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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
Developmental toxicity / teratogenicity
Administrative data
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 1977
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: Well performed study prior to GLP and OECD-TG, but meeting the necessary scientific and current guideline requirements.
Data source
Referenceopen allclose all
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 977
- Report date:
- 1977
- Reference Type:
- publication
- Title:
- Demonstration of A-Alizarin staining of Bone
- Author:
- Hurley, L.
- Year:
- 1 965
- Bibliographic source:
- Supplement to Teratology Workshop Manual, Berkeley California, January 25-30, 1965, pp. 121-122
- Reference Type:
- publication
- Title:
- Teratology Principles and Techniques
- Author:
- Wilson, J. and Warkany, J.
- Year:
- 1 965
- Bibliographic source:
- University of Chicago Press, Chicago, Illinois, 1965, pp. 271-277
Materials and methods
Test guideline
- Qualifier:
- no guideline followed
- Principles of method if other than guideline:
- - Prior to establishment of OECD technical guidelines
- Objective of the study: A study was initiated to determine the potential teratogenicity of phenothiazine upon gravid rats.
- See section material and methods for further details - GLP compliance:
- no
- Remarks:
- Prior to GLP. However, a QA-statement is included.
- Limit test:
- no
Test material
- Reference substance name:
- Phenothiazine
- EC Number:
- 202-196-5
- EC Name:
- Phenothiazine
- Cas Number:
- 92-84-2
- Molecular formula:
- C12H9NS
- IUPAC Name:
- 10H-phenothiazine
- Details on test material:
- - Sponsor: West Chemical Product's, Inc.
- Lot No.: NB 36-155
Constituent 1
Test animals
- Species:
- rat
- Strain:
- other: Albino
- Details on test animals or test system and environmental conditions:
- - Origin: Charles River
- Breeding: Breeding took place at the Charles River Breeding Laboratories, Inc., North Wilmington, Massachusetts
- Animals were shipped to the testing laboratory on day 5 of gestation
- Sex: only female rats were obtained for the study
- Food: Purina Rat Chow, Ralston Purina Co., St. Louis, Missouri, ad libitum
- Water: ad libitum
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- other: corn oil
- Details on exposure:
- - Solutions were prepared by adding corn oil to the material
- Final concentrations were either 0.3, 1.0 or 3.0 percent phenothiazine (w/v)
- Doses were administered at 5 mL per kg of body weight
- Oral administration via gavage, by means of a hypodermic syringe equipped with a ball-tipped intubation needle - Analytical verification of doses or concentrations:
- not specified
- Details on analytical verification of doses or concentrations:
- No data
- Details on mating procedure:
- - Mating was done at the Charles River Breeding Laboratories, Inc., Notrh Wilmington, Massachusetts
- Copulation was confirmed by sperm-positive results of vaginal examinations
- Day zero is defined as the day of insemination
- Animals were shipped to the testing laboratory on day 5 of gestation
- All dams received were assigned to a treatment group, but only those confirmed pregnant were included in the reported data - Duration of treatment / exposure:
- - All test animals were given the material daily from the 6th day of gestation period through the 15th day inclusive
- Frequency of treatment:
- - A total of 10 doses was applied
- Duration of test:
- - During mating and shipment on gestation day 5 animals were at the Charles River Breeding Laboratories, Inc., North Wilmington, Massachusetts
- From gestation day 5 until gestation day 20 animals were at the facilities of Industrial Bio-Test Laboratories
Doses / concentrations
- Remarks:
- Doses / Concentrations:
15 mg/kg/day, 50 mg/kg/day, 150 mg/kg/day
Basis:
actual ingested
All dams were weighed daily for the purpose of dosage administration
- No. of animals per sex per dose:
- 21 treated female rats per group, not all were pregnant. Details see table "Outline of Experiment" in section "Any other information on material and methods incl. tables"
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - All females were sacrificed by chloroform asphyxation on the 20th day of gestation
Examinations
- Maternal examinations:
- BODY WEIGHT DATA
- Daily weighing for the purpose of dosage administration
- Data recorded and reported includes those at day 6 of gestation (initial dosing), day 9, day 12, day 15 (final dosing) and at day 20 (sacrifice)
MORTALITIY AND REACTIONS
- All noted maternal deaths and untoward behavioural reactions were recorded - Ovaries and uterine content:
- - An incision was made in the abdominal wall and the full extent of both uterine horns were exposed immediately
- Implantation sites were counted, special attention being paid to resorption sites or any uterine abnormalities
- Number of corpora lutea was determined and recorded at this time - Fetal examinations:
- REPRODUCTIVE AND EXTERNAL TERATOGENIC EFFECTS
- Fetal swellings were counted
- Number of viable fetuses present in the uterus was determined (spontaneous movement and a more ruddy color distinguishing live from dead animals)
- Fetuses were removed from the uterus by cutting the umbillical cord
- Blotting paper was used to remove excess amniotic fluid and blood prior to the weighing of the animals
- External examination paid special attention to the following abnormaities: please see table "Examined Abnormalities" in section "Any other information on materials and methods incl. tables".
