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EC number: 421-320-0 | CAS number: 118289-55-7 CP-89,575
- 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:
- sub-chronic toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- December 1995-January 1996
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: Study was conducted according to OECD and in accordance with GLP. The study material is well characterize
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 997
- Report date:
- 1997
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
- Qualifier:
- according to guideline
- Guideline:
- EU Method B.7 (Repeated Dose (28 Days) Toxicity (Oral))
- Principles of method if other than guideline:
- The method followed was that outlined in Annex to Directive 92/69/EEC, Part B, Method B7, and OECD guideline for testing of chemicals No.407 "Repeated Dose Oral Toxicity- Rodent: 28 day or 14 day study".
The study was run in two stages. Due to a clerical error in the protocol regarding the high dosage necessitating termination Group 4, the study was run in two stages. The first stage consisted of the intermediate, low dosage and control groups. The second stage consisted of the high dosage group and concurrent control - GLP compliance:
- yes
- Limit test:
- yes
Test material
- Reference substance name:
- 6-chloro-5-(2-chloroethyl)-1,3-dihydroindol-2-one
- EC Number:
- 421-320-0
- EC Name:
- 6-chloro-5-(2-chloroethyl)-1,3-dihydroindol-2-one
- Cas Number:
- 118289-55-7
- Molecular formula:
- Hill formula: C10 H9 Cl2 N O CAS formula: C10 H9 Cl2 N O
- IUPAC Name:
- 6-chloro-5-(2-chloroethyl)-2,3-dihydro-1H-indol-2-one
- Test material form:
- solid: crystalline
- Details on test material:
- Expiry date: September 1996
Purity: >99%
Date received: 14 September 1995
Pharmaceutical intermediate,
Constituent 1
Test animals
- Species:
- rat
- Strain:
- other: Sprague-Dawley origin (Crl:CD BR VAF PLUS™)
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River (UK) Ltd., Margate, Kent, England
- Age at study initiation: 28 ± 1 days old,
- Weight at study initiation: in a weight range of 69 to 87 g on arrival
- Fasting period before study: Food was withdrawn overnight prior to collection of samples
- Housing: All rats were initially caged, as far as possible, in groups of five according to sex in metal cages with wire mesh floors
- Diet (e.g. ad libitum): standard pelleted laboratory rodent diet
- Water (e.g. ad libitum): tap water
- Acclimation period: 5 days before
ENVIRONMENTAL CONDITIONS
- Temperature (°C): range 17 to 22
- Humidity (%): 36 to 59
- Air changes (per hr): approximately 19
- Photoperiod (hrs dark / hrs light):12artificial light (0700-1900 hours) in each 24- hour period.
IN-LIFE DATES: From: Sept 8th, 1993 To: Sept. 28th, 1993
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- other: 1 % methyl cellulose aqueous solutioncontaining 1% Tween 80
- Details on oral exposure:
- The high dosage was selected on the basis of available toxicity data and a preliminary oral toxicity investigation performed at Huntingdon Life Sciences schedule number PFZ/750. intermediate and low dosage levels were selected on the basis of the key dosages relative to EEC labelling requirements
- Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- dose level:Control, 15, 150 mg/kg other group had a control and then 300mg/kg dosing groups.
- Duration of treatment / exposure:
- concentration: Groups 2, 3 and 6 using a syringe and rubber catheter at a dose volume of 10 ml/kg/day.
Control animals received the vehicle at the same dose volume - Frequency of treatment:
- Each animal received a constant dosage based on its most recently recorded bodyweight. Animals were treated once daily for at least twenty-eight consecutive days.
Doses / concentrationsopen allclose all
- Remarks:
- Doses / Concentrations:
300 mg/kg
Basis:
other: by gavage
- Remarks:
- Doses / Concentrations:
150 mg/kg
Basis:
other: by gavage
- Remarks:
- Doses / Concentrations:
15 mg/kg
Basis:
other: by gavage
- No. of animals per sex per dose:
- Groups of ten rats (five males and five females)
- Control animals:
- yes
- Details on study design:
- Prior to dosing, the test substance formulations for Groups 2, 3 and 6 were mixed by inversion. Subsequent mixing using a magnetic stirrer occurred for a period of at least 10 minutes before dosing commenced.Blood was withdrawn under light ether anaesthesia from the orbital sinus of all rats prior to termination (Week 4). Further removal of blood samples for re-analysis was carried out for individual animals, on Day 28. After 28 days of treatment (Day 29) all animals surviving treatment were killed by carbon dioxide asphyxiation and a complete autopsy undertaken.Specified organs were weighed and relevant tissue samples were fixed for microscopic examination
- Positive control:
- N/A
Examinations
- Sacrifice and pathology:
- After 28 days of treatment (Day 29) all animals surviving treatment were killed by carbon dioxide asphyxiation and a complete autopsy undertaken.Specified organs were weighed and relevant tissue samples were fixed for microscopic examination
- Statistics:
- If the data consisted predominantly of one particular value (relative frequency of the mode exceeded 75% ), the proportion of values different from the mode were analysed by Fisher's exact test (1) followed by Mantel's test for a trend in proportions (2). Otherwise:
Bartlett's test (3) was applied to test for heterogeneity of variance between treatments. If significant heterogeneity was found at the 1% level, a logarithmic transformation was tried to see if a more stable variance structure could be obtained.
