Registration Dossier
Registration Dossier
Data platform availability banner - registered substances factsheets
Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.
The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.
Diss Factsheets
Use of this information is subject to copyright laws and may require the permission of the owner of the information, as described in the ECHA Legal Notice.
EC number: 202-196-5 | CAS number: 92-84-2
- 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
![](https://echa.europa.eu/o/diss-blank-theme/images/factsheets/A-REACH/factsheet/print_toxicological-information.png)
Endpoint summary
Administrative data
Description of key information
- Sub-chronic oral feed study with dogs
- Prior to implementation of GLP and OECD guidelines
- Dose-dependent effects on the haematological system
- Result: NOAEL = 6 mg/kg body weight/day
Key value for chemical safety assessment
Repeated dose toxicity: via oral route - systemic effects
Link to relevant study records
- Endpoint:
- sub-chronic toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 1973-11-29 to 1974-07-18
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: Well performed study prior to GLP and OECD-TG meeting the necessary scientific and current guideline requirements.
- Qualifier:
- no guideline followed
- Principles of method if other than guideline:
- - Prior to establishment of OECD technical guidelines
- Objective of the study: Evaluation and characterisation of subchronic oral toxicity of pharmaceutical grade phenothiazine following oral administration via food to beagle dogs for 13 weeks; several doses were tested;
- See section material and methods for further details - GLP compliance:
- no
- Remarks:
- Prior to GLP
- Limit test:
- no
- Species:
- dog
- Strain:
- Beagle
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- - Age: Young adults
- Health status: healthy
- Animals: 40 purebred beagles (20 males and 20 females)
- Selection: Dogs were selected on the basis of preliminary clinical laboratory screens
- Assignment to groups: Randomly assigned
- Food: Ground Wayne Dog Meal, ad libitum - Route of administration:
- oral: feed
- Vehicle:
- unchanged (no vehicle)
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS:
- Test material was incorporated into the basal laboratory died (Ground Wayne Dog Meal) on a weight by weight basis and mixed in a twin shell blender to provide the appropriate dietary levels for each group
DIET PREPARATION
- Rate of preparation of diet (frequency): Fresh diets were prepared each week
- Mixing appropriate amounts with (Type of food): Ground Wayne Dog Meal - Analytical verification of doses or concentrations:
- not specified
- Duration of treatment / exposure:
- - Treatment: 13 weeks
- Exposure: via feed seven days a week - Frequency of treatment:
- - Daily, feed was available seven days a week
- Remarks:
- Doses / Concentrations:
50ppm, 200ppm, 500ppm and 2000ppm
Basis:
nominal in diet - No. of animals per sex per dose:
- 4 male and 4 female dogs per dose
- Control animals:
- yes
- Details on study design:
- - Group assignment, please see table "Animal Groups and Dietary Levels" in section "Any other information on materials and methods"
- Positive control:
- No positive controls included
- Observations and examinations performed and frequency:
- OBSERVATION AND RECORDS
- DAILY: Appearance, behaviour, appetit, elimination and signs of pharmacologic effect
- WEEKLY: Individual body weights and food and compound consumption
CLINICAL LABORATORY STUDIES (HEMATOLOGICAL, BIOCHEMISTRY, URINE ANALYSIS, SEE BELOW)
- Performed on all dogs initially and at four and 13 weeks
HEMATOLOGICAL STUDIES
- Hematocrit
- Hemoglobin
- Erythrocyte count
- Total and differential leukocyte count
BIOCHEMISTRY STUDIES
- Determinations of fasting blood sugar
- Blood urea nitrogen
- Bromsulphalein liver function test
- Serum glutamic-pyruvic transaminase
URINE ANALYSIS
- Specific gravity
- pH
- Glucose
- Ketones
- Total protein
- Bilirubin
- Microscopic examination of the sediment - Sacrifice and pathology:
- TERMINATION
- After 13 weeks of treatment, all animals were sacrificed by exsanguination under surital anesthesia
- Complete necropsies were performed
ORGAN WEIGHTS (FROM EACH DOG)
- Thyroids
- Heart
- Liver
- Spleen
- Kidneys
- Adrenals
- Testes
TISSUE PRESERVATION (OBTAINED FROM EACH DOG)
- See Table: "Tissue Preservation" in section "Any other information on materials and methods"
HISTOPATHOLOGICAL EVALUATION
- Control and high dose group dogs (i.e. groups 1 and 4): All tissues listed in Table: "Tissue Preservation" in section "Any other information on materials and methods" were stained with hematoxylin and eosin and were examined microscopically
- 500ppm-group: spleen, bone marrow and rib junctiom were stained with hematoxylin and eosin and were examined microscopically
- 50ppm, 200ppm, 500ppm: liver and kidneys were stained with hematoxylin and eosin and were examined microscopically - 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 specified
- 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:
- effects observed, treatment-related
- Behaviour (functional findings):
- not specified
- 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:
- no effects observed
- Details on results:
- APPEARANCE, BEHAVIOUR, BODY WEIGHT CHANGES AND SIGNS OF COMPOUND EFFECT
- Body weight and food consumption are given in tables "Group mean body weights (kg.) at selected intervals" and "Average daily drug intake (mg/kg/day)" in section "Remarks on results including tables and figures".