FETAL SKELETAL AND INTERNAL DEVELOPEMENT
- All fetuses obtained were examined
- Evaluation of skeletal development was conducted using Alizarin staining according to Hurley et al., employing 2/3 of the fetuses of each sex from each litter
- Internal development was evaluated using free-hand razor blade section technique of Wilson et al. upon the remaining fetuses
- Please see references for a complete description - Statistics:
- - Maternal body weights (gestation days 6, 9, 12, 15 and 20), maternal body weight gains (gestation days 6 through 15 and 6 through 20) and fetal body weight data consisted of a One-Way Analysis of Variance with significant effects disclosed by that treatment further studied by Scheffe's Multiple Comparison
- Statistical evaluation of the numbers of corpra lutea, implantation sites, resorption sites and fetuses (total number as well as the numbers of male and female fetuses) were conducted employing Chi-Square Test of Independence - Indices:
- No data
- Historical control data:
- No data
Results and discussion
Results: maternal animals
Maternal developmental toxicity
- Details on maternal toxic effects:
- Maternal toxic effects:yes
Details on maternal toxic effects:
See section "Remarks on results including tables and figures".
Effect levels (maternal animals)
open allclose all
- Dose descriptor:
- NOAEL
- Effect level:
- ca. 50 mg/kg bw/day
- Basis for effect level:
- other: maternal toxicity
- Dose descriptor:
- NOAEL
- Effect level:
- > 150 mg/kg bw/day
- Basis for effect level:
- other: developmental toxicity
Results (fetuses)
- Details on embryotoxic / teratogenic effects:
- Embryotoxic / teratogenic effects:no effects
Details on embryotoxic / teratogenic effects:
See section "Remarks on results including tables and figures".
Effect levels (fetuses)
- Remarks on result:
- other: see Any other information on results incl. tables for details.
Fetal abnormalities
- Abnormalities:
- not specified
Overall developmental toxicity
- Developmental effects observed:
- not specified
Any other information on results incl. tables
A) MATERNAL DATA
BODY WEIGHT DATA
- Mean body weights are presented in the table “Body weight” in this section
- The 15 mg/kg/day and the 50 mg/kg/day were comparable to the control
- No statistically significant intergroup differences
- Body weights in the 150 mg/kg/day group were less than those of the concurrent controls at gestation day 12 and 15, with day 12 results not being statistically significant
- Body weight on gestation day 15 and body weight gain from gestation day 6 through 15 was significantly reduced in the 150 mg/kg/day group
Table: Body weight
Group [Dose Level/Day] |
Body Weight [g] Day of Gestation |
Body Weight Gain [g] |
|||||
6 |
9 |
12 |
15 |
20 |
Days 6 – 15 |
Days 6 – 20 |
|
Control |
214 |
238 |
260 |
287 |
362 |
73 |
148 |
T-I [15 mg/kg] |
217 |
238 |
259 |
286 |
365 |
69 |
148 |
T-II [50 mg/kg] |
209 |
229 |
250 |
278 |
347 |
69 |
138 |
T-III [150 mg/kg] |
212 |
226 |
246 |
267** |
352 |
55** |
140 |
** Statistically significant reduced at the 99% confidence level
MORTALITY
- There were no maternal deaths
REACTIONS
- No unusual behavioral reactions were observed, neither among control or test animals
- One 150 mg/kg/day animal developed a sore on the right side of her neck, which has begun to heal prior to study termination
REPRODUCTIVE EFFECTS
- Mean results are presented in table “Reproductive Effects” in this section
- One control dam was found to have excessive amounts of blood in both uterine horns, another control in one uterine horn only
- One dam of the 50 mg/kg/day group had brown-green colored placentas and left uterine horn
- All other dams examined were free of gross uterine abnormalities
- Numbers of corpora lutea, implantation sites, resorption sites and fetuses were similar for test and control dams
Table: Reproductive Effects
