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

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

NOAEL was considered to be 300 mg/kg/day for P generation when Wistar male and female rat were treated with test chemical orally by gavage for 63 days.

Thus, the test chemical is not likely to be toxic as per the criteria mentioned in CLP regulation.  

Link to relevant study records

Reference

Endpoint:

screening for reproductive / developmental toxicity

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 form BASF Corporation

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:

Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test in Wistar Rats treated with test chemical

GLP compliance:

not specified

Limit test:

no

Species:

rat

Strain:

Wistar

Sex:

male/female

Route of administration:

oral: gavage

Type of inhalation exposure (if applicable):

not specified

Vehicle:

not specified

Details on exposure:

not specified

Details on mating procedure:

- M/F ratio per cage:1: 1 ratio - Length of cohabitation:Overnight - Proof of pregnancy: [vaginal plug / sperm in vaginal smear] referred to as [day 0 / day 1] of pregnancyThe day on which sperm was detected was referred to as gestation day (GD) 0 and the following day as GD 1.

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

More than 63 days

Frequency of treatment:

Daily

Details on study schedule:

not specified

Dose / conc.:

0 mg/kg bw/day (actual dose received)

Dose / conc.:

100 mg/kg bw/day (actual dose received)

Dose / conc.:

300 mg/kg bw/day (actual dose received)

Dose / conc.:

1 000 mg/kg bw/day (actual dose received)

No. of animals per sex per dose:

not specified

Control animals:

yes, concurrent vehicle

Details on study design:

not specified

Positive control:

not specified

Parental animals: Observations and examinations:

Survival, Clinical sign, Hemoglobin and clinical chemistry were examined.

Oestrous cyclicity (parental animals):

Not specified

Sperm parameters (parental animals):

Not specified

Litter observations:

Not specified

Postmortem examinations (parental animals):

Gross pathology and histopathology was examined.

Postmortem examinations (offspring):

Not specified

Statistics:

Not specified

Reproductive indices:

Not specified

Offspring viability indices:

Not specified

Clinical signs:

not specified

Dermal irritation (if dermal study):

not specified

Mortality:

not specified

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):

When treated with 1000 mg/kg/day, Increased creatinine levels were observed in male and female rats and Increased urea and potassium levels in female rats were observed.

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Immunological findings:

not specified

Organ weight findings including organ / body weight ratios:

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 at 1000 mg/kg/day

Histopathological findings: neoplastic:

not specified

Other effects:

not specified

Reproductive function: oestrous cycle:

not specified

Reproductive function: sperm measures:

not specified

Reproductive performance:

not specified

Dose descriptor:

NOAEL

Effect level:

300 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

haematology

histopathology: non-neoplastic

Remarks on result:

other: No effect observed

Critical effects observed:

not specified

System:

other: not specified

Organ:

not specified

Treatment related:

not specified

Dose response relationship:

not specified

Relevant for humans:

not specified

Clinical signs:

not specified

Dermal irritation (if dermal study):

not specified

Mortality / viability:

not specified

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:

not specified

Urinalysis findings:

not specified

Sexual maturation:

not specified

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

not specified

Histopathological findings:

not specified

Other effects:

not specified

Behaviour (functional findings):

not specified

Developmental immunotoxicity:

not specified

Dose descriptor:

other: not specified

Generation:

other: not specified

Based on:

not specified

Sex:

not specified

Basis for effect level:

other: not specified

Remarks on result:

other: not specified

Critical effects observed:

not specified

System:

other: not specified

Organ:

not specified

Treatment related:

not specified

Dose response relationship:

not specified

Relevant for humans:

not specified

Reproductive effects observed:

not specified

Treatment related:

not specified

Relation to other toxic effects:

not specified

Dose response relationship:

not specified

Relevant for humans:

not specified

Conclusions:

NOAEL was considered to be 300 mg/kg/day for P generation when Wistar male and female rat were treated with test chemical orally by gavage for 63 days.

Executive summary:

In a Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test, Westar male and female rat were treated with test chemical in the concentration of 0, 100, 300 and 1000 mg/kg bw/day orally by gavage for 63 days. Increased creatinine levels were observed in male and female rats and increased urea and potassium levels in female rats were observed at 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. No effect at 100 and 300 mg/kg bw was observed. NOAEL was considered to be 300 mg/kg/day for P generation when Wistar male and female rat were treated with test chemical orally by gavage for 63 days.

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

300 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

Data is Klimisch 4 and from secondary source

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

Reproductive toxicity:

Studies available for the test chemicals was reviewed to determine the toxic nature of[2-[[2-cyano-3-[ 4-( diethylam ino) phenyl]-1-oxoallyl]oxy]ethyl][3-[[2-cyano-3-[ 4-( diethylamino )phenyl]-1-oxoallyl]oxy]propyl]dimethylammon ium chloride.The studies are as mentioned below:

Study 1

In a Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test, Westar male and female rat were treated with test chemical in the concentration of 0, 100, 300 and 1000 mg/kg bw/day orally by gavage for 63 days. Increased creatinine levels were observed in male and female rats and increased urea and potassium levels in female rats were observed at 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. No effect at 100 and 300 mg/kg bw was observed. Therefore, NOAEL was considered to be 300 mg/kg/day for P generation when Wistar male and female rat were treated with test chemical orally by gavage for 63 days.