- All of the test animals were comparable to the controls with respect to behaviour, appetite, elimination
- Body weight was either maintained (+/-5%) or gained while on study
- Rate of growth between groups was comparable
- Both males and females of the 500ppm group showed lower relative weight gains over the 13-week treatment period; however, these animals were slightly heavier than their counterparts at the initiation of the treatment
- Occasional instances of soft feces were observed; however, the occurence was among the control as well as the test animals and were considered to be of little significance
- Haircoat of the forelimbs, chest and dorsal thoraic areas of all high level test animals was stained orange in color beginning during the first week of study and contiunuing until termination
- Latter finding is probably a result of the oxidation of small amounts of phenothiazine adhering to the hair following feeding
- Food consumption was not adversely affected as a result of treatment
- Evaluation of food consumption data resulted in actual daily drug intake as indicated in table "Average daily drug intake (mg/kg/day)" in section "Remarks on results including tables and figures".
CLINICAL LABORATORY STUDIES (HEMATOLOGICAL DATA, BLOOD CHEMISTRY DATA, URINE ANALYSIS)
A) HEMATOLOGICAL DATA:
- Lowering of hematocrit, hemoglobin and erythrocyte count values in two male and one female 2000ppm dog at the four week interval
- Erythrocyte count in two further female 2000ppm dogs reduced
- At 13 weeks hematocrit, hemoglobin and erythrocyte count were again lowered in three male 2000ppm level dogs
- All remaining values were within acceptable normal limis and comparable with control values
B) BLOOD CHEMISTRY DATA:
- Slight lowering of blood sugar values at one female 200ppm and 500ppm dose dog, as well as in one male and in all 2000ppm female dogs
- All other parameters assessed at four and thirteen weeks were generally within acceptable parameters and comparable to control values
C) URINE ANALYSIS
- Generally unremarkable results
- Exception: Traces of sugar in one 2000ppm male at for weeks and four dogs (one 50ppm, two 200ppm and one 500ppm) at week 13
GROSS PATHOLOGY
- No consistent gross tissue changes which could be attributed to the administration of the test item
- Exception: dark colored spleen in all 2000ppm animals
- Please also see table "Summary of Necropsy Findings at 13 Weeks" in section "Remarks on results including tables and figures".
ORGAN WEIGHTS
- Examination of the data showed all values for the test animals to be within acceptable normal limits and comparable with control values
- Exception: spleen weights and spleen/body weight ratios of two 2000ppm female dogs were increased
MICROSCOPIC PATHOLOGY
- Tissue alterations included: marked splenic congestion with areas of increased extramedullary hematopoiesis
- Deposition of hemosiderin in the spleen, liver, kidney and bone marrow
- Increased cellularity of the bone marrow with a marked increase in erythroid elements
- These changes were related to the toxic effects of phenothiazine on the red blood cells and were present in all 2000ppm animals
- Hemosiderin deposition was present, but to a lower degree in the liver and kidney sections of three males and one female of the 500ppm group
- One 500ppm male dog also had slightly increased extramedullary hematopoiesis and hemosiderin pigment deposition in the spleen with a slight increase in erythroid elements in the bone marrow
- Changes in the spleen and bone marrow sections from the remaining 500ppm dogs were equivocal and within the range of normal variability
MICROSCOPIC PATHOLOGY - INCIDENTAL LESIONS
- Subendocardial hemorrhages in the hearts of one female control dog and one female 2000ppm dog
- A heart valve containing dilated vessels and small thrombi were found at one female 2000ppm dog
- Congenital defect of the auricle and heart valve of one female 500ppm
- Small cysts were present in the pituitary of one female 2000ppm dog
- Cystic area was present in th parathyroid of another female 2000ppm dog
- One female 500ppm dog had a congenital defect in one lobe of the lung resembling a severe bullous ephysema
- One male 50ppm dog had complete aplasia of the left kidney with compensatory hypertrophy of the right kidney
- Scattered incidence of splenic sucapsular hemorrhage and inflammatory cells in the livers and kidneys was seen in both control and treated animals - Dose descriptor:
- NOAEL
- Effect level:
- ca. 6 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: clinical signs; haematology
- Critical effects observed:
- not specified
- Conclusions:
- The animals responded well physiologically and the response of the animals at the 500ppm level is of minor biological significance.
