Registration Dossier

Administrative data

Description of key information

Repeated dose toxicity: Oral

The No Observed adverse effect level (NOAEL) for  test chemical  is considered to be 1000 mg/kg bw in rats for subchronic  study.

Repeated dose study: Inalation

According to Annex IX of the REACH regulation, testing by the inhalation route is appropriate only if exposure of humans via inhalation is likely. Taking into account the low vapour pressure of the substance Ferrate(4-), hexakis(cyano-C)-, Et2-[6-(ethylamino)-3-(ethylimino)-2,7-dimethyl-3H-xanthen-9-yl]ben (12237-63-7)  which is reported as 8.62571e-13 mmHg at 25 C. Also considering the particle size distribution of the substance the majority of the particles was found to be in the size of 150 micron -10 micron which is much larger size range compared to the inhalable particulate matter .Thus, exposure to inhalable dust, mist and vapour of the chemical Ferrate(4-), hexakis(cyano-C)-, Et 2-[6-(ethylamino)-3-(ethylimino)-2,7-dimethyl-3H-xanthen-9-yl]ben is highly unlikely. Therefore this study is considered for waiver.

Repeated dose study: Dermal

The acute toxicity value for Ferrate(4-), hexakis(cyano-C)-, Et 2-[6-(ethylamino)-3-(ethylimino)-2,7-dimethyl-3H-xanthen-9-yl]ben.(12237-63-7)  (as provided in section 7.2.3) is >2000 mg/kg body weight. Also, given the use of the chemical; repeated exposure by the dermal route is unlikely since the use of gloves is common practice in industries. Thus, it is expected that Ferrate(4-), hexakis(cyano-C)-, Et 2-[6-(ethylamino)-3-(ethylimino)-2,7-dimethyl-3H-xanthen-9-yl]ben shall not exhibit 28 day repeated dose toxicity by the dermal route. In addition, there is no data available that suggests that Ferrate(4-), hexakis(cyano-C)-, Et 2-[6-(ethylamino)-3-(ethylimino)-2,7-dimethyl-3H-xanthen-9-yl]ben. shall exhibit repeated dose toxicity by the dermal route. Hence this end point was considered for waiver.

Key value for chemical safety assessment

Toxic effect type:
dose-dependent

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: oral
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Remarks:
Experimental Data for the data from various test chemicals
Justification for type of information:
Data for the target chemical is summarized based on the data from various test chemicals
Reason / purpose:
read-across source
Reason / purpose:
read-across source
Qualifier:
according to
Guideline:
other: Refer below principle
Principles of method if other than guideline:
WoE derived based on the experimental data from various test chemicals
GLP compliance:
not specified
Limit test:
no
Species:
rat
Strain:
other: 1,Charles River CD Sprague-Dawley 2,Crl:CD (SD)
Details on species / strain selection:
No data
Sex:
male/female
Details on test animals and environmental conditions:
1,TEST ANIMALS
- Source:
Female rats: Charles River Breeding Laboratories, Portage, Michigan.
Male rats: Langshaw Farms, Augusta, Michigan
- Age at study initiation: 18 weeks
- Weight at study initiation: No data
- Fasting period before study: No data
- Housing: The animals were housed in wire bottomed cages
- Diet (e.g. ad libitum): Purina Certified Rodent Chow No. 5002 ad libitum
- Water (e.g. ad libitum): Water ad libitum
- Acclimation period: 4 weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22.2 ± -15.5 ˚C
- Humidity (%): 50 ± 15%
- Air changes (per hr): No data
- Photoperiod (hrs dark / hrs light): 12 hrs light/dark cycle

IN-LIFE DATES: From: To: No data

2,Details on test animal
TEST ANIMALS
- Source: No data
- Age at study initiation: 9 weeks
- Weight at study initiation: No data
Route of administration:
oral: gavage
Details on route of administration:
No data
Vehicle:
water
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS: The test chemical was mixed with water as vehicle at dose levels of 0, 100, 500 or 1500 mg/kg body weight and prepared daily

