
0 |
2 |
0 |
0 |
0 |
||
females |
++ |
0 |
- |
0 |
0 |
- |
- |
|
+++ |
0 |
- |
0 |
0 |
- |
- |
||
++++ |
0 |
- |
0 |
0 |
- |
- |
||
Forestomach |
||||||||
Mucosa degeneration |
Males |
+ |
0 |
0 |
4 |
0 |
- |
0 |
++ |
0 |
0 |
1 |
0 |
- |
0 |
||
females |
+ |
0 |
- |
0 |
- |
- |
- |
|
++ |
0 |
- |
0 |
- |
- |
- |
+, very slight; ++, slight; +++, moderate; ++++ severe
-; no investigated
Applicant's summary and conclusion
- Conclusions:
- The registration substance was investigated for its repeated dose toxicity according to the OECD Gudieline 407. Liver was identified as target organ, possibly related to metabolic overload. Further minimal effect on the blood system could be derived. In males, minimal effects o the forestomach and kideny were found additionally. The NOEL of 40 mg/kg bw was obtained.
No classification is warranted with respect to the endpoint repeated dose toxicity. - Executive summary:
The registration substance was investigated according to the OECD Guideline 407. Rats were given via gavage with the test material at doses of 0, 8, 40, 200 and 1000 mg/kg bw. Recovery groups were established for the 1000 and 200 mg/kg groups and the solvent control group.
No deaths occurred. No effects due to administration of the test substance were seen on body weight and feed consumption during the period of administration or on the urinalyses at the time administration was concluded.
Salivation, decrease in spontaneous movement, decrease in respiratory rate, increase in leukocyte counts, decrease in blood sugar, decrease in chlorine, increase in liver weight and increase in eosinophilic bodies in the liver attributable to administration of the test substance were seen in the groups of 200 mg/kg or higher. Further hematology alteration was observed in males and females and effects on forestomach and kidney in males. Most of the effects were either fully reversible within the observation period of 14 days or the degree of severity decreased significantly.
On the basis of the foregoing results, it can be concluded that the principal effects of this substance are on the liver in males and females and on the proventriculus and kidneys in males. It was presumed that the NOEL in rats under the conditions of this test was 40 mg/kg/day.
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