- Executive summary:
Phenothiazine (pharmaceutical grade) was evaluated for sub-chronic toxicity following dietary administration to four groups of three male and three female beagle dogs for 13 weeks at dietary levels of 50, 200, 500 and 2000ppm. A fifth group of dogs served as control and received only the basal laboratory diet. Parameters evaluated for compound induced effect included survival, appearance, appetite, elimination, body weight changes, clinical laboratory data, gross necropsy findings, organ weights and organ/body weight ratios, as well as microscopic pathology.
All control and test animals survived the study and there was no indication of a compound related effect among the test groups with regard to appearance with regard to appearance, behavior, appetite, elimination and body weight changes. The observation of orange-stained fur on the forelimbs, chest and dorsal thoracic area of the high level dogs was ascribed to the oxidation product resulting from small amounts of phenothiazine adhering to the fur following feeding. Hematological data suggest a decrease in values among the principal elements of the profile (hemoglobin, hematocrit and total erythrocyte counts). Three of the six high level exhibited slight decreases in values for these parameters at both four and 13 weeks. The effect of phenothiazine in producing a hemolytic anemia at high dosage levels is well documented in the literature and this observed effect is probably related to that response. Blood chemistry data revealed decreased values for fasting glucose in four of six high level dogs at week 4 which was not observed at week 13.
Necropsy findings were generally unremarkable except for notation of dark colored spleens in all of the high level dogs. Spleen weights and spleen/body weight ratios were elevated in two of three high dose females.
Microscopic examination of tissues revealed marked splenic congestion and extramedullary hematopoiesis of the spleen; deposition of hemosiderin in the spleen, liver, kidney and bone marrow and increased cellularity of the bone marrow, particularly in erythroid elements. These effects were observed in all high level dogs and are reflective of the hemolytic effect of phenothiazine on red blood cells. There was a marginal effect in the dogs at 500ppm, where four of six dogs demonstrated hemosiderin deposition in the liver and kidney. One male exhibited increased extramedullary hematopoiesis in the spleen. However, the other elements of the phenothiazine-induced effects (increase in cellularity of the bone marrow and a reflection of the effect in the hematological studies) suggest that the animals responded well physiologically and the response of the animals at the 500ppm level is of minor biological significance.
Reference
Table: Group mean body weights (kg.) at selected intervals
Interval [weeks] |
MALES |
||||
Dosage Level [ppm] |
|||||
0 |
50 |
200 |
500 |
2000 |
|
0 |
8.9 |
9.1 |
9.3 |
10.8 |
8.3 |
4 |
9.8 |
10.7 |
10.7 |
11.0 |
9.3 |
8 |
10.2 |
11.3 |
11.1 |
11.2 |
10.0 |
13 |
10.6 |
11.9 |
11.7 |
11.6 |
10.1 |
% Increase |
19 |
30 |
26 |
7 |
22 |
Interval [weeks] |
FEMALES |
||||
Dosage Level [ppm] |
|||||
0 |
50 |
200 |
500 |
2000 |
|
0 |
6.5 |
7.7 |
8.0 |
8.6 |
7.8 |
4 |
9.2 |
9.1 |
9.3 |
9.2 |
8.8 |
8 |
9.7 |
9.8 |
9.7 |
9.5 |
9.2 |
13 |
9.7 |
10.2 |
10.1 |
9.5 |
9.7 |
% Increase |
49 |
32 |
26 |
10 |
24 |
Table: Average daily drug intake (mg/kg/day)
Feeding Level [ppm] |
Drug intake (mg/kg/day) |
|
MALES |
FEMALES |
|
0 |
0 |
0 |
50 |
1.54 |
1.59 |
200 |
6.06 |
6.82 |
500 |
16.93 |
17.68 |
2000 |
69.30 |
67.05 |
Table: Summary of Necropsy Findings at 13 weeks
Observation |
Group no |
1 |
2 |
3 |
4 |
5 |
|||||
Sex |
M |
F |
M |
F |
M |
F |
M |
F |
M |
F |
|
|
|||||||||||
Thyroids– Connected |
|
|
|
|
|
1 |
|
|
|
|
|
Lung– Right cardiac lobe enlarged and distended with air. Portions are only thin membraneous remnants of the lung. Completely filled with air. Other portions resemble an alveolar Emphysema. Right diaphragmatic lobe smaller than normal |
|
|
|
|
|
|
|
|
|
1 |
|
Heart– Subendocardial brush stroke reddening in left ventricle |
|
|
|
|
|
|
|
1 |
|
|
|
Heart– Two small firm nodes in right atrioventricular valve |
|
|
|
|
|
|
|
1 |
|
|
|
Heart– Heart worm in right ventricle |
|
|
|
|
|
|
|
|
|
1 |
|
Heart– Left auricle thickened with lumen partially closed |
|
|
|
|
|
|
|
|
|
1 |
|