If no significant heterogeneity was detected (or if a satisfactory transformation was found), a one-way analysis of variance was carried out followed by Williams' test (5) for a dose related response.
If significant heterogeneity of variance was present and could not be removed by a logarithmic transformation, the Kruskal-Wallis analysis of ranks (4) was used. This analysis was followed by the non-parametric equivalent of Williams' test (Shirley's test,. (6)).
Results and discussion
Results of examinations
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- Two female animals (579 & 589) treated with 300 mg/kg/day : killed on humane grounds on Days 16 and 20 respectively, Clinical signs prior to sacrifice were piloerection, thin appearance, pallor of extremities, hunched posture, lethargy, increased salivation and swollen muzzle There were no clinical signs for rats treated at 15 or 150 mg/kg/day throughout the treatment period. Fur loss on shoulders was recorded for two male rats (47 o & 49o) treated at 300 mg/kg/day from Day 22 to termination. This finding often accompanies increased salivation and can be a result of fur getting wet. Alternatively, fur loss may have been due to fighting and is not considered to be of toxicological importance piloerection on D1 ( 1F/1)
- Mortality:
- mortality observed, treatment-related
- Description (incidence):
- Two female animals (579 & 589) treated with 300 mg/kg/day : killed on humane grounds on Days 16 and 20 respectively, Clinical signs prior to sacrifice were piloerection, thin appearance, pallor of extremities, hunched posture, lethargy, increased salivation and swollen muzzle There were no clinical signs for rats treated at 15 or 150 mg/kg/day throughout the treatment period. Fur loss on shoulders was recorded for two male rats (47 o & 49o) treated at 300 mg/kg/day from Day 22 to termination. This finding often accompanies increased salivation and can be a result of fur getting wet. Alternatively, fur loss may have been due to fighting and is not considered to be of toxicological importance piloerection on D1 ( 1F/1)
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- There were no statistically significant differences from control for bodyweight gain for rats of the intermediate and low dosage groups.
- Food consumption and compound intake (if feeding study):
- no effects observed
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- no effects observed
- Ophthalmological findings:
- not examined
- Haematological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- In higher group lower packed cell volume, haemoglobin concentration, and red blood cell counts with subsequent marginal disturbances in the calcuated indicexes but .there was no evidence of hemolysis or blood loss and aetiology questionable.
- Clinical biochemistry findings:
- effects observed, treatment-related
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- spleen slightly lower and liver slightly higher than control- males- high dose group
- Gross pathological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- The macroscopic examinations performed at terminal kill revealed caecal distension in 4/5 male and 2/3 female rats treated at 300 mg/kg/day and in 2/5 male rats treated with 150 mg/kg/day.
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- The macroscopic examinations performed at terminal kill revealed caecal distension, at high and mid doses, Increased pelvic dilatation in the kidney, reduction in adipose tissue and a small thymus at high dose.
- Histopathological findings: neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- A minor immunosuppressive effect, chiefly manifested in the thymus and splenic peri-arteriolar lymphoid sheath, was noted at the high dosage level. In the kidneys some inflammatory and hyperplastic changes of the renal pelvis were seen in the high dose.
- Details on results:
- In a small number of animals receiving 300 mg/kg/ day there was a varying degree of minor renal pelvic dilatation as well as occasional pelvic inflammation/pyelitis. In two female animals there was also an associated hyperplasia of the pelvic transitional epithelium
The following comments are made in summary: Mortality
Two female rats from the high dosage of 300 mg/kg were killed on humane grounds on Days 16 and
20. Clinical signs prior to sacrifice were piloerection, thin, pallor of extremities, hunched posture, lethargy, increased salivation and swollen muzzle.
