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Diss Factsheets

Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
reproductive toxicity, other
Remarks:
Chronic toxicity and carcinogenicity
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 NTRL report

Data source

Referenceopen allclose all

Reference Type:
secondary source
Title:
Initial Submission:Chronic Toxicity and Carcinogenicity Study in Rats with in Utero and Lifetime Exposure to test material in the Diet
Author:
Environmental Protection Agency
Year:
1992
Bibliographic source:
National Technical Reports Library, 1992
Reference Type:
secondary source
Title:
Reproductive toxicity study of test chemical was performed in rats.
Author:
Scientific Committee on Cosmetic Products
Year:
2004
Bibliographic source:
COLIPA

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
other: as below
Principles of method if other than guideline:
Chronic toxicity and carcinogenicity study of test material in rat
GLP compliance:
not specified
Limit test:
no
Justification for study design:
not specified

Test material

Constituent 1
Chemical structure
Reference substance name:
Disodium 3-hydroxy-4-[(4-methyl-2-sulphonatophenyl)azo]-2-naphthoate
EC Number:
227-497-9
EC Name:
Disodium 3-hydroxy-4-[(4-methyl-2-sulphonatophenyl)azo]-2-naphthoate
Cas Number:
5858-81-1
Molecular formula:
C18H14N2O6S.2Na
IUPAC Name:
disodium 4-[(E)-2-(4-methyl-2-sulfophenyl)diazen-1-yl]-3-oxidonaphthalene-2-carboxylate
Details on test material:
- Name of test material: disodium 4-[(E)-2-(4-methyl-2-sulfophenyl)diazen-1-yl]-3-oxidonaphthalene-2-carboxylate/ Lithol Rubine B - Molecular formula: C18H14N2O6S.2Na- Molecular weight: 432.38 g/mole- Substance type: Organic

Test animals

Species:
rat
Strain:
other: Charies river CD®
Details on species / strain selection:
not specified
Sex:
male/female
Details on test animals or test system and environmental conditions:
- Source: Charies river Breeding Laboratories. Iac. Wilningeon - Age at study initiation: (P) x wks; (F1) x wks: P: 36 days- Weight at study initiation: (P) Males: 75-155 g, Female: 75-114 g- Fasting period before study: No data available - Housing: Animals were housed individually in hanging wire mash cages. - Diet (e.g. ad libitum): Purina Laboratory diet, ad libitum. During post weaning segment Purina Laboratory diet, Rodent Laboratory Chow@#5001 and Certified Rodent Chow were used respectively. - Water (e.g. ad libitum): Tap water, ad libitum- Acclimation period: 15 daysENVIRONMENTAL CONDITIONS- Temperature (°C): 21.66°C- Humidity (%): 53 %- Air changes (per hr): No data available - Photoperiod (hrs dark / hrs light): 12 hr light/12hr dark

Administration / exposure

Route of administration:
oral: feed
Type of inhalation exposure (if applicable):
not specified
Vehicle:
other: Purina Laboratory diet
Details on exposure:
not specified
Details on mating procedure:
- M/F ratio per cage: 1:1 ratio - Length of cohabitation:7 days - Proof of pregnancy: [vaginal plug / sperm in vaginal smear] referred to as [day 0 / day 1] of pregnancySperm and /or copulatory plug observed in the following morning were considered to be Day 0 of gestation. - After ... days of unsuccessful pairing replacement of first male by another male with proven fertility. No data available - Further matings after two unsuccessful attempts: [no / yes (explain)] No data available- After successful mating each pregnant female was caged (how):Individually - Any other deviations from standard protocol:No data available
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
126 week
Frequency of treatment:
Daily
Details on study schedule:
not specified
Doses / concentrations
Remarks:
0,0, 25, 150, or 1000 mg/kg bw/day
No. of animals per sex per dose:
Total : 1300F0 generation 0 mg/kg body weight/day: 60 male, 60 Female 0 mg/kg body weight/day: 60 male, 60 Female 25 mg/kg body weight/day: 60 male, 60 Female 150 mg/kg body weight/day: 60 male, 60 Female 1000 mg/kg body weight/day: 60 male, 60 Female F1 generation 0 mg/kg body weight/day: 70 male, 70 Female 0 mg/kg body weight/day: 70 male, 70 Female 25 mg/kg body weight/day: 70 male, 70 Female 150 mg/kg body weight/day: 70 male, 70 Female 1000 mg/kg body weight/day: 70 male, 70 Female
Control animals:
yes, concurrent vehicle
Details on study design:
not specified
Positive control:
not specified

