Registration Dossier

Repeated dose toxicity: via oral route;

NOAEL was considered to be 300 mg/kg/day in Wistar male and female rats, when they were treated withReaction mass of 1-Propanaminium, 3-[[2-cyano-3-[4-(diethylamino)phenyl]-1-oxo-2-propen-1-yl]oxy]-N-[2-[[2-cyano-3-[4-(diethylamino)phenyl]-1-oxo-2-propen-1-yl]oxy]ethyl]-N,N-dimethyl- & chloride by oral gavage for subchronic study.

Repeated inhalation study:

According to Annex IX of the REACH regulation, testing by the inhalation route is appropriate only if exposure of humans via inhalation is likely. Taking into account the low vapour pressure of the substance Reaction mass of 1-Propanaminium, 3-[[2-cyano-3-[4-(diethylamino)phenyl]-1-oxo-2-propen-1-yl]oxy]-N-[2-[[2-cyano-3-[4-(diethylamino)phenyl]-1-oxo-2-propen-1-yl]oxy]ethyl]-N,N-dimethyl-& chloride) which is reported as 9.225759e-22mHg at 25 C. Therefore this study is considered for waiver.

Repeated dermal study;

The acute toxicity value for substance Reaction mass of 1-Propanaminium, 3-[[2-cyano-3-[4-(diethylamino)phenyl]-1-oxo-2-propen-1-yl]oxy]-N-[2-[[2-cyano-3-[4-(diethylamino)phenyl]-1-oxo-2-propen-1-yl]oxy]ethyl]-N,N-dimethyl-& chloride (as provided in section 7.2.3) is in range of >2000mg/kg body weight. Also, given the use of the chemical; repeated exposure by the dermal route is unlikely since the use of gloves is common practice in industries. Thus, it is expected that Reaction mass of 1-Propanaminium, 3-[[2-cyano-3-[4-(diethylamino)phenyl]-1-oxo-2-propen-1-yl]oxy]-N-[2-[[2-cyano-3-[4-(diethylamino)phenyl]-1-oxo-2-propen-1-yl]oxy]ethyl]-N,N-dimethyl-& chloride shall not exhibit 28 day repeated dose toxicity by the dermal route. In addition, there is no data available that suggests that Reaction mass of 1-Propanaminium, 3-[[2-cyano-3-[4-(diethylamino)phenyl]-1-oxo-2-propen-1-yl]oxy]-N-[2-[[2-cyano-3-[4-(diethylamino)phenyl]-1-oxo-2-propen-1-yl]oxy]ethyl]-N,N-dimethyl-& chloride exhibit repeated dose toxicity by the dermal route. Hence this end point was considered for waiver.

