Calcium 3-hydroxy-4-[(4-methyl-2-sulphonatophenyl)azo]-2-naphthoate

Toxicity to reproduction

Administrative data

Endpoint:

screening for reproductive / developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study

Justification for type of information:

Data is from J-check

Data source

Reference

Reference 1

Reference Type:

review article or handbook

Title:

Repeated oral administration toxicity / reproductive developmental toxicity combined test using D & C Red No. 7 rat

Author:

J -Check

Year:

2018

Bibliographic source:

Ministry of Health, Labour and Welfare", "Ministry of the Environment" and "National Institute of Technology and Evaluation, J –Check, 2018

Reference 2

Reference Type:

secondary source

Title:

SIDS Initial Assessment Report for 2-Naphthalenecarboxylic acid, 3-hydroxy-4-[(4- methyl-2-sulfophenyl)azo]-, calcium salt (D & C Red No. 7)

Author:

OECD SIDS

Year:

1993

Bibliographic source:

OECD HPV, Chemicals Programme. SIDS Dossier, 1993

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 Repeat Dose and Reproductive / Developmental Toxicity screening Test of D & C Red No. 7 in Rats

GLP compliance:

not specified

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Calcium 3-hydroxy-4-[(4-methyl-2-sulphonatophenyl)azo]-2-naphthoate

EC Number:

226-109-5

EC Name:

Calcium 3-hydroxy-4-[(4-methyl-2-sulphonatophenyl)azo]-2-naphthoate

Cas Number:

5281-04-9

Molecular formula:

C18H14N2O6S.Ca

IUPAC Name:

calcium 3-hydroxy-4-[(1E)-2-(4-methyl-2-sulfonatophenyl)diazen-1-yl]naphthalene-2-carboxylate

Test material form:

solid

Details on test material:

- Name of test material (as cited in study report): 2-Naphthalenecarboxylic acid, 3-hydroxy-4-[(4-methyl-2-sulfophenyl)azo]-, calcium salt- Molecular formula (if other than submission substance): C18H14N2O6S.Ca- Molecular weight (if other than submission substance): 424.445 g/mole- Smiles notation (if other than submission substance): c12c(c(c(C(=O)[O-])cc1cccc2)O)\N=N\c1c(cc(C)cc1)S(=O)(=O)[O-].[Ca+2]- InChl (if other than submission substance): 1S/C18H14N2O6S.Ca/c1-10-6-7-14(15(8-10)27(24,25)26)19-20-16-12-5-3-2-4-11(12)9-13(17(16)21)18(22)23;/h2-9,21H,1H3, (H,22,23)(H,24,25,26);/q;+2/p-2/b20-19+;- Substance type: Organic - Physical state: Solid - Analytical purity: 87%- Impurities (identity and concentrations): 13%

Specific details on test material used for the study:

- Name of test material (as cited in study report): 2-Naphthalenecarboxylic acid, 3-hydroxy-4-[(4-methyl-2-sulfophenyl)azo]-, calcium salt- Molecular formula (if other than submission substance): C18H14N2O6S.Ca- Molecular weight (if other than submission substance): 424.445 g/mole- Smiles notation (if other than submission substance): c12c(c(c(C(=O)[O-])cc1cccc2)O)\N=N\c1c(cc(C)cc1)S(=O)(=O)[O-].[Ca+2]- InChl (if other than submission substance): 1S/C18H14N2O6S.Ca/c1-10-6-7-14(15(8-10)27(24,25)26)19-20-16-12-5-3-2-4-11(12)9-13(17(16)21)18(22)23;/h2-9,21H,1H3, (H,22,23)(H,24,25,26);/q;+2/p-2/b20-19+;- Substance type: Organic - Physical state: Solid

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: (P) x wks; (F1) x wks: 8 weeks - Weight at study initiation: (P) Males: x-x g; Females: x-x g; (F1) Males: x-x g; Females: x-x g: female 196.5 to 227.4 g, males 253.5 ~ 299.6 g- Fasting period before study:- Housing: Animals were individually housed in a wire mesh floor cage (Nihon Cage) and raised. For the mother animals after 18th gestation, metal floorboards were laid on the floor of breeding cages, and wood chips (White Flake (R), Japan Charles River) were appropriately supplied as bedding.- Diet (e.g. ad libitum): Solid feed (CA - 1, Japan Clea), ad libitum- Water (e.g. ad libitum): Tap water, ad libitum- Acclimation period: 1 week ENVIRONMENTAL CONDITIONS- Temperature (°C): 24 ± 1 °C.- Humidity (%): 55 ± 5%- Air changes (per hr): Ventilation frequency of about 15 times / hour - Photoperiod (hrs dark / hrs light): Lighting room of a barrier system adjusted for 12 hours of lighting (7 am to 7 pm).