Examinations

Parental animals: Observations and examinations:
Mortality , clinical sign, body weight, food and compound consumption, ophthalmoscopic examination, haematology, clinical chemistry, urinalysis, virology and microbiology were observed
Oestrous cyclicity (parental animals):
Any irregularities in the estrous cycle were investigated
Sperm parameters (parental animals):
not specified
Litter observations:
Live birth, sex, survival, body weigh, food and compound consumption, ophthalmoscopic examination, haematology, clinical chemistry, urinalysis, virology and microbiology were observed
Postmortem examinations (parental animals):
Gross abnormalities and organ weight were examined.
Postmortem examinations (offspring):
Gross abnormalities, organ weight and histopathology were examined.
Statistics:
Statistically analysis were performed by using fertility indices, gestation 4, 14 and 21 day survival indices were compared by using Chi- square test and /or Fishur’s extract probability. The mean number of liveborn pups per litter and the litter mean per weight at day 0,4,14 and 21 were compared by analysis of variance (one way classification), Barletts test for homogenicty of variances and the appropriate t-test (for equal and unequal variances).For F1 rat: all pair wise statistical comparison were two tailed with the probability level for significance at 0.01. Body weight, food consumption and absolute and relative body weight were compared by analysis of variances and appropriate t-test. Data for animals with malignant tumors, with beings and all tumors combined were analyzed separately by sex. Homogenicity was analysed by cor’s test and cehan-Breslow generalized Krunkal-Wallis test. For the histopathologically proired neoplastic lesions incidencus the two control groups were tested against each other.
Reproductive indices:
Fertility index, gestation index and effect on parturition and lactation were examined.
Offspring viability indices:
Yes, on day 0, 4 and 14

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
not specified
Dermal irritation (if dermal study):
not specified
Mortality:
no mortality observed
Description (incidence):
When treated with 150 mg/kg bw, 3 rats were died.When reated with 1000 mg/kg bw one rat died and in control 3 rats were died.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
No effect on body weight of treated rat was observed as comparable to control.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
No effect on food consumption of treated male and female rats was observed as comparable to control.
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
no effects observed
Description (incidence and severity):
No change in treated male and female rats was observed as compared to control.
Haematological findings:
no effects observed
Description (incidence and severity):
No change in treated male and female rats was observed as compared to control.
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
No effect on Clinical chemistry of treated male and female rats was observed as compared to control.
Urinalysis findings:
no effects observed
Description (incidence and severity):
No effect on urinalysis of treated male and female rats was observed as compared to control.
Behaviour (functional findings):
not specified
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
An acceleration of testicular changes (degeneration of the testicular tubules) was observed in treated male rat, a common effect in ageing rats. However, at the termination of the study, the increased incidence was not of statistical significance.
Histopathological findings: neoplastic:
not specified
Other effects:
no effects observed
Description (incidence and severity):
Virology:No effect on virology of treated male and female rats was observed as compared to control.Microbiology:No effect on Microbiology of treated male and female rats was observed as compared to control.

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
not specified
Reproductive function: sperm measures:
not specified
Reproductive performance:
no effects observed
Description (incidence and severity):
No effect on Fertility index, gestation index and effect on parturition and lactation were observed as compared to control.

Effect levels (P0)

Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
clinical signs
mortality
body weight and weight gain
reproductive performance
Remarks on result:
other: No effect observed

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:
not specified
Dermal irritation (if dermal study):
not specified
Mortality / viability:
no mortality observed
Description (incidence and severity):
No effect on survival of F1 offspring were observed as compared to control.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
When treated with 1000 mg/kg bw, significant decrease in body weight were observed in male rat as comparable to control. When treated with 25 and 150 mg/kg bw, slightly decreased body weight was observed as comparable to control. Decrease in body weight were recovred in treated rats.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
No effect on food consumption of treated male and female offspring’s was observed as comparable to control.
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
no effects observed
Description (incidence and severity):
No change in treated male and female offsprings rats was observed as compared to control.
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:
no effects observed
Description (incidence and severity):
No effect on organ weight of treated male and female offspring was observed as compared to control.
Gross pathological findings:
no effects observed
Description (incidence and severity):
No gross pathological changes were observed in treated male and female offspring as compared to control.
Histopathological findings:
no effects observed
Description (incidence and severity):
An acceleration of testicular changes (degeneration of the testicular tubules) was observed in treated male rat, a common effect in ageing rats. However, at the termination of the study, the increased incidence was not of statistical significance.
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:
1 000 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
viability
mortality
body weight and weight gain
food consumption and compound intake
ophthalmological examination
haematology
clinical biochemistry
urinalysis
organ weights and organ / body weight ratios
gross pathology
other: No effect observed
Remarks on result:
other: overall no developmental toxic effects observed

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 1000 mg/kg/day for F0 generation and F1 geneartion when Charies river CD®male and female rat were exposed to test material orally in feed.
Executive summary:

In a chronic toxicity and carcinogenicity study,Charies river CD®male and female rat were exposed to test material in the concentration 0, 0, 25, 150 and 1000 mg/kg/day orally in feed. In the parental generation,3 rats were died at 150 mg/kg bw, one rat died at 1000 mg/kg bw and 3 rats were died in in control. No effect onbody weight and food consumption,ophthalmoscopic examination, haematology, clinical chemistry, urinalysis, virology and microbiologyof treated male and female rats was observed as comparable to control.Similarly, No effect on reproductive performance such as Fertility index, gestation index and effect on parturition and lactation were observed as compared to control. No effect onorgan weight and gross pathology were observed as compared to control in P and F1 generation. In addition, anacceleration of testicular changes (degeneration of the testicular tubules) was observed in treated male rat, a common effect in ageing rats. However, at the termination of the study, the increased incidence was not of statistical significance. Therefore, NOAEL was considered to be 1000 mg/kg/day for F0 generation and F1 geneartion when Charies river CD®male and female rat were exposed to test material orally in feed.