Reference

Endpoint:: repeated dose toxicity: oral, other
Remarks:: Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test
Type of information:: experimental study
Adequacy of study:: weight of evidence
Reliability:: 4 (not assignable)
Rationale for reliability incl. deficiencies:: secondary literature
Justification for type of information:: Data is from secondary source.
Qualifier:: according to guideline
Guideline:: OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Principles of method if other than guideline:: In order to evaluate the toxicity of test chemical Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test was conducted in male and female Wistar Rats.
GLP compliance:: not specified
Limit test:: no
Specific details on test material used for the study:: - Name of test material : Reaction mass of 1-Propanaminium, 3-[[2-cyano-3-[4-(diethylamino)phenyl]-1-oxo-2-propen-1-yl]oxy]-N-[2-[[2-cyano-3-[4-(diethylamino)phenyl]-1-oxo-2-propen-1-yl]oxy]ethyl]-N,N-dimethyl- & chloride- Molecular formula : C35H46ClN5O4- Molecular weight : 636.232 g/mol- Smiles notation : C(CCOC(\C(=C\c1ccc(cc1)N(CC)CC)C#N)=O)[N+](C)(C)CCOC(\C(=C\c1ccc(cc1)N(CC)CC)C#N)=O.[ClH-]- InChl : 1S/C35H46N5O4.ClH/c1-7-38(8-2)32-16-12-28(13-17-32)24-30(26-36)34(41)43-22-11-20-40(5,6)21-23-44-35(42)31(27-37)25-29-14-18-33(19-15-29)39(9-3)10-4;/h12-19,24-25H,7-11,20-23H2,1-6H3;1H/q+1;/p-1/b30-24+,31-25+;- Substance type: Organic- Physical state: Liquid
Species:: rat
Strain:: Wistar
Sex:: male/female
Details on test animals or test system and environmental conditions:: Not specified
Route of administration:: oral: gavage
Vehicle:: not specified
Analytical verification of doses or concentrations:: not specified
Duration of treatment / exposure:: 28 days for male 55 days for female
Frequency of treatment:: Daily
Remarks:: 0,100, 300 and 1000 mg/kg bw/day
No. of animals per sex per dose:: Not specified
Control animals:: yes, concurrent vehicle
Details on study design:: Not specified
Positive control:: Not specified
Observations and examinations performed and frequency:: CAGE SIDE OBSERVATIONS: Yes DETAILED CLINICAL OBSERVATIONS: Yes BODY WEIGHT: Not specified FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Not specified - Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Not specified 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: Not specified WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Not specified OPHTHALMOSCOPIC EXAMINATION: Not specified HAEMATOLOGY: Not specified CLINICAL CHEMISTRY: Yes ,Parameters such as creatinine, urea and potassium level were observedURINALYSIS: Not specified NEUROBEHAVIOURAL EXAMINATION: Not specified
Sacrifice and pathology:: GROSS PATHOLOGY: Yes, the male animals were necropsied after 28 days of administration of test chemical.HISTOPATHOLOGY: Yes , Animals were observed microscopically.
Clinical signs:: no effects observed
Description (incidence and severity):: No significant effect was observed at dose level of 0,100, 300 and 1000 mg/kg bw/day in treated group compare to control.
Mortality:: no mortality observed
Description (incidence):: No significant effect was observed at dose level of 0,100, 300 and 1000 mg/kg bw/day in treated group compare to control.
Body weight and weight changes:: not specified
Food consumption and compound intake (if feeding study):: not specified
Food efficiency:: not specified
Water consumption and compound intake (if drinking water study):: not specified
Ophthalmological findings:: not specified
Haematological findings:: not specified
Clinical biochemistry findings:: effects observed, treatment-related
Description (incidence and severity):: Significant increase in creatinine levels were observed at the dose level of 1000 mg/kg bw/day in treated group compare to control.Even Increased urea and potassium levels were observed at the dose level of 1000 mg/kg bw/day in treated female group compare to control.
Urinalysis findings:: not specified
Behaviour (functional findings):: not specified
Immunological findings:: not specified
Organ weight findings including organ / body weight ratios:: not specified
Gross pathological findings:: not specified
Neuropathological findings:: not specified
Histopathological findings: non-neoplastic:: effects observed, treatment-related
Description (incidence and severity):: Minimally increased occurrence of single cell necrosis or apoptosis in the liver of six males and three females were observed at the dose level of 1000 mg/kg bw/day in treated group compare to control.
Histopathological findings: neoplastic:: not specified
Other effects:: not specified
Dose descriptor:: NOAEL
Effect level:: 300 other: mg/kg/day
Based on:: test mat.
Sex:: male/female
Basis for effect level:: other: No significant effect was observed at this dose.
Critical effects observed:: not specified
Treatment related:: not specified
Dose response relationship:: not specified
Relevant for humans:: not specified
Conclusions:: NOAEL was considered to be 300 mg/kg/day in Wistar male and female rats, when they were treated withReaction mass of 1-Propanaminium, 3-[[2-cyano-3-[4-(diethylamino)phenyl]-1-oxo-2-propen-1-yl]oxy]-N-[2-[[2-cyano-3-[4-(diethylamino)phenyl]-1-oxo-2-propen-1-yl]oxy]ethyl]-N,N-dimethyl- & chloride by oral gavage for subchronic study.
Executive summary:: In a Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test was conducted for test chemical by OECD guideline 422.The test chemical was exposed to Wistar male and female rat were in the concentration of 0, 100, 300 and 1000 mg/kg bw/day by oral gavage for 56 days . The animals were observed for mortality, clinical sign, clinical chemistry, gross pathology and histopathology. Increased creatinine levels were observed in male and female rats while increased urea and potassium levels in female rats at dose level of 1000 mg/kg/day. In addition, minimal increased occurrence of single cell necrosis or apoptosis in the liver of six males and three females at 1000 mg/kg/day were observed. No significant adverse effect at 100 and 300 mg/kg bw was observed. Therefore NOAEL was considered to be 300 mg/kg/day in Wistar male and female rats, when they were treated with test chemical by oral gavage for subchronic study.

