4,4'-carbonimidoylbis[N,N-diethylaniline] monohydrochloride

Endpoint summary

Description of key information

Repeated dose toxicity: oral

The No Observed Adverse Effect Level (NOAEL) for Calcozine YeIlow SPF Unblended is considered to be 100 mg/Kg bw/day.

Repeated dose toxicity: inhalation
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 4,4'-carbonimidoylbis[N,N-diethylaniline] monohydrochloride, which is reported as 0.00000000015 Pa. Thus, exposure to inhalable dust, mist and vapour of the chemical 4,4'-carbonimidoylbis[N,N-diethylaniline] monohydrochloride  is highly unlikely. Therefore this study is considered for waiver.

Repeated dse toxicity: dermal
The acute toxicity value for 4,4'-carbonimidoylbis[N,N-diethylaniline] monohydrochloride (as provided in section 7.2.3) is >2000 mg/kg body weight. Thus, it is expected that 4,4'-carbonimidoylbis[N,N-diethylaniline] monohydrochloride shall not exhibit 28 day repeated dose toxicity by the dermal route. In addition, there is no data available that suggests that 4,4'-carbonimidoylbis[N,N-diethylaniline] monohydrochloride shall exhibit repeated dose toxicity by the dermal route. Hence this end point was considered for waiver.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

repeated dose toxicity: oral, other

Remarks:

Combined repeated dose & carcinogenicity

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

data from handbook or collection of data

Justification for type of information:

Data is from NTRL report

Qualifier:

according to guideline

Guideline:

other: Refer below principle

Principles of method if other than guideline:

Repeated dose orl toxicity study was performed to determine the toxic nature of Calcozine YeIlow SPF Unblended upon repeated exposure by oral route

GLP compliance:

not specified

Limit test:

no

Specific details on test material used for the study:

- Name of test material: Calcozine Yellow SFW Unblended
- EC name: 4,4'-carbonimidoylbis(N,N-diethylaniline) hydrochloride
- Molecular formula: C21H29N3ClH
- Molecular weight: 359.942 g/mol
- Substance type: Organic
- Physical state: No data
- Impurities (identity and concentrations): No data

Species:

rat

Strain:

other: Albino

Details on species / strain selection:

No data

Sex:

male/female

Details on test animals or test system and environmental conditions:

No data

Route of administration:

oral: feed

Details on route of administration:

No data

Vehicle:

other:

Remarks:

Feed

Details on oral exposure:

PREPARATION OF DOSING SOLUTIONS: Calcozine Yellow SPF was mixed with feed to give a dietary level of 0.1%

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): Feed
- Concentration in vehicle: 50 mg/Kg bw/day
- Amount of vehicle (if gavage): No data
- 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:

20-21 months

Frequency of treatment:

No data

Remarks:

0 or 100 mg/Kg bw/day

No. of animals per sex per dose:

No data

Control animals:

yes, concurrent vehicle

Details on study design:

No data

Positive control:

Auramine

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: No data
- 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: No data

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: No data
- 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: Yes

Other examinations:

No data

Statistics:

No data

Clinical signs:

not specified

Mortality:

mortality observed, treatment-related

Body weight and weight changes:

effects observed, non-treatment-related

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

Gross pathological findings:

effects observed, non-treatment-related

Neuropathological findings:

not specified

Histopathological findings: non-neoplastic:

effects observed, non-treatment-related

Histopathological findings: neoplastic:

effects observed, non-treatment-related

Other effects:

not specified

Details on results:

Clinical signs and mortality: Mortality was comparable to or better than that observed in untreated control group

Body weight and weight gain: A less marked reduction in body weight gain was observed in the rats fed Calcozine Yellow SFW Unblended.

Food consumption and compound intake: No data

Food efficiency: No data

Water consumption and compound intake: No data

Opthalmoscopic examination: No data

Haematology: No data

Clinical chemistry: No data

Urinanalysis: No data

Neurobehaviour: No data

Organ weights: No changes were observed in organ weight as compared to untreated control animals.

Gross pathology: Nodules were observed on the livers only 25% (7/28) of the test rats at the time of final sacrifice. No unusual growth was observed in the control rat livers.

No other outstanding differences were noted in any of the groups upon gross pathologic examination.