DIET PREPARATION
- Rate of preparation of diet (frequency): No data
- Mixing appropriate amounts with (Type of food): No data
- Storage temperature of food: No data

VEHICLE
- Justification for use and choice of vehicle (if other than water): No data
- Concentration in vehicle: 0, 100, 500 or 1500 mg/kg bw
- Amount of vehicle (if gavage): 10 mL/Kg
- Lot/batch no. (if required): No data
- Purity: No data
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
No data
Duration of treatment / exposure:
1,14 days
2,Male: 42 days / - Female: 41 - 47 days (from 14 days before mating to day 4 of lactation)
Frequency of treatment:
Daily from 6-15 days of gestation
Remarks:
0, 100, 500 or 1500 mg/kg bw
Remarks:
Test group: 0, 40, 200 or 1000 mg/Kg/day
Recovery group: 0, 1000 mg/kg/day
No. of animals per sex per dose:
1,Total: 100 females
0 mg/Kg bw: 25 females
100 mg/Kg bw: 25 females
500 mg/Kg bw: 25 females
1500 mg/Kg bw: 25 females
Control animals:
yes, concurrent vehicle
Details on study design:
No data
Positive control:
No data
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: During the study period
- Cage side observations checked in table [No.?] were included. Mortality

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

BODY WEIGHT: Yes
- Time schedule for examinations: body weights were recorded on days 6, 9, 12 and 16 of gestation

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

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 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

OPHTHALMOSCOPIC EXAMINATION: No data
- Time schedule for examinations: No data
- Dose groups that were examined: No data

HAEMATOLOGY: No data
- Time schedule for collection of blood: No data
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: No data
- Parameters checked in table [No.?] were examined. No data

CLINICAL CHEMISTRY: No data
- Time schedule for collection of blood: No data
- Animals fasted: No data
- How many animals: No data
- Parameters checked in table [No.?] were examined. No data

URINALYSIS: Yes
- Time schedule for collection of urine: No data
- Metabolism cages used for collection of urine: No data
- Animals fasted: No data
- Parameters checked in table [No.?] were examined. No data

NEUROBEHAVIOURAL EXAMINATION: No data
- Time schedule for examinations: No data
- Dose groups that were examined: No data
- Battery of functions tested: sensory activity / grip strength / motor activity / other: No data

OTHER: No data
Sacrifice and pathology:
GROSS PATHOLOGY: Yes

HISTOPATHOLOGY: No data
Other examinations:
No data
Statistics:
No data
Clinical signs:
not specified
Description (incidence and severity):
No data
Mortality:
mortality observed, non-treatment-related
Description (incidence):
1,Survival was 100% in the controls and the groups receiving 100 and 500 mg/kg of dye. Six rats in the high-dose group (1500 mg/kg) died during the dosing period.
2, No mortality were observed at dose level of 0, 40, 200 or 1000 mg/Kg/day of treated group compare to control.
Body weight and weight changes:
effects observed, non-treatment-related
Description (incidence and severity):
There were slight reductions in body-weight gains in 1500 mg/Kg bw group, compared with controls, throughout the dosing period
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:
effects observed, treatment-related
Description (incidence and severity):
Orange discoloration of the urine was noted in all treated rats during the treatment period.
Behaviour (functional findings):
not specified
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
1,At autopsy, green discoloration of the amniotic fluid was noted in 1, 10 and 16 rats in the 100, 500 and 1500 mg/kg/day groups, respectively, and the small intestines were green in colour in many rats in the 500 mg/Kg group.
2,No effects were observed at dose level of 0, 40, 200 or 1000 mg/Kg/day of treated group compare to control.
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
not specified
Other effects:
not specified
Dose descriptor:
NOAEL
Effect level:
1 500 mg/kg bw (total dose)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: No significant effects were noted at the mentioned dose level
Dose descriptor:
NOAEL
Effect level:
1 000 other: mg/Kg/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No significant effect were observed at this dose
Remarks on result:
other: No toxic effect were observed
Critical effects observed:
not specified
Conclusions:
The No Observed adverse effect level (NOAEL) for  test chemical  is considered to be in a dose range of 1000mg/kg bw in rats for subchronic study
Executive summary:

Data available for the test chemicals was reviewed to determine the toxic nature of the test chemical. The studies are as mentioned below:

In another combined repeated dose repro-devp. Screen was performed to determine the toxic nature of test chemical upon repeated exposure by oral route.An aqueous solution of the dye was administered by garage to groups of 25 Charles River Sprague-Dawley rats at doses of 100, 500 and 1500 mg/kg on days 6- 19 of gestation. A control group received water on a comparable basis. Individual doses were determined on the basis of body weights recorded on days 6, 9, 12 and 16 of gestation.Survival was 100% in the controls and the groups receiving 100 and 500 mg/kg of dye. Six rats in the high-dose group (1500 mg/kg) died during the dosing period. There were slight reductions in body-weight gains in 1500 mg/Kg bw group, compared with controls, throughout the dosing period.Orange discoloration of the urine was noted in all treated rats during the treatment period.At autopsy, green discoloration of the amniotic fluid was noted in 1, 10 and 16 rats in the 100, 500 and 1500 mg/kg/day groups, respectively, and the small intestines were green in colour in many rats in the 500 mg/Kg group. Based on the above observations made, the No Observed adverse effect level (NOAEL) for test chemical is considered to be 1500 mg/kg bw.

In yet another combined repeated dose and reproduction / developmental screening, study was performed to evaluate the toxic nature of Pigment Orange 13. Male and female Crl:CD (SD) rats were used in the study. The test compound was dissolved in water and used at dose levels of 0, 40, 200 or 1000 mg/Kg/day. The male rats were treated for 42 days and female rats were treated for 41-47 days. Recovery group of 0 and 1000 mg/Kg/day was also included in the study. The treated animals were noted for clinical signs, functional battery observations, body weight, food consumption, urinanalysis, hematology, blood chemistry, organ weight changes and histopathology. No adverse effects were noted in the various parameters studied. Based on the observations made, The No Observed Adverse Effect Level (NOAEL) for the test chemical is considered to be 1000 mg/Kg/day when male and female Crl: CD (SD) rats were exposed for subchronic toxicity study duration .              

Based on the data available, the No Observed adverse effect level (NOAEL) for  test chemical  is considered to be in a dose range of 1000mg/kg bw in rats for subchronic study.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
Weight of evidence prepared from various qualified publication.

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records
Reference
Endpoint:
repeated dose toxicity: inhalation, other
Data waiving:
other justification
Justification for data waiving:
other:
Endpoint conclusion
Endpoint conclusion:
no study available
Quality of whole database:
Waiver

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records
Reference
Endpoint:
repeated dose toxicity: dermal, other
Data waiving:
other justification
Justification for data waiving:
other:
Endpoint conclusion
Endpoint conclusion:
no study available
Quality of whole database:
Waiver

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

The data available for the test chemicals was reviewed to determine the toxic nature upon repeated exposure by oral route. The studies are as mentioned below:

Repeated dose toxicity: Oral

In another combined repeated dose repro-devp. Screen was performed to determine the toxic nature of test chemical upon repeated exposure by oral route.An aqueous solution of the dye was administered by garage to groups of 25 Charles River Sprague-Dawley rats at doses of 100, 500 and 1500 mg/kg on days 6- 19 of gestation. A control group received water on a comparable basis. Individual doses were determined on the basis of body weights recorded on days 6, 9, 12 and 16 of gestation.Survival was 100% in the controls and the groups receiving 100 and 500 mg/kg of dye. Six rats in the high-dose group (1500 mg/kg) died during the dosing period. There were slight reductions in body-weight gains in 1500 mg/Kg bw group, compared with controls, throughout the dosing period.Orange discoloration of the urine was noted in all treated rats during the treatment period.At autopsy, green discoloration of the amniotic fluid was noted in 1, 10 and 16 rats in the 100, 500 and 1500 mg/kg/day groups, respectively, and the small intestines were green in colour in many rats in the 500 mg/Kg group. Based on the above observations made, the No Observed adverse effect level (NOAEL) for test chemical is considered to be 1500 mg/kg bw.