Administration / exposure

Route of administration:

oral: gavage

Type of inhalation exposure (if applicable):

not specified

Vehicle:

other: 5% Gum Arabic solution

Details on exposure:

PREPARATION OF DOSING SOLUTIONS: Test substance was suspended in an aqueous solution of 5% gum arabic, and the content was adjusted so that the dosage volume at one time would be 10 ml / kg at any dose. VEHICLE- Justification for use and choice of vehicle (if other than water): Test substance was almost insoluble in water and acetone and hence 5% Gum Arabic solution were used. - Concentration in vehicle: 0, 100, 300, 1000 mg/kg/day - Amount of vehicle (if gavage): 10 ml / kg bw - Lot/batch no. (if required):- Purity:

Details on mating procedure:

- M/F ratio per cage:1: 1. - Length of cohabitation:14 days - Proof of pregnancy: [vaginal plug / sperm in vaginal smear] referred to as [day 0 / day 1] of pregnancyConfirmation of copulation was made every morning by examining the presence of sperm in the vaginal plug and vaginal plaque in the vagina and females confirmed to be mated were separated from the male starting from that day as the 0th day of gestation. - After ... days of unsuccessful pairing replacement of first male by another male with proven fertility.Not specified - Further matings after two unsuccessful attempts: [no / yes (explain)]Not specified- After successful mating each pregnant female was caged (how): Individually

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

Males, 42 daysFemales, from 14 days prior to mating to Day 3 of lactation

Frequency of treatment:

Daily

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

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

Doses / concentrations 2

Dose / conc.:

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

Doses / concentrations 3

Dose / conc.:

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

Doses / concentrations 4

Dose / conc.:

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

No. of animals per sex per dose:

Total: 1040 (vehicle) mg/kg/day: 13 male, 13 female 100 mg/kg/day: 13 male, 13 female 300 mg/kg/day: 13 male, 13 female 1000 mg/kg/day: 13 male, 13 female

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: Dose was selected based on Preliminary dose setting test. 0 (solvent control) and 1000 mg / kg of D & C Red No. 7 were orally administered repeatedly to 5 male and 5 female Sprague-Dawley (Crj: CD) rats once a day for 14 days and the administration end date, and repeated administration toxicity of D & C Red No. 7 to male and female rats was examined. Thus for the purpose of searching for toxicity, the maximum dose was 1000 mg / kg / day, and the following were divided by the common ratio 3 to set the intermediate dose to 300 mg / kg / day and the lowest dose to 100 mg / kg / day.

Examinations

Parental animals: Observations and examinations:

Survival, Clinical sign, Body weight and weight gain and food consumption were examined.

Oestrous cyclicity (parental animals):

Not specified

Sperm parameters (parental animals):

Not specified

Litter observations:

Birth rate, litter weight and Sex ratio were examined.

Postmortem examinations (parental animals):

Organ weight, gross pathology and histopathology was examined.

Postmortem examinations (offspring):

Grossly visible abnormalities was examined.

Statistics:

The mating rate and conception rate were subjected to χ ^ 2 test. All other data were tested for uniformity of variance of each group by the Bartlett method, with the value obtained for each individual or the average value for each litter as one sample. As a result, when the variance is made uniform, a one-way analysis of variance is carried out, and when significance is observed between the groups, the control group and each test substance administered group and the control group are administered by the Dunnett method or the Scheff method The difference between the mean values was tested between. When the variance was not uniform, Kruskal-Wallis rank test was conducted, and when significantness was observed between the groups, a Dunnett type or Scheff type test for the difference between the control group and each test substance administered group went. The level of significance was set to 5% and 1%.

Reproductive indices:

Female fertility index, copulation index, Gestation index, viability index, Live birth index, implantation index, delivery index, Number of females with stillborn pups were examined.

Offspring viability indices:

Yes

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:

no effects observed

Description (incidence and severity):

Red feces exhibiting the same color tone as the test substance administered was observed daily during the administration period. In addition, the formation of crust was observed in a very small number of animals, but abnormalities in general condition regarded as toxicity change were not observed in either administration group in both males and females.

Dermal irritation (if dermal study):

not specified

Mortality:

no mortality observed

Description (incidence):

No effect on survival of treated male and female rats were observed.

Body weight and weight changes:

no effects observed

Description (incidence and severity):

No significant differences were observed between body weight and increasing amount between each test substance administered group and control group in any period before commencement, during pregnancy, and after parturition.

Food consumption and compound intake (if feeding study):

no effects observed

Description (incidence and severity):

No significant change was observed in any of the test substance administered groups as compared with the control group.

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

not specified

Haematological findings:

no effects observed

Description (incidence and severity):

When treated with 300 and 1000 mg/kg bw, significant decrease in mean red blood cell hemoglobin level and dose-dependent decrease in white blood cell count were observed but no significant difference was observed between the group and the control group. No change suggesting the effect of the test substance was observed for the results of the leukocyte classification.

Clinical biochemistry findings:

no effects observed

Description (incidence and severity):

When treated with 1000 mg/kg bw, significant decrease in total cholesterol, potassium concentration and significantly increased chlorine concentration and GOT activity and Significant decreases in inorganic phosphorus and calcium concentrations were observed in treated rats. No other presumed changes due to the administration of the test substance were observed in the other test items.