Study 2

In a Reproductive/Teratogenic toxicity study Dutch Belted female Rabbits were treated with test chemical in the concentration of 0, 30, 100 and 250 mg/kg body weight/day by oral gavage. One rabbits died each in 30 and 250 mg/kg bw/day including control. One rabbit aborted on day 28 of gestation at 250 mg/kg bw/day as compared to control. Pneumonia was observed in three rabbit which were died. Orange discoloration of the urine was observed in all the treated rabbits between days 7 and 28 of gestation as compared to control. No effect on body weight and body weight gain and No effect on Post-implantation loss/dam, Total implantations/dam and Corpora lutea/dam were observed in treated rabbits as compared to control. Similarly, there were no biologically meaningful or statistically significant differences in the number of litters, Foetal sex and gross pathological changes were observed in treated rabbits as compared to control. In addition, No effect on viability of foetus, foetal body weight and sex of foetus were observed as compared to control. At 30 and 100 mg/kg be/day, malformations were observed in two foetuses from two litters. However, these values fell within the ranges of historical control data. There were no biologically meaningful or statistically significant differences in number of fetuses with malformations, number of foetuses or litters with developmental variations were observed in foetuses of any of the treated groups. Therefore, Reproductive NOAEL was considered to be 250 mg/kg body weight /day for F0 and F1 generation when Dutch Belted female rabbits were treated with test chemical orally by gavage from day 6 to 27 of gestation.

Study 3

In a Repeated Dose Toxicity Study Newly weaned albino male and female rats treated with test chemical in the concentration of 0, 200, 1000 and 2000 mg/kg/day orally in feed for 90 days. All animals were died at 5th week of study at 5000 mg/kg bw. Except for one female which succumbed in the 9^thweek. No mortality was observed in 200 and 1000 mg/kg bw treated rats. All animals looked very sick in the second week of the experiment at 5000 mg/kg bw. No abnormalities in appearance were observed in 200 and 1000 mg/kg bw treated rats. Decrease in body weight were observed in treated rats at 1000 and 5000 mg/kg bw as compared to control. Slight decrease in body weight but not significant as compared to control from week 6 onwards at 200 mg/kg bw. Decrease in food consumption were observed in treated rats at 5000 mg/kg bw and slight decrease in food consumption were observed in treated rats at 200 and 1000 mg/kg bw as compared to control. Decrease in food efficiency were observed in treated rats at 5000 mg/kg bw and slight decrease in food efficiency were observed in treated rats at 1000 mg/kg bw as compared to control. Decrease in food efficiency were observed in treated rats at 200 mg/kg bw as compared to control. Similarly, significant increase in percentage of neutrophils and White blood cell counts were observed in treated male and female rats at 1000 mg/kg bw and significant increase in Packed cell volume were observed in male rats at 200 mg/kg bw but no dose-relationship was observed. Increase in SGOT activity of females and decreased in SAP activity of males were observed at 1000 mg/kg bw, decreased SGOT activity in males at 200 mg/kg bw but not observed at 1000 mg/kg bw and is therefore considered incidental. Slight decrease in G6Pase activity with increasing levels of Tinopal was observed in females only. When the enzyme activity is expressed per unit body weight the figures show a slight tendency to increase with increasing levels of Tinopal in males, while in females there are no distinct differences between the groups. Very slight decrease in G6PD enzyme activity with increasing levels of Tinopal in females. Here, too, this decrease disappeared when the enzyme activity was expressed per unit body weight. In addition, increase in relative weights of the kidney, liver and the brain and decrease in testis and ovary weight were observed at 1000 mg/kg bw as compared to control. No effect on reproductive organ weight of 200 mg/kg bw treated male and female rats were observed as compared to control. Large, pale kidneys in all male and female rats at 1000 mg/kg bw. Most of the male rats in this group had strikingly small testicles, other les ions noted at autopsy, such as unilateral hydronephrocis, eurly signs of murine pneuronia, and proteinaceous plugs in urinary bladder, are frequently encountered in the strain of used rats. They may therefore, not be related to the ingestion of the test compound. Necrosis, swelling, irregular vacuolization (Sudan III negative) and granular deterioration (eosinophylic, PAS-negative granules) of tubular epithelial cells in the renal cortex of all male and felllll1e rats at 1000 mg/kg bw. Sloughed necrotic tubular material was often found in tubular lumens. The nuclei of viable tubulur cells varied considerably in size and chromatin content. Dilated tubules lined by flattened epithelium and filled with proteinaceous casts were seen in most animals. Moderate degree of bilateral testicular atrophy were observed in male rats at 1000 mg/kg bw. A number of seminiferous tubules only contained Sertoli cells and occasional spermatogonia containing an irregularly vacuolated cytoplasm, Partial inhibition of spermatogenosis occurred in other tubules in which many polynucleated giant cells were seen. Varying numbers of seminiferous tubules still showed a normal development of sperm cells. In the epididymic tubules cellular debris, scattered spermatozoa and a few giant cells were found. Therefore, NOAEL was considered to be 200 mg/kg/day for P generation when Newly weaned albino male and female rats treated with test chemical orally by feed for 90 days.

Based on the data available for the target test chemical and read across chemicals,[2-[[2-cyano-3-[ 4-( diethylam ino) phenyl]-1-oxoallyl]oxy]ethyl][3-[[2-cyano-3-[ 4-( diethylamino )phenyl]-1-oxoallyl]oxy]propyl]dimethylammon ium chlorideis considered to be safe at dose 300 mg/Kg/day. Hence the test chemical is not likely to be toxic as per the criteria mentioned in CLP regulation.  

Effects on developmental toxicity

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Justification for classification or non-classification

Based on the data available for the target test chemical and read across chemicals,[2-[[2-cyano-3-[ 4-( diethylam ino) phenyl]-1-oxoallyl]oxy]ethyl][3-[[2-cyano-3-[ 4-( diethylamino )phenyl]-1-oxoallyl]oxy]propyl]dimethylammon ium chlorideis considered to be safe at dose 300 mg/Kg/day. Hence the test chemical is not likely to be toxic as per the criteria mentioned in CLP regulation.