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

300 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

K2 data from qulified publication.

Endpoint conclusion:

no study available

Endpoint conclusion:

no study available

Endpoint conclusion:

no study available

Endpoint conclusion:

no study available

Repeated dose toxicity: via oral route;

Experimental study for target test chemical and data available for the read across chemicals was reviewed to determine the toxic nature of Reaction mass of 1-Propanaminium, 3-[[2-cyano-3-[4-(diethylamino)phenyl]-1-oxo-2-propen-1-yl]oxy]-N-[2-[[2-cyano-3-[4-(diethylamino)phenyl]-1-oxo-2-propen-1-yl]oxy]ethyl]-N,N-dimethyl-& chloriderepeated exposure by oral route. The study is as mentioned below: As the read across substances share high similarity in structure and functional group .Therefore, it is acceptable to derive information on toxicity from the analogue substance for target test substance. The studies are mention below;

In a Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test was conducted for test chemical by OECD guideline 422.The test chemical was exposed to Wistar male and female rat were in the concentration of 0, 100, 300 and 1000 mg/kg bw/day by oral gavage for 56 days . The animals were observed for mortality, clinical sign, clinical chemistry, gross pathology and histopathology. Increased creatinine levels were observed in male and female rats while increased urea and potassium levels in female rats at dose level of 1000 mg/kg/day. In addition, minimal increased occurrence of single cell necrosis or apoptosis in the liver of six males and three females at 1000 mg/kg/day were observed. No significant adverse effect at 100 and 300 mg/kg bw was observed. Therefore NOAEL was considered to be 300 mg/kg/day for Reaction mass of 1-Propanaminium, 3-[[2-cyano-3-[4-(diethylamino)phenyl]-1-oxo-2-propen-1-yl]oxy]-N-[2-[[2-cyano-3-[4-(diethylamino)phenyl]-1-oxo-2-propen-1-yl]oxy]ethyl]-N,N-dimethyl-& chloride in Wistar male and female rats, when they were treated with test chemical by oral gavage for subchronic study.

The study was conducted to determine the Maximum tolerated dose of test chemical in Charles river CD-1 mice .When administered Orally via the diet at dose levels of 0.001, 0.01, 0.1, 1.0 and 5.0% (1.66, 16.66, 166.66, 1666.66, 8333.33mg/kg bw/day)pure color for a period of 90-91 days. Animals were observed for mortality,clinical sign, food consumoption,organ weight,gross and histipathology.All animals receiving 5.0% color died by the second week of test substance administration, and two males receiving 1.0% died during the course of the study. With the exception of five animals which died accidentally, all other animals survived the duration of the study. Based on the results obtained with respect to hepatotoxicity and body weight changes along with the histopathologies the NOAEL was considered to be 166.66mg/kg for test chemical. AS no significant effct were observed at this dose . Therefore NOAEL was consideed to be 166.66mg/kgbw/day in Charles river CD-1 mice by oral died for 90-91 days.

