Disodium 2-(2,4,5,7-tetrabromo-6-oxido-3-oxoxanthen-9-yl)benzoate

Toxicity to reproduction

Administrative data

Endpoint:

one-generation reproductive 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 from peer-reviewed journal

Data source

Reference

Reference Type:

publication

Title:

Developmental Toxicity and Psychotoxicity Evaluation of test chemical in Rats

Author:

Charles V. Vorhees et.al

Year:

2018

Bibliographic source:

Arch Toxicol (1983)

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

other: As mentioned below

Principles of method if other than guideline:

The reproductive effect of test chemical was evaluated in Sprague-Dawley rats when administered orally in one-generation.

GLP compliance:

not specified

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Disodium 2-(2,4,5,7-tetraiodo-6-oxido-3-oxoxanthen-9-yl)benzoate

EC Number:

240-474-8

EC Name:

Disodium 2-(2,4,5,7-tetraiodo-6-oxido-3-oxoxanthen-9-yl)benzoate

Cas Number:

16423-68-0

Molecular formula:

C20H8I4O5.2Na

IUPAC Name:

disodium 2-(2,4,5,7-tetraiodo-6-oxido-3-oxoxanthen-9-yl)benzoate

Test material form:

solid: particulate/powder

Remarks:

migrated information: powder

Details on test material:

- Name of test material (as cited in study report): Erythrosine
- Molecular formula (if other than submission substance): C20-H6-I4-Na2-O5
- Molecular weight (if other than submission substance): 879.86
- InChl Key (if other than submission substance): RAGZEDHHTPQLAI-UHFFFAOYSA-L
-Substance type- Organic
- Physical state: Solid (powder)
- Analytical purity:91%
- Impurities (identity and concentrations):9 %

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Laboratory Supply Co., Indianapolis, Indiana, USA
- Age at study initiation: adult rats
- Weight at study initiation: (P) Males: 200-220 g; Females: 200-220 g
- Fasting period before study: No data available
- Housing: No data available
- Use of restrainers for preventing ingestion (if dermal): Not applicable
- Diet (e.g. ad libitum): The experimental diets were freely available throughout postnatal development to the offspring of all delivering dams (up to the end of the experiments at 90-110 days of age of the offspring).
- Water (e.g. ad libitum): No data available
- Acclimation period: 5 days before assignment to treatment groups

ENVIRONMENTAL CONDITIONS
- Temperature (°C): No data available
- Humidity (%):No data available
- Air changes (per hr): No data available
- Photoperiod (hrs dark / hrs light): No data available

IN-LIFE DATES: From: To:No data available

Administration / exposure

Route of administration:

oral: feed

Type of inhalation exposure (if applicable):

not specified

Vehicle:

not specified

Details on exposure:

Details on exposure
PREPARATION OF DOSING SOLUTIONS: Test chemical mixed in powdered Purina rat chow.

VEHICLE
- Justification for use and choice of vehicle (if other than water):Purina rat chow were used.
- Concentration in vehicle: 0.0, 0.25, 0.5 and 1.0 %

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 pregnancy:The presence of sperm in the daily vaginal lavage of the females and designated as day zero of gestation.

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

For male:fed diets containing the dye for 2 weeks
For female:The dye was fed to each treatment group for 2 weeks prior to breeding, 1-14 days during breeding then to the females during gestation and lactation.

Frequency of treatment:

Daily

Details on study schedule:

On the day following birth two males and two females from each litter were designated for preweaning testing. Two additional males and two additional females per litter which were not tested
prior to weaning were designated for postweaning testing at weaning.

Usually the first 5-15 pairs of animals enrolled in the study in each group

Doses / concentrations

Remarks:

Doses / Concentrations:
0.0, 0.25, 0.5, or 1.0%( 250, 500 and 1000 mg/kg bw/d)
Basis:
no data

No. of animals per sex per dose:

Total: 196
0.0%: 19 male, 19 female
0.25%: 22 male, 22 female
0.5 %: 18 male, 18 female
1.0%: 21 male, 21 female
50 mg/kg (positive control): 18 male, 18 female

Control animals:

yes

Details on study design:

No data available

Positive control:

For experiment 1:offspring injected daily with 50 mg/kg of hydroxyurea on postnatal days 2-10 of life as a positive control
For experiment 2: no positive control were used.

Examinations

Parental animals: Observations and examinations:

Parental animals observation and examinations
CAGE SIDE OBSERVATIONS: No data
- Time schedule:No data
- Cage side observations checked in table [No.?] were included.No data

DETAILED CLINICAL OBSERVATIONS: No data
- Time schedule:No data

BODY WEIGHT: Yes
- Time schedule for examinations:weekly except during breeding

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes ,every third day
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No data

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data
- Time schedule for examinations: No data

OTHER: No data

Oestrous cyclicity (parental animals):

No data available

Sperm parameters (parental animals):

No data available

Litter observations:

Litters were examined and data collected on litter size, sex distribution, weight, and number of dead or malformed offspring.
The offspring were assessed on a series of tests using the Cincinnati Psychoteratogenicity Screening Test Battery, plus weight, food consumption, physical landmarks of development, and brain weight.

Postmortem examinations (parental animals):

SACRIFICE
- Male animals: All surviving animals [describe when, e.g. as soon as possible after the last litters in each generation were produced.]
- Maternal animals: All surviving animals [describe when, e.g. after the last litter of each generation was weaned.]