The macroscopic examination of rat no. 57 revealed crater like depressions, thickened and white forestomach, congested lungs, brown stained fur of the cranial region and forepaws, minimal adipose tissue, a raised subcapsular area on the spleen and a small uterus. The microscopic examination concluded that ulceration of the non-glandular epithelium of the stomach was the factor contributing to the death of the animal.
Macroscopic examination of rat 58 revealed moist fur in the perioral region, pale thyroids, oedematous thymus, minimal adipose tissue and pale kidneys. The microscopic examination concluded that pyelitis, tubular basophilia and inflammatory exudate in the pelvic cavity of the kidneys were the factors contributing to the death of this animal.
Bodyweight
Bodyweight gains were slightly lower than control for male rats treated at 300 mg/kg/day. Haematology
For high dosage group male and female rats higher platelet counts and lower neutrophil, lymphocyte,
eosinophil, basophil and white blood cell counts were recorded. Neutrophil, lymphocyte and white blood cell counts were also lower than control for rats of the intermediate dosage group.
Lower than control packed cell volume (PCV), haemoglobin concentration (Hb) and red blood cell counts (RBC) and consequent marginal disturbances in the calculated indices were recorded for rats receiving 300 mg/kg/day. PCV, Hb and RBC were also lower than control and MCV and MCH higher than control for rats at 150 mg/kg/day.
Biochemistry
Higher than control glutamic-pyruvic transaminase (GPT) and glutamic-oxaloacetic transaminase (GOT) levels were recorded for male rats of the high dosage group. Urea nitrogen and glucose levels were higher than control for male rats treated at 300 mg/kg/day.
Organ weights
Spleen weights (absolute) were lower than control and liver weights (bodyweight adjusted) were higher than control for male rats of the high dosage group.
Macroscopic pathology
For rats of the high dosage group increased pelvic dilatation (males only), small thymus (males and females) and a reduction in adipose tissue (males and females) were observed.
Caecal distention was recorded in male and female rats of the high dosage group and among male rats from the intermediate dosage group.
Microscopic pathology
A minor immunosuppressive effect, chiefly manifested in the thymus and splenic peri-arteriolar lymphoid sheath, was noted at the high dosage level. In the kidneys some inflammatory and hyperplastic changes of the renal pelvis were also seen in the high dosage group.
Other findings
There were no other differences from control for the remaining parameters measured, including clinical signs, food consumption and water consumption, that were considered to be related to treatment.
Effect levels
open allclose all
- Dose descriptor:
- NOEL
- Effect level:
- 150 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: Concluded to be no-observed-adverse-effect level (NOAEL) for CP-89 ,575 in the rat.
- Dose descriptor:
- NOEL
- Effect level:
- 15 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: No-observed-effect level (NOEL) for CP-89,575 in the rat when administered orally for 28 days.
Target system / organ toxicity
- Critical effects observed:
- not specified
Any other information on results incl. tables
Immune system: A slight increase in the paracortical cellularity in the cervical lymph nodes of occasional animals may be associated with these disturbances to the immune system.
Dosagelevel(mg/kg/day) |
0 |
15 |
Males 150 |
0 |
300 |
0 |
15 |
Females 150 0 |
300 |
|
Spleen |
|
|
|
|
|
|
|
|
|
|
ReducedcellularityofPALS |
0 |
0 |
0 |
0 |
3 |
0 |
0 |
0 |
0 |
3 |
Thymus |
|
|
|
|
|
|
|
|
|
|
Involution |
0 |
0 |
0 |
0 |
4 |
0 |
0 |
0 |
0 |
2 |
Cervicallymphnode |
|
|
|
|
|
|
|
|
|
|
Increased cellularity (generalised) |
3 |
1 |
1 |
5 |
1 |
1 |
2 |
1 |
4 |
2 |
Reduced cellularity (generalised) |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
2 |
Increasedcellularity-paracortex |
0 |
0 |
|
0 |
1 |
0 |
0 |
1 |
0 |
0 |
Applicant's summary and conclusion
- Conclusions:
- Target organs for toxicity of the high dosage level of 300 mg/kg/day were the immune system and kidney
intermediate dosage of 150 mg/kg/day : concluded to be no-observed-adverse-effect level (NOAEL) for CP-89 ,575 in the rat.
15 mg/kg/day: no-observed-effect level (NOEL) for CP-89,575 in the rat when administered orally for 28 days
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