Combined repeated dose & carcinogenicity was performed to determine the toxic nature of test chemical upon repeated exposure by oral route of exposure. Male and female albino rats were fed the test chemical at dose levels of 100 mg/Kg bw/day using diet for 20-21 months. Auramine was used as a positive control chemical. The animals were observed for mortality, body weight changes, gross pathology and neoplastic and non-neoplastic histopathology. Survival observed in the test animals was comparable to that noted in untreated control group. A less marked reduction in body weight gain was observed in the treated rats as compared to controls. Nodules were observed on the livers only 25% (7/28) of the test rats at the time of final sacrifice which was less as compared to the nodules observed in positive control 59% (20 /34). No other outstanding differences were noted in any of the groups upon gross pathologic examination. There was significant liver injury among animals from both the positive' control and test groups which was attributed to the positive control and test materials.The incidence of hyperplasia observed was comparable in positive control and treated animals. Minor focal lesions of degeneration, necrosis , fatty metamorphosis , inflammation, bile duct proliferation and cholangiofibrosis were present in the liver of control, positive control and test animals. However the severity of these Iesions was generally greater in the livers of the positive control animals than in the Iivers of control or test animals. The lesions noted in other tissues upon microscopic examination of the from control, positive control and test animals were attributed to naturally occurring disease and were considered to be normal for albino rats of this age and strain. Hepatomas were present in 2/9 male and 1/19 female that survived the length of the investigation. There were no hepatomas observed in any of the treated animals that died prior to the conclusion of the study. On the basis of observations made, the no observed adverse effect level (NOAEL) for test chemical is considered to be 100 mg/Kg bw/day.

Based on the data available for the target chemical, Reaction mass of 1-Propanaminium, 3-[[2-cyano-3-[4-(diethylamino)phenyl]-1-oxo-2-propen-1-yl]oxy]-N-[2-[[2-cyano-3-[4-(diethylamino)phenyl]-1-oxo-2-propen-1-yl]oxy]ethyl]-N,N-dimethyl-&chloride is not likely to be toxic by oral route as per the criteria mentioned in CLP regulation.

Repeated inhalation study:

According to Annex IX of the REACH regulation, testing by the inhalation route is appropriate only if exposure of humans via inhalation is likely. Taking into account the low vapour pressure of the substance Reaction mass of 1-Propanaminium, 3-[[2-cyano-3-[4-(diethylamino)phenyl]-1-oxo-2-propen-1-yl]oxy]-N-[2-[[2-cyano-3-[4-(diethylamino)phenyl]-1-oxo-2-propen-1-yl]oxy]ethyl]-N,N-dimethyl-& chloride) which is reported as 9.225759e-22mHg at 25 C. Therefore this study is considered for waiver.

Repeated dermal study;

The acute toxicity value for substance Reaction mass of 1-Propanaminium, 3-[[2-cyano-3-[4-(diethylamino)phenyl]-1-oxo-2-propen-1-yl]oxy]-N-[2-[[2-cyano-3-[4-(diethylamino)phenyl]-1-oxo-2-propen-1-yl]oxy]ethyl]-N,N-dimethyl-& chloride (as provided in section 7.2.3) is in range of >2000mg/kg body weight. Also, given the use of the chemical; repeated exposure by the dermal route is unlikely since the use of gloves is common practice in industries. Thus, it is expected that Reaction mass of 1-Propanaminium, 3-[[2-cyano-3-[4-(diethylamino)phenyl]-1-oxo-2-propen-1-yl]oxy]-N-[2-[[2-cyano-3-[4-(diethylamino)phenyl]-1-oxo-2-propen-1-yl]oxy]ethyl]-N,N-dimethyl-& chloride shall not exhibit 28 day repeated dose toxicity by the dermal route. In addition, there is no data available that suggests that Reaction mass of 1-Propanaminium, 3-[[2-cyano-3-[4-(diethylamino)phenyl]-1-oxo-2-propen-1-yl]oxy]-N-[2-[[2-cyano-3-[4-(diethylamino)phenyl]-1-oxo-2-propen-1-yl]oxy]ethyl]-N,N-dimethyl-& chloride exhibit repeated dose toxicity by the dermal route. Hence this end point was considered for waiver.

Based on the observations made and on the basis of the data summarized from read across chemicals, Reaction mass of 1-Propanaminium, 3-[[2-cyano-3-[4-(diethylamino)phenyl]-1-oxo-2-propen-1-yl]oxy]-N-[2-[[2-cyano-3-[4-(diethylamino)phenyl]-1-oxo-2-propen-1-yl]oxy]ethyl]-N,N-dimethyl-& chloride does not exhibit toxic nature upon repeated exposure by oral, inhalation and dermal route of exposure and hence is not likely to classify as per the criteria mentioned in CLP regulation.