Group [Dose Level/Day] |
Pregnant Females Examined |
Autopsy Findings (Mean/Female) |
Females With One or More Resorption Sites |
||||
Corpora Lutea |
Implantation Sites |
Resorption Sites |
Fetuses |
Total |
Percent |
||
Control |
20 |
10.7 |
9.8 |
1.0 |
8.8 |
8 |
40.0 |
T-I [15 mg/kg] |
18 |
10.5 |
9.2 |
0.4 |
8.8 |
6 |
33.3 |
T-II [50 mg/kg] |
21 |
10.9 |
9.7 |
0.1** |
9.6 |
3 |
14.3 |
T-III [150 mg/kg] |
20 |
11.5 |
10.6 |
0.7 |
10.0 |
10 |
50.0 |
** Statistically significant reduced at the 99% confidence level
B) FETAL DEVELOPMENT DATA
BODY WEIGHTS
- Body weights are presented in table “Fetal Body Weight Data” in this section
- In utero body weights of fetuses from treated animals were essentially the same as from controls
- There were no significant differences in sex ratios among pups from test and control litters
Table: Fetal Body Weight Data
Group [Dose Level/Day] |
Number of Males |
Mean Body Weight |
Number of Females |
Mean Body Weight |
Control |
97 |
3.7 |
79 |
3.4 |
T-I [15 mg/kg] |
78 |
3.8 |
80 |
3.6 |
T-II [50 mg/kg] |
101 |
3.7 |
100 |
3.6 |
T-III [150 mg/kg] |
106 |
3.9 |
93 |
3.6 |
EXTERNAL DEVELOPMENT
- External abnormalities noted among fetuses are listed in table “External Abnormalities” in this section
- All other fetuses (except for those listed) were free of apparent malformations
- Dam 38 of T-I exhibited an edematous late resorption
Table: External Abnormalities
Group [Dose Level/Day] |
Finding |
Control |
- Dam no 2: 1 fetus with hematoma - Dam no 6: 1 fetus with hematoma - Dam no 21: 1 fetus with hematoma |
T-I [15 mg/kg] |
- Dam no 27: 6 of 11 fetuses with a hematoma - Dam no 33: 1 runt fetus |
T-II [50 mg/kg] |
- Dam no 45: 2 of 8 fetuses with a hematoma - Dam no 59: 1 runt fetus |
T-III [150 mg/kg] |
- Dam no 70: 3 of 10 fetuses with a hematoma - Dam no 76: 1 discolored (yellow) fetus - Dam no 78: 4 of 11 fetuses with a hematoma - Dam no 81: 1 runt fetus |
SKELETAL DEVELOPMENT
- Results of skeletal development are summarized in table “Fetal Skeletal Development” in this section
- Control and treated groups compared favorably
- No major skeletal anomalies were noted
Table: Fetal Skeletal Development
Group [Dose Level/Day] |
Fetuses Examined |
Findings |
Incidence |
% of Total Examined |
Control |
120 (19) |
*Incompletely ossified sternum section(s) *Non-ossified sternum section(s) *Supernumerary ribs Angulated ribs |
113 (19) 49 (14) 5 (2) 1 |
94.2 40.8 4.2 0.8 |
Total number of fetuses with findings Total numbers of abnormal fetuses Total number of fetuses with no abnormal findings |
120 (19) 1 119 (19) |
100.0 0.8 99.2 |
||
T-I [15 mg/kg] |
104 (18) |
*Incompletely ossified sternum section(s) *Non-ossified sternum section(s) |
103 (18) 36 (15) |
99.0 34.6 |
Total number of fetuses with findings Total numbers of abnormal fetuses Total number of fetuses with no abnormal findings |
104 (18) – 104 (18) |
100.0 – 100.0 |
||
T-II [50 mg/kg] |
130** (21) |
*Incompletely ossified sternum section(s) *Non-ossified sternum section(s) *Supernumerary ribs Angulated and deteriorated ribs Mal-formed parietal skull bones Mal-formed interparietal skull bones Mal-formed occipital skull bones |
129 (21) 53 (18) 2 (2) 1 1 1 1 |
99.2 40.8 1.5 0.8 0.8 0.8 0.8 |
Total number of fetuses with findings Total numbers of abnormal fetuses Total number of fetuses with no abnormal findings |
130 (21) 1 129 (21) |
100.0 0.8 99.2 |
||
T-III [150 mg/kg] |
130 (20) |
*Incompletely ossified sternum section(s) *Non-ossified sternum section(s) * Incompletely ossified frontal+parietal skull bones *Supernumerary ribs Angulated ribs |
127 (20) 49 (17) 1 7 (4) 3 (1) |
97.7 37.7 0.8 5.4 2.3 |
Total number of fetuses with findings Total numbers of abnormal fetuses Total number of fetuses with no abnormal findings |
130 (20) 3 (1) 127 (20) |
100.0 2.3 97.7 |
Note: Numbers in parentheses indicate
the number of litters.
