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Diss Factsheets

Toxicological information

Toxicity to reproduction

Currently viewing:

Administrative data

Endpoint:
screening for reproductive / developmental toxicity
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Justification for type of information:
Data is fom J-check

Data source

Reference
Reference Type:
other: J check
Title:
Unnamed
Year:
2011

Materials and methods

Test guideline
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 Rats
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Basic violet 1
EC Number:
616-846-4
Cas Number:
8004-87-3
Molecular formula:
C24H28N3
IUPAC Name:
Basic violet 1
Test material form:
other: DYE
Details on test material:
- Name of test material (as cited in study report): C.I. Basic Violet 1- Molecular formula: C24H28ClN3- Molecular: 393.95 g/mol- Substance type: Organic-OTHER- The enclosed study provides information on a commercial mixture.The mixture contains 21 % of C.I. Basic Violet 1 in a commercial mixture of CALCOZINE black CSP powder.

Test animals

Species:
rat
Strain:
Crj: CD(SD)
Sex:
male/female
Details on test animals or test system and environmental conditions:
- Age at study initiation of dosing: 10 weeks old

Administration / exposure

Route of administration:
oral: gavage
Type of inhalation exposure (if applicable):
not specified
Vehicle:
other: 0.5 % Methylcellulose aqueous solution
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: Dose were prepared by suspendingtest substance in 0.5 % Methylcellulose aqueous solution at 0, 1.6, 8 and 40 mg/kg bw. DIET PREPARATION - Rate of preparation of diet (frequency): - Mixing appropriate amounts with (Type of food): - Storage temperature of food: VEHICLE - Justification for use and choice of vehicle (if other than water): 0.5 % Methylcellulose aqueous solution - Concentration in vehicle: 0, 1.6, 8 and 40 mg/kg bw. - Amount of vehicle (if gavage): 5 mL/kg - Lot/batch no. (if required): - Purity:
Details on mating procedure:
not specified
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
Male: 42 day Female: 41 - 48 days (from 14 days before mating to day 4 of lactation)
Frequency of treatment:
Daily
Details on study schedule:
not specified
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day (actual dose received)
Dose / conc.:
1.6 mg/kg bw/day (actual dose received)
Dose / conc.:
8 mg/kg bw/day (actual dose received)
Dose / conc.:
40 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
Total: 1060 mg/kg/day: 7 male, 12 female 1.6 mg/kg/day: 12 male, 12 female8 mg/kg/day: 12 male, 12 female40 mg/kg/day: 7 male, 12 femaleRecory group:0 mg/kg/day: 5 male, 5 female 40 mg/kg/day: 5 male, 5 female
Control animals:
yes, concurrent vehicle
Positive control:
not specified

Examinations

Parental animals: Observations and examinations:
Survival, clinical sign, body weight, food consumption and urineanalysis, FOB, Urinalysis (Male only), were examined.
Oestrous cyclicity (parental animals):
Estrous cyclicity, copulation and implantation were examined.
Sperm parameters (parental animals):
not specified
Litter observations:
Number of pups, number of live pups, sex ratio on days 0 and 4, clinical signs and body weight were examined.
Postmortem examinations (parental animals):
Hematology, clinical chemistry, Organ weight, gross pathology and histopathology were examined.
Postmortem examinations (offspring):
Gross pathology were examined.
Statistics:
not specified
Reproductive indices:
Fertility , gestation period, implantation index, live birth index, delivery index were examined.
Offspring viability indices:
Viability index on 0 and 4 day were examined.