In yet another combined repeated dose and reproduction / developmental screening, study was performed to evaluate the toxic nature of Pigment Orange 13. Male and female Crl:CD (SD) rats were used in the study. The test compound was dissolved in water and used at dose levels of 0, 40, 200 or 1000 mg/Kg/day. The male rats were treated for 42 days and female rats were treated for 41-47 days. Recovery group of 0 and 1000 mg/Kg/day was also included in the study. The treated animals were noted for clinical signs, functional battery observations, body weight, food consumption, urinanalysis, hematology, blood chemistry, organ weight changes and histopathology. No adverse effects were noted in the various parameters studied. Based on the observations made, The No Observed Adverse Effect Level (NOAEL) for the test chemical is considered to be 1000 mg/Kg/day when male and female Crl: CD (SD) rats were exposed for subchronic toxicity study duration .              

Based on the data available, the No Observed adverse effect level (NOAEL) for  test chemical  is considered to be in a dose range of 1000mg/kg bw in rats for subchronic study.

Repeated dose study: Inalation

According to Annex IX of the REACH regulation, testing by the inhalation route is appropriate only if exposure of humans via inhalation is likely. Taking into account the low vapour pressure of the substance Ferrate(4-), hexakis(cyano-C)-, Et2-[6-(ethylamino)-3-(ethylimino)-2,7-dimethyl-3H-xanthen-9-yl]ben (12237-63-7)  which is reported as 8.62571e-13 mmHg at 25 C. Also considering the particle size distribution of the substance the majority of the particles was found to be in the size of 150 micron -10 micron which is much larger size range compared to the inhalable particulate matter .Thus, exposure to inhalable dust, mist and vapour of the chemical Ferrate(4-), hexakis(cyano-C)-, Et 2-[6-(ethylamino)-3-(ethylimino)-2,7-dimethyl-3H-xanthen-9-yl]ben is highly unlikely. Therefore this study is considered for waiver.

Repeated dose study: Dermal

The acute toxicity value for Ferrate(4-), hexakis(cyano-C)-, Et 2-[6-(ethylamino)-3-(ethylimino)-2,7-dimethyl-3H-xanthen-9-yl]ben.(12237-63-7)  (as provided in section 7.2.3) is >2000 mg/kg body weight. Also, given the use of the chemical; repeated exposure by the dermal route is unlikely since the use of gloves is common practice in industries. Thus, it is expected that Ferrate(4-), hexakis(cyano-C)-, Et 2-[6-(ethylamino)-3-(ethylimino)-2,7-dimethyl-3H-xanthen-9-yl]ben shall not exhibit 28 day repeated dose toxicity by the dermal route. In addition, there is no data available that suggests that Ferrate(4-), hexakis(cyano-C)-, Et 2-[6-(ethylamino)-3-(ethylimino)-2,7-dimethyl-3H-xanthen-9-yl]ben. shall exhibit repeated dose toxicity by the dermal route. Hence this end point was considered for waiver.

Based on the data available and applying the weight of evidence approach, the test chemical does not exhibit toxic nature upon repeated exposure by oral, inhalation and dermal route of exposure and hence is not likely to classify as per the criteria mentioned in CLP regulation.

Justification for classification or non-classification

Based on the data available and applying the weight of evidence approach, the test chemical does not exhibit toxic nature upon repeated exposure by oral, inhalation and dermal route of exposure and hence is not likely to classify as per the criteria mentioned in CLP regulation.