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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
fertility, other
Remarks:
Combined repeated dose and carconogenicity test
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 from peer reviewed journal.

Data source

Reference
Reference Type:
publication
Title:
Chronic Toxicity of the given test chemical to Rats
Author:
K. J. DAVIS ET AL.
Year:
1966
Bibliographic source:
TOXICOLOGY AND APPLIED PHARAMACOLOGY

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
other: Combined Repeated Dose and Carcinogenicity
Principles of method if other than guideline:
Combined Repeated Dose and Carcinogenicity was performed to determine the toxic nature of the test chemical in Osborne Mendel rats
GLP compliance:
not specified
Limit test:
no
Justification for study design:
not specified

Test material

Constituent 1
Chemical structure
Reference substance name:
Disodium 3-[(2,4-dimethyl-5-sulphonatophenyl)azo]-4-hydroxynaphthalene-1-sulphonate
EC Number:
224-909-9
EC Name:
Disodium 3-[(2,4-dimethyl-5-sulphonatophenyl)azo]-4-hydroxynaphthalene-1-sulphonate
Cas Number:
4548-53-2
Molecular formula:
C18H16N2O7S2.2Na
IUPAC Name:
Disodium 3-[(2,4-dimethyl-5-sulphonatophenyl)azo]-4-hydroxynaphthalene-1-sulphonate
Test material form:
solid
Details on test material:
- Name of test material (as cited in study report): Ponceau SX
- Molecular formula : C18H16N2O7S2.2Na
- Molecular weight : 480.4276 g/mol
- Smiles notation: [Na+].[Na+].Cc1cc(C)c(cc1N=Nc2cc(c3ccccc3c2O)S(=O)(=O)[O-])S(=O)(=O)[O-]
- InChl :1S/C18H16N2O7S2.2Na/c1-10-7-11(2)16(28(22,23)24)8-14(10)19-20-15-9-17(29(25,26)27)12-5-3-4-6-13(12)18(15)21;;/h3-9,21H,1-2H3,(H,22,23,24)(H,25,26,27);;/q;2*+1/p-2/b20-19+;;
- Substance type: Organic
- Physical state: Solid

Test animals

Species:
rat
Strain:
Osborne-Mendel
Details on species / strain selection:
No Data Available
Sex:
male/female
Details on test animals or test system and environmental conditions:
Rats were caged individually.

Administration / exposure

Route of administration:
oral: feed
Type of inhalation exposure (if applicable):
not specified
Vehicle:
other: Commercial Laboratory Chow diet
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
DIET PREPARATION
The test chemical was mixed into a commercial laboratory chow diet for each feeding study.
Details on mating procedure:
Mating was not performed
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
No Data Available
Duration of treatment / exposure:
two-years
Frequency of treatment:
daily
Details on study schedule:
no data available
Doses / concentrations
Remarks:
0, 500, 1000 mg/kg bw/day
No. of animals per sex per dose:
control - 200(100/ sex)
500 mg/kgbw/day - 100 (50/sex)
1000 mg/kgbw/day - 100 (50/sex)
Control animals:
yes, concurrent no treatment
Details on study design:
Two-year tests were run in which 400 rats were distributed into various treatment groups. The test chemical was mixed into a commercial laboratory chow diet for each feeding study.Rats were individually caged. Each animal received in the Pathology Laboratory was given a careful gross examination, and all lesions were recorded. Of those not received, most were discarded because of advanced postmortem autolysis. So far as can be determined, none of the discarded animals had tumors. Lesions which could not clearly be identified as neoplastic or nonneoplastic, and tumors, the type of which was uncertain or uncommon, were also sectioned and examined microscopically. Tissues sectioned include the following: liver, lung, heart, spleen, pancreas, stomach, small intestine, colon, kidney, adrenal, thyroid, testis (or ovary and uterus), leg muscles, leg bones with included marrow, and any tumor or other unusual condition.Sections of the mamary glands were also observed for tumours.
Positive control:
no data available

Examinations

Parental animals: Observations and examinations:
no data available
Oestrous cyclicity (parental animals):
no data available
Sperm parameters (parental animals):
no data available
Litter observations:
no data available
Postmortem examinations (parental animals):
Each animal received in the Pathology Laboratory was given a careful gross examination, and all lesions were recorded. Of those not received, most were discarded because of advanced postmortem autolysis. So far as can be determined, none of the discarded animals had tumors. Lesions which could not clearly be identified as neoplastic or nonneoplastic, and tumors, the type of which was uncertain or uncommon, were also sectioned and examined microscopically.
Tissues sectioned include the following: liver, lung, heart, spleen, pancreas, stomach, small intestine, colon, kidney, adrenal, thyroid, testis (or ovary and uterus), leg muscles, leg bones with included marrow, and any tumor or other unusual condition.Sections of the mamary glands were also observed for tumours.
Statistics:
no data available
Reproductive indices:
no data available
Offspring viability indices:
no data available