GROSS NECROPSY: yes
- Gross necropsy consisted of [external and internal examinations including the cervical, thoracic, and abdominal viscera.]

HISTOPATHOLOGY / ORGAN WEIGHTS
The tissues indicated in Table [#] were prepared for microscopic examination and weighed, respectively.

Postmortem examinations (offspring):

Malformed offspring were observed.

Statistics:

Frequency data (e.g., mortality) were analyzed by Fisher's test

Reproductive indices:

No data available

Offspring viability indices:

Viability indice on day 1-90 were examined.

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

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Description (incidence and severity):

There were no significant differences found among the groups in the experiment for food consumption prior to breeding or during gestation or lactation in the parental animals.

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:

not specified

Histopathological findings: non-neoplastic:

not specified

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 significant effects of any of the measures of reproductive performance were found in either experiment

Details on results (P0)

Body weight: effects were not, however, reflected in any significant changes in body weights.
Food consumption: There were no significant differences found among the groups in the first Red-3 experiment for food consumption prior to breeding or during gestation or lactation in the parental animals.
Reproductive performance: No significant effects of any of the measures of reproductive performance were found in either experiment

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:

other: No compound related effects observed on body weight,food consumption and reproductive performance

Remarks on result:

other: No toxic effects were observed

Target system / organ toxicity (P0)

Critical effects observed:

not specified

System:

other: not specified

Organ:

not specified

Results: F1 generation

General toxicity (F1)

Clinical signs:

not specified

Dermal irritation (if dermal study):

not specified

Mortality / viability:

not specified

Body weight and weight changes:

no effects observed

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 malformations were seen upon external examination

Histopathological findings:

not specified

Other effects:

not specified

Developmental neurotoxicity (F1)

Behaviour (functional findings):

no effects observed

Description (incidence and severity):

No advers effect were observed onPsychotoxicity of treated pups as compared to control.

Developmental immunotoxicity (F1)

Developmental immunotoxicity:

not specified

Details on results (F1)

Body weight and Food consumption: No significant reductions were found in offspring food consumption or body weight in either experiment from birth through day 90 of postnatal life.

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:

other: No effects observed on external examination of offspring,food consumption,body weight.

Target system / organ toxicity (F1)

Critical effects observed:

not specified

System:

other: not specified

Organ:

not specified

Overall reproductive toxicity

Reproductive effects observed:

not specified

Treatment related:

not specified

Any other information on results incl. tables

Reproductive performance of test chemical

	Treat- ment	No. of pairs bred	No. of dams producing litters (%)	No. of small litters (<8	No. of litters remaining	Mean (SE) gestation length	Mean (SE) litter size	M/F ratio
Exp.1	R3 1.0	19	16(84.2)	2	14	22.6(0.3)	10.9(0.8)	0.86
	R3 0.5	22	19(86.4)	5	14	22.5(0.2)	10.5(0.7)	0.96
	R3 0.25	18	14(77.8)	2	12	22.3(0.2)	10.7(0.7)	1.35
	R3 0.0	21	18(85.7)	0	18	22.6(0.1)	11.7(0.5)	0.89
	R3 HU	18	12(66.7)	2	10	22.3(0.1)	10.7(0.7)	1.11
Exp.2	R3 1.0	22	16(72.7)	1	15	21.9(0.1)	11.3(0.5)	1.04
	R3 0.5	21	15(71.4)	2	13	22.0(0.2)	11.1(0.8)	0.80
	R3 0.25	21	19(90.5)	2	17	22.1(0.1)	11.2(0.5)	1.15
	R3 0.0	20	14(70.0)	0	14	22.7(0.2)	10.6(0.6)	1.28

Applicant's summary and conclusion

Conclusions:

NOAEL was considered to be 1.0 % (1000 mg/kg/day) for F0 and F1 generation when Sprague-dawley male and female rat were exposed to test chemical .

Executive summary:

The reproductive and developmental effects of test chemical have been investigated in a 1-generation study in rats. The test chemical was administered at dietary dose levels of 0, 0.25, 0.5and 1.0 % (250, 500 and 1000 mg /kg bw/d) togroups of male and female Sprague-Dawley rats for two weeks prior to breeding, 1-14 days during breeding, then to females during gestation and lactation. The experimental diets were freely available to the offspring throughout postnatal development up to the age of 90-110 days. Body weights were measured weekly except during breeding. On the dayfollowing birth, all litters were examined and data collected on litter size, sex distribution,weight, and number of dead or malformed offspring. A variety of behavioural tests were determined in the offspring. Further, brainweights of day 90 were determined in the offspring. The experiment was replicated after2 years using the same exposure regimen.

The test chemical produced no effects on paternal or offspring weight or food consumption. No significant effects of any of the measures ofreproductive performance (proportion of females producing litters to those bred, thenumber of small litters, gestation length, litter size, sex ratio) were observed. No malformations were seen upon external examination. Preweaning offspring mortality was significantly increased at the 1.0 % and 0.5 % dose levels in the first experiment, but not inthe second. No adverse effects on offspring growth or adult regional brain weight were observed.No adverse effects were found in the present experiments on parental weight, food consumption, or reproductive performance.Therefore,NOAEL was considered to be 1.0 % (1000 mg/kg/day) for F0 and F1 generation when Sprague-dawleymale andfemale rat were exposed to test chemical .