* Considered to be an incidental finding
** One fetus inadvertently destroyed during process.
INTERNAL DEVELOPMENT
- Results of internal development are summarized in table “Fetal Internal Development” in this section
- Findings in control and treated animals were similar, the incidence of findings within the normally expected range
- Changes in the size of the atrium reflect naturally occurring variations commonly observed in the strain of rat employed and are considered to be incidental findings and are not considered to be treatment-related
Table: Fetal Internal Development
Group [Dose Level/Day] |
Fetuses Examined |
Findings |
Incidence |
% of Total Examined |
Control |
56 (19) |
*Small atria Renal caudal ectopia Unilateral increased renal pelvic caviation |
27 (15) 1 1 |
48.2 1.8 1.8 |
Total number of fetuses with findings Total numbers of abnormal fetuses Total number of fetuses with no abnormal findings |
29 (15) 2 (2) 54 (19) |
51.8 3.6 96.4 |
||
T-I [15 mg/kg] |
54 (18) |
*Small atria Unilateral increased renal pelvic caviation |
16 (8) 1 |
29.6 1.9 |
Total number of fetuses with findings Total numbers of abnormal fetuses Total number of fetuses with no abnormal findings |
16 (8) 1 53 (17) |
29.6 1.9 98.1 |
||
T-II [50 mg/kg] |
70 (21) |
*Small atria |
27 (14) |
38.6 |
Total number of fetuses with findings Total numbers of abnormal fetuses Total number of fetuses with no abnormal findings |
27 (14) – 70 (21) |
38.6 – 100.0 |
||
T-III [150 mg/kg] |
69 (20) |
*Small atria Unilateral increased renal pelvic caviation Bilateral increased renal pelvic cavitation Slight edema |
21 (4) 1 1 1 |
30.4 1.4 1.4 1.4 |
Total number of fetuses with findings Total numbers of abnormal fetuses Total number of fetuses with no abnormal findings |
24 (15) 3 (3) 66 (19) |
34.8 4.3 95.7 |
Note: Numbers in parentheses indicate
the number of litters.
* Considered to be an incidental finding
Applicant's summary and conclusion
- Conclusions:
- There were no deaths or unusual behavioral reactions noted among the test or control animals. The results of the gestation day 20 sacrifice revealed no reproductive effect which could be correlated with the exposure to the tested material. There were no deaths or unusual behavioral reactions noted among the test or control animals. The results of the gestation day 20 sacrifice revealed no reproductive effect which could be correlated with the exposure to the tested material.
- Executive summary:
A teratogenic study was conducted employing albino rats orally treated with 0, 15, 50 or 150 mg phenothiazine per kg body weight per day during gestation days 6 through 15 inclusive. The following results were obtained during the investigation.
Body weight and body weight gains of the control, 15 and 50 mg/kg/day group dams were similar throughout the investigation. The gestation day 15 body weights and the calculated body weight gains during the exposure period (gestation day 6 through 15) obtained for dams given 150mg phenothiazine per kg per day were significantly less than those of the concurrent control dams. The gestation day 12 body weights of these females were also slightly less than the control females, though these data, as well as all other body weights obtained among these dams were free of statistical significance. There were no deaths or unusual behavioral reactions noted among the test or control animals. The results of the gestation day 20 sacrifice revealed no reproductive effect which could be correlated with the exposure to the tested material.The body weights of fetuses obtained from dams given phenothiazine were essentially the same as those of the concurrent control fetuses. The examination of fetuses for external developmental anomalies revealed no major structural abnormalities. The evaluations of fetal skeletal and internal development were similar for test and control group fetuses, the incidence of occurrences of findings being within the normally expected range experienced at the respective testing laboratory.
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