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
no effects observed
Description (incidence and severity):
The ingestion of the test chemical had no effect on survival, growth, or weights at autopsy of heart, liver, kidney, spleen, or testes in the test animals
Dermal irritation (if dermal study):
not specified
Mortality:
no mortality observed
Description (incidence):
The ingestion of the test chemical had no effect on survival, growth, or weights at autopsy of heart, liver, kidney, spleen, or testes in the test animals
Body weight and weight changes:
no effects observed
Description (incidence and severity):
The ingestion of the test chemical had no effect on survival, growth, or weights at autopsy of heart, liver, kidney, spleen, or testes in the test animals
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
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):
Findings, such as liver enlargement, abscesses, distendedurinary bladders, ovarian cysts, distended uteri, enlarged parathyroids, enlargement of seminal vesicles and other miscellaneous changes, were present in approximately equal incidence and degree in test and control rats. No effect due to ingestion of the test chemical on either tumor incidence or tumor type was noted in Osborne Mendel strain on this two-year experiment.
Histopathological findings: neoplastic:
no effects observed
Description (incidence and severity):
No effect due to ingestion of the test chemical on either tumor incidence or tumor type was noted in Osborne Mendel rats on this two-year experiment. Rats of the Osborne- Mendel strain had more tumors (especially mammary).Incidence of tumor formation in mammary glands were found to be in control and treatment groups. Thus, they are considered to be incidemtal and non treatment related in nature and strain specific.
Other effects:
not specified

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
not specified
Reproductive function: sperm measures:
not specified
Reproductive performance:
not specified

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:
gross pathology
histopathology: non-neoplastic
histopathology: neoplastic
Remarks on result:
not determinable due to absence of adverse toxic effects

Results: P1 (second parental generation)

Effect levels (P1)

Remarks on result:
not measured/tested

Results: F1 generation

Effect levels (F1)

Remarks on result:
not measured/tested

Results: F2 generation

General toxicity (F2)

Other effects:
not specified

Developmental neurotoxicity (F2)

Behaviour (functional findings):
not specified

Developmental immunotoxicity (F2)

Developmental immunotoxicity:
not specified

Effect levels (F2)

Remarks on result:
not measured/tested

Overall reproductive toxicity

Reproductive effects observed:
no
Treatment related:
no

Any other information on results incl. tables

Lesions observed in the 2 year feeding study

Parameter

Control

1%

2%

Number of rats started

200

100

100

Number of survivors at 80 weeks

158

75

78

Number received by pathology

171

89

89

Number of males with tumors

25

9

10

Number of females with tumors

42

14

22

Total number of rats with tumors

67

23

32

Tumor type in each rat

 

 

 

Fibroadenoma, mammary                          

19

9

12

Adenocarcinoma

18

6

7

Lymphosarcoma

18

7

5

Lymphoblastoma

5

0

0

Fibrosacroma

0

0

4

Interstitial cell tumor

5

4

2

Endometrial sarcoma

3

1

0

Other tumors

10

1

5

Other pathology

 

 

 

Chronic pneumonia

34

18

16

Granular kidneys

49

23

23

Splenic enlargement

27

16

13

Splenic atrophy

17

16

9

Testicular atrophy

8

8

4

Adrenal enlargement

5

2

3

Chronic arteritis

2

2

0

Applicant's summary and conclusion

Conclusions:
Findings, such as liver enlargement, abscesses, distended urinary bladders, ovarian cysts, distended uteri, enlarged parathyroids, enlargement of seminal vesicles and other miscellaneous changes, were present in approximately equal incidence and degree in test and control rats. No effect due to ingestion of the test chemical on either tumor incidence or tumor type was noted in Osborne Mendel strain on this two-year experiment.Considering all the observations, the No Observed Adverse Effect Level was considered to be 1000 mg/kgbw/day in Osborne Mendel rats.
Executive summary:

Combined Repeated Dose and Carcinogenicity was performed to determine the toxic nature of the test chemical in Osborne Mendel rats. Two-year tests were run in which 400 male and female Osborne Mendel rats were distributed into various treatment groups. The treatment groups were - 100 rats/dose (50/sex) and 100 rats/sex for controls. The test chemical (500 mg/kg bw/day, 1000 mg/kg bw/day) was mixed into a commercial laboratory chow diet for each feeding study. Rats were individually caged. Each animal received in the Pathology Laboratory was given a careful gross examination, and all lesions were recorded. Of those not received, most were discarded because of advanced postmortem autolysis. So far as can be determined, none of the discarded animals had tumors. Lesions which could not clearly be identified as neoplastic or non-neoplastic, and tumors, the type of which was uncertain or uncommon, were also sectioned and examined microscopically. Tissues sectioned include the following: liver, lung, heart, spleen, pancreas, stomach, small intestine, colon, kidney, adrenal, thyroid, testis (or ovary and uterus), leg muscles, leg bones with included marrow, and any tumor or other unusual condition. Sections of the mammary glands were also observed for tumors. Findings, such as liver enlargement, abscesses, distended urinary bladders, ovarian cysts, distended uteri, enlarged parathyroid, enlargement of seminal vesicles and other miscellaneous changes, were present in approximately equal incidence and degree in test and control rats. Rats of the Osborne- Mendel strain had more tumors (especially mammary).Incidence of tumor formation in mammary glands were found to be in control and treatment groups. Thus, they are considered to be incidental and non-treatment related in nature and strain specific. No effect due to ingestion of the test chemical on either tumor incidence or tumor type was noted in Osborne Mendel strain on this two-year experiment. Considering all the observations, the No Observed Adverse Effect Level was considered to be 1000 mg/kg bw/day in Osborne Mendel rats.