Heart– Right atrioventricular valve thickened |
|
|
|
|
|
|
|
|
|
1 |
|
Kidney– Left missing |
|
|
1 |
|
|
|
|
|
|
|
|
Spleen– Black nodes at margin |
|
|
|
2 |
3 |
|
|
|
|
|
|
Spleen– Grey discoloration on surface |
|
|
|
|
1 |
|
|
|
|
|
|
Spleen– Dark in color |
|
|
|
|
|
|
4 |
4 |
|
|
|
Spleen– Enlarged |
|
|
|
|
|
|
|
1 |
|
|
|
Urinary Bladder– Red area on neck |
|
|
|
|
|
|
1 |
|
|
|
|
Small intestine– Round worms |
|
|
|
1 |
1 |
1 |
2 |
1 |
1 |
|
Endpoint conclusion
- Endpoint conclusion:
- adverse effect observed
- Dose descriptor:
- NOAEL
- 6 mg/kg bw/day
- Study duration:
- subchronic
- Species:
- dog
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
In the present study repeated dose toxicity of pharmaceutical grade phenothiazine was assessed. Although no specific guideline was followed (study was conducted prior to implementation of GLP and OECD guidelines) the section material and methods provides sufficient information to allow an assessment of the conclusion and results drawn from the study. However, the present study lacks some information about the test item used, e.g. the purity of the test item and consequently the impurities are not given. Since starting material for a synthesis of phenothiazine is diphenylamine, diphenylamine can be regarded as the most relevant impurity. Following the summary and conclusion drawn from the European Union Risk Assessment Report on diphenylamine (final version approved on 2008-05-29), mostly haematological effects are to be expected after repeated dose exposure to diphenylamine. The same is true for phenothiazine, but to a lesser extent. In the study report it is indicated that pharmaceutical grade phenothiazine was used. Therefore it can be assumed that the test item phenothiazine was of a rather high purity with a negligible content of diphenylamine. Since, as mentioned above, the reported effects after repeated dose exposure to both substances are similar,with the effects due to phenothiazine being lower, a possible contamination with diphenylamine may not be considered relevant - especially when keeping in mind that pharmaceutical grade phenothiazine was tested.
The design of the present study comprised four different dose groups and one control group (see IUCLID 5). While haematological effects were found dose-dependent, it was possible to identify a NOAEL. Even in the second highest dose tested (500 ppm group, corresponding food intake: ca. 17 mg/kg body weight/day) only effects of minor biological significance were found. In the 2000 ppm high-dose group (corresponding food intake: ca. 67 mg/kg body weight/day) showed haematological effects reflective for the haemolytic effect of phenothiazine on red blood cells. This, however, is a known effect of phenothiazine and has to be seen in relation to the classification criteria for specific target organ toxicity after repeated exposure (STOT-RE) as laid down in 1272/2008/EC. There it is written that any consistent and significant adverse change in haematology may justify classification as STOT-RE. In the respective guidance to 1272/2008/EC these criteria are further specified. Albeit it was possible to derive a NOAEL in the present repeated dose study with dogs, criteria for classification as STOT-RE (haematology) according to 1272/2008/EC are met. This is especially true for the finding of haemosiderinuria which is supported by relevant histopathological findings in the kidney in combination with other changes indicating significant haemolytic anaemia, such as a reduction in Haemoglobin at ≥ 10 %. In all males of the high dose group this criterion was met after four and thirteen weeks of exposure.
Repeated dose toxicity: via oral route - systemic effects (target organ) cardiovascular / hematological: other
Justification for classification or non-classification
Haemolytic anaemia is one of the main findings in the present study. There was a dose-dependent increase in haemoglobin reduction, accompanied with haemosiderinuria in the kidney. Within the male dogs of the high dose group this effect was most pronounced. Taking the examples for significant adverse changes in haematology as given in the ECHA Guidance on CLP into account, it is justified to classify phenothiazine as STOT-RE cat. 2.
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.
![ECHA](/o/diss-blank-theme/images/factsheets/A-REACH/factsheet/echa_logo.png)