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
When treated with 40 mg/kg/day, Decreased spontaneous activity, Prone position, Bradypnea, Abnormal respiratory tones, Hypothermia, Abnormal gait, Soft stool, Emaciation, Abdominal distention, Dirty around anus, Soiled perineal region, External genital bleeding and test article-colored feces were observed in dead treated rats as compared to control. Soft stool and dirty around anus in male and female and External genital bleeding in Female survival rats were observed. Colored feces were observed in 1.6 and 8 mg/kg bw treated rats.
Dermal irritation (if dermal study):
not specified
Mortality:
mortality observed, treatment-related
Description (incidence):
When treated with 40 mg/kg bw, 1 male and 4 female died and 3 male and 1 female were sacrificed due to morbidity. No effect on survival of treated rats were observed at 1.6 and 8 mg/kg bw as compared to control.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
When treated with 40 mg/kg/day, decrease in body-weight and body-weight gain were observed in male and body weight gain in female rats as compared to control
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
When treated with 40 mg/kg/day, decrease in food consumption was observed in male and female rats as compared to control.
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
Description (incidence and severity):
When treated with 40 mg/kg/day, Increase in the PLT was observed in male and female rats as compared to control.
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
When treated with 40 mg/kg/day, Increase in the AST and ALT in male, CPK and BUN were observed in extremely killed male and female rat. Decrease in the TP and alpha 1-glb, Increase in the Alb, A/G and BUN in male and Increase in the BUN (tendency) in Female rats were observed as compared to control in survival animals.
Urinalysis findings:
no effects observed
Description (incidence and severity):
No effect was observed in male rats as compared to control.
Behaviour (functional findings):
effects observed, treatment-related
Description (incidence and severity):
When treated with 40 mg/kg/day, Bradypnea, Prone position, Decrease in spontaneous activity, Incomplete eyelid opening and abnormal gait in died animals and no effect on surviving animals were observed.
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
no effects observed
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
When treated with 40 mg/kg/day, Trachea; Desquamation of epithelium and inflammatory cell infiltration of mucosa (Male 1/4, Female 2/5), Glandular stomach; Atrophy of epithelial cell (Male 1/4, Female 1/5), Small/large intestine; Hypertrophy of epithelial cell (sporadically observed in Male and Female), Liver; Hypertrophy of centrilobular hepatocyte (Male 3/4, Female 3/5), Necrosis (Male 1/4, Female 2/5), Vacuolation (Male 1/4), Adrenal; Hypertrophy of zona fasciculata (Male 2/4, Female 5/5), Bone marrow; Deficient erythropoiesis and granulopoiesis (Male 3/4, Female 2/5), Spleen; Atrophy of follicle / marginal zone (Male 2/4, Female 5/5) and periarterial lymphatic sheath (Male 3/4, Female 5/5), Thymus; Atrophy (Male 4/4, Female 3/5) /necrosis of lymphocyte (Male 3/4, Female 4/5), Lymph node; Atrophy of follicle / paracortex (Male 3/4, Female 5/5), Spinal cord / fourth ventricle / testis / urinary bladder; Hemorrhage or hemorrhagic infarction (Male 1/4), Vagina; Hemorrhage (Female 2/5), Mucoid degeneration of mucosa (Female 2/5), Lung; Hemorrhage of alveolus, edema of alveolus and inflammatory cell infiltration (Female 1/5) were observed as compared to control in extremis killed animals. Liver; Hypertrophy of centrilobular hepatocyte (Male 2/4), Duodenum; Hypertrophy of epithelial cell (Male 2/4, Female 6/7) and Mesenteric lymph node and Sinus histiocytosis (Male 1/4, Female 3/7) were observed as compared to control in survival animals.
Histopathological findings: neoplastic:
not specified
Other effects:
not specified

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
no effects observed
Description (incidence and severity):
No effect on Estrous cyclicity, copulation and inplantation were observed.
Reproductive function: sperm measures:
not specified
Reproductive performance:
no effects observed
Description (incidence and severity):
No effect on Reproductive performance of treated male and femlae rats were observed as compared to control.

Effect levels (P0)

Dose descriptor:
NOAEL
Effect level:
40 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
reproductive function (oestrous cycle)
reproductive performance
other: No effect
Remarks on result:
other: No effects on reproductive function

Target system / organ toxicity (P0)

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

Results: F1 generation

General toxicity (F1)

Clinical signs:
no effects observed
Description (incidence and severity):
No Clinical signs were observed in treated pups as compared to control.
Dermal irritation (if dermal study):
not specified
Mortality / viability:
no mortality observed
Description (incidence and severity):
No effect on suvival of pups were observed as compared to control.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
No effect on body weight of pups were observed as compared to control.
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:
no effects observed
Description (incidence and severity):
No gross pathological changes were observed in treated pups as compared to control.
Histopathological findings:
not specified
Other effects:
not specified

Developmental neurotoxicity (F1)

Behaviour (functional findings):
not specified

Developmental immunotoxicity (F1)

Developmental immunotoxicity:
not specified

Effect levels (F1)

Dose descriptor:
NOAEL
Generation:
F1
Effect level:
40 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
viability
clinical signs
mortality
body weight and weight gain
gross pathology
other: No effect
Remarks on result:
other: not specified

Target system / organ toxicity (F1)

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

Overall reproductive toxicity

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

Applicant's summary and conclusion

Conclusions:
NOAEL was considered to be 40 mg/kg/day for P and F1 generation when Crl:CD (SD) male and female rats treated with test material orally by gavage.
Executive summary:

In a Combined Repeated Dose Toxicity Study with the Reproduction/ Developmental Toxicity Screening Test,Crl:CD (SD)male and female rats treated with test material in the concentration of 0, 1.6, 8 and 40 mg/kg/day orally by gavage in0.5 % Methylcellulose aqueous solution. 1 male and 4 female died and 3 male and 1 female were sacrificed due to morbidity at 40 mg/kg bw. No effect on survival of treated rats were observed at 1.6 and 8 mg/kg bw as compared to control, Decreased spontaneous activity, Prone position, Bradypnea, Abnormal respiratory tones, Hypothermia, Abnormal gait, Soft stool, Emaciation, Abdominal distention, Dirty around anus, Soiled perineal region, External genital bleeding and test article-colored feces were observed in dead treated rats as compared to control. Soft stool and dirty around anus in male and female and External genital bleeding in Female surviving rats at 40 mg/kg/day. Colored feces were observed in 1.6 and 8 mg/kg bw treated rats.Decrease in body-weight and body-weight gain were observed in male and body weight gain in female rats and decrease in food consumption were observed in male and female rats as compared to control at40 mg/kg/day.Bradypnea, Prone position, Decrease in spontaneous activity,incompleteeyelid opening and abnormal gait in died animals and noeffects on surviving animals wereobserved.No effect on ureinanalysis wasobserved in male rats as compared to control.Similarly,Increase in the PLT was observed in male and female ratsas compared to control at40 mg/kg/day. Increase in the AST and ALT in male, CPK and BUN were observed in extremely killed male and female rat at 40 mg/kg/day. Decrease in the TP and alpha 1-glb, Increase in the Alb, A/G and BUN in male and increase in the BUN (tendency) in Female rats were observed as compared to control in survival animals. No effect on organ weight of treated was male and female rats were observed as compared to control. Light violet aqueous content and discoloration of mucus membrane in all of the alimentary tract containing oral cavity, subcutaneous tissues and uterus (sporadically noticed in Male and Female), Hydrothorax in thoracic cavity (Male 1/4, Female 2/5), Small thymus (Male 3/4, Female 2/5), Small spleen (Male 1/4, Female 2/5), Edema in thymus (Male 1/4), Reddish urine in gallbladder (Male 1/4), Red discoloration in mucosa of the bladder (Male 1/4), Red discoloration of testis (Male 1/4), Red discoloration of adipose tissue around the testis (Male 1/4), Dilatation of stomach (Female 4/5), Enlargement of adrenal (Female 4/5), Gas retention in stomach (Female 2/5), Dark red viscous retention in vagina (Female 2/5), Dilatation of cecum (Female 1/5), Gas retention in cecum (Female 1/5) observed in extremely killed animals and Light violet aqueous content in alimentary tract in surviving male and female rats at 40 mg/kg/day. Light violet aqueous content in stomach and cecum were observed in male rats (3/12) at 8 mg/kg/day. Trachea; Desquamation of epithelium and inflammatory cell infiltration of mucosa (Male 1/4, Female 2/5), Glandular stomach; Atrophy of epithelial cell (Male 1/4, Female 1/5), Small/large intestine; Hypertrophy of epithelial cell (sporadically observed in Male and Female), Liver; Hypertrophy of centrilobular hepatocyte (Male 3/4, Female 3/5), Necrosis (Male 1/4, Female 2/5), Vacuolation (Male 1/4), Adrenal; Hypertrophy of zona fasciculata (Male 2/4, Female 5/5), Bone marrow; Deficient erythropoiesis and granulopoiesis (Male 3/4, Female 2/5), Spleen; Atrophy of follicle / marginal zone (Male 2/4, Female 5/5) and periarterial lymphatic sheath (Male 3/4, Female 5/5), Thymus; Atrophy (Male 4/4, Female 3/5) /necrosis of lymphocyte (Male 3/4, Female 4/5), Lymph node; Atrophy of follicle / paracortex (Male 3/4, Female 5/5), Spinal cord / fourth ventricle / testis / urinary bladder; Hemorrhage or hemorrhagic infarction (Male 1/4), Vagina; Hemorrhage (Female 2/5), Mucoid degeneration of mucosa (Female 2/5), Lung; Hemorrhage of alveolus, edema of alveolus and inflammatory cell infiltration (Female 1/5) were observed as compared to control in extremis killed animals and Liver; Hypertrophy of centrilobular hepatocyte (Male 2/4), Duodenum; Hypertrophy of epithelial cell (Male 2/4, Female 6/7), Mesenteric lymph node and Sinus histiocytosis (Male 1/4, Female 3/7) were observed as compared to control in survival animals at 40 mg/kg/day. In addition no reproductive effect such as Estrous cyclicity, copulation and implantation, Fertility rat, gestation period, implantation index, live birth index, delivery index were observed in treated rats as compared to control. No effect on viability, development and growth of pups were observed in treated rats as compared to control. Therefore, NOAEL was considered to be 40 mg/kg/day for P and F1 generation whenCrl:CD (SD)male and female rats treated with test material orally by gavage.