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:

effects observed, treatment-related

Description (incidence and severity):

Increased incidence of renal tubule regeneration in males at 300 and 1000 mg/kg bw, and the increased incidence of renal tubule regeneration and necrotic or foamy tubular epithelial cells in females at 100, 300 and 1000 mg/kg bw were observed. These lesions increased in severity and incidence in a dose-dependent manner.

Histopathological findings: neoplastic:

not specified

Other effects:

not specified

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 Number pregnant per dose level, Female fecundicity index, Female fertility index, Male fertility index, Number aborting, Number of resorptions, Gestation index, Live birth index, Number of females with live born pups, Number of females with all stillborn pups, Post implantation loss, Number of corpus luteum, number of implantation and implantation and duration of Pregnancy was observed in treated rats as compared to control.

Effect levels (P0)

Dose descriptor:

NOAEL

Effect level:

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

Based on:

test mat.

Sex:

male/female

Basis for effect level:

clinical signs

mortality

body weight and weight gain

food consumption and compound intake

haematology

organ weights and organ / body weight ratios

gross pathology

reproductive performance

Remarks on result:

other: No effect on reproductive performance and organ

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 viability on nursing day 0 and nursing 4th day of pups were observed as compared to control.

Body weight and weight changes:

no effects observed

Description (incidence and severity):

No significant effect on birth weight at any measurement time 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:

not specified

Histopathological findings:

not specified

Other effects:

no effects observed

Description (incidence and severity):

Sex ratio: No difference was observed in the sex ratio between the groups.Birth rate: No effect on birth rat of pups were observed as compared to control.

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 (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

viability

clinical signs

mortality

body weight and weight gain

other: Birth rate and Sex ratio

Remarks on result:

other: No effect 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 male and female for P and F1 generation when Crj:CD (Sprague-Dawley) male and female rats were treated with Calcium salt of 3-hydroxy-4 - [(4-methyl-2-sulfophenyl) azo] -2-naphthalenecarboxylic acid orally by gavage for male 42 days and female from 14 days prior to mating to Day 3 of lactation.

Executive summary:

In a reproduction/developmental screening Test,  Crj:CD (Sprague-Dawley) male and female rats were treated with Calcium salt of 3-hydroxy-4 - [(4-methyl-2-sulfophenyl) azo] -2-naphthalenecarboxylic acid in the concentration of0,100, 300, 1000 mg/kg/day orally by gavage for Males 42 days and female from 14 days prior to mating to Day 3 of lactation. Red feces exhibiting the same color tone as the test substance administered was observed daily during the administration period. In addition, the formation of crust was observed in a very small number of animals, but abnormalities in general condition regarded as toxicity change were not observed in either administration group in both males and females. No effect on survival of treated male and female rats was observed. No significant differences were observed between body weight and increasing amount between each test substance administered group and control group in any period before commencement, during pregnancy, and after parturition. No significant change was observed in food consumption any of the test substance administered groups as compared with the control group. Similarly, significant decrease in mean red blood cell hemoglobin level and dose-dependent decrease in white blood cell count were observed at 300 and 1000 mg/kg bw, but no significant difference was observed between the group and the control group. No change suggesting the effect of the test substance was observed for the results of the leukocyte classification. Significant decrease in total cholesterol, potassium concentration and significantly increased in chlorine concentration and GOT activity and Significant decreases in inorganic phosphorus and calcium concentrations were observed at 1000 mg/kg bw in treated rats. No other presumed changes due to the administration of the test substance were observed in the other test items. Significant increase in kidney weight was observed at 1000 mg/kg bw in treated rats as compared to control. No effect on absolute or relative weight of testis and epididymis were observed between the control and the treated groups. No treatment related macroscopic change was observed in treated rats as compared to control. Increased incidence of renal tubule regeneration in males at 300 and 1000 mg/kg bw, and the increased incidence of renal tubule regeneration and necrotic or foamy tubular epithelial cells in females at 100, 300 and 1000 mg/kg bw. These lesions increased in severity and incidence in a dose-dependent manner. In addition, no reproductive effect were observed such as on Number pregnant per dose level, Female fecundicity index, Female fertility index, Male fertility index, Number aborting, Number of resorptions, Gestation index, Live birth index, Number of females with live born pups, Number of females with all stillborn pups, Post implantation loss, Number of corpus luteum, number of implantation and implantation and duration of Pregnancy of female, and Sex ratio, viability and body weight of pups on day 0 and 4. Therefore, NOAEL was considered to be 1000 mg/kg/day for male and female for P and F1 generation when Crj:CD (Sprague-Dawley) male and female rats were treated with Calcium salt of 3-hydroxy-4 - [(4-methyl-2-sulfophenyl) azo] -2-naphthalenecarboxylic acid orally by gavage for male 42 days and female from 14 days prior to mating to Day 3 of lactation.