Histopathology:

Non neoplastic: Significant liver injury was noted among animals from test groups which was attributed to the test materials. The primary lesion consisted of focal to diffuse hyperplasia of the liver cells. Minor focal lesions of degeneration, necrosis , fatty me tamorphosis , inflammation, bile duct proliferation and cholangiofibrosis were present in the liver of treated animals. The lesions noted upon microscopic examination of the other- tissues from test animal group were attributed to naturally occurring disease and were considered to be normal for albino rats of this age and strain.

Neoplastic: Hepatomas were present in 2/9 male and 1/19 female that survived the length of the investigation. There were no hepatomas observed in any of the treated animals that died prior to the conclusion of the study. However, there were no hepatomas observed in any of the test animals that died prior to the conclusion of the investigation.

Dose descriptor:

NOAEL

Effect level:

100 mg/kg bw (total dose)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No significant alterations were noted at mentioned dose level

Critical effects observed:

not specified

Conclusions:

The No Observed Adverse Effect Level (NOAEL) for Calcozine YeIlow SPF Unblended is considered to be 100 mg/Kg bw/day.

Executive summary:

Combined repeated dose & carcinogenicity was performed to determine the toxic nature of Calcozine YeIlow SPF (IUPAC name: 4,4'-carbonimidoylbis (N,N-diethylaniline) hydrochloride) upon repeated exposure by oral route of exposure. Male and female albino rats were fed the test chemical at dose levels of 100 mg/Kg bw/day using diet for 20-21 months. Auramine was used as a positive control chemical. The animals were observed for mortality, body weight changes, gross pathology and neoplastic and non-neoplastic histopathology. Survival observed in the test animals was comparable to that noted in untreated control group. A less marked reduction in body weight gain was observed in the treated rats as compared to controls. Nodules were observed on the livers only 25% (7/28) of the test rats at the time of final sacrifice which was less as compared to the nodules observed in positive control 59% (20 /34). No other outstanding differences were noted in any of the groups upon gross pathologic examination. There was significant liver injury among animals from both the positive' control and test groups which was attributed to the positive control and test materials.The incidence of hyperplasia observed was comparable in positive control and treated animals. Minor focal lesions of degeneration, necrosis , fatty metamorphosis , inflammation, bile duct proliferation and cholangiofibrosis were present in the liver of control, positive control and test animals. However the severity of these Iesions was generally greater in the livers of the positive control animals than in the Iivers of control or test animals. The lesions noted in other tissues upon microscopic examination of the from control, positive control and test animals were attributed to naturally occurring disease and were considered to be normal for albino rats of this age and strain. Hepatomas were present in 2/9 male and 1/19 female that survived the length of the investigation. There were no hepatomas observed in any of the treated animals that died prior to the conclusion of the study. On the basis of observations made, the no observed adverse effect level (NOAEL) for Calcozine YeIlow SPF unblended is considered to be 100 mg/Kg bw/day.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

100 mg/kg bw/day

Study duration:

chronic

Species:

rat

Quality of whole database:

Data is from NTRL report

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Repeated dose toxicity oral:

Data for the target chemical along with its structurally related substance was reviewed to determine the toxic nature of 4,4'-carbonimidoylbis(N,N-diethylaniline) monohydrochloride upon repeated exposure by oral route. The summary is as mentioned below:

In NTRL study reportOTS0539600; B 8723; 1992,Combined repeated dose & carcinogenicity was performed to determine the toxic nature of Calcozine YeIlow SPF (IUPAC name: 4,4'-carbonimidoylbis (N,N-diethylaniline) hydrochloride) upon repeated exposure by oral route of exposure. Male and female albino rats were fed the test chemical at dose levels of 100 mg/Kg bw/day using diet for 20-21 months. Auramine was used as a positive control chemical. The animals were observed for mortality, body weight changes, gross pathology and neoplastic and non-neoplastic histopathology. Survival observed in the test animals was comparable to that noted in untreated control group. A less marked reduction in body weight gain was observed in the treated rats as compared to controls. Nodules were observed on the livers only 25% (7/28) of the test rats at the time of final sacrifice which was less as compared to the nodules observed in positive control 59% (20 /34). No other outstanding differences were noted in any of the groups upon gross pathologic examination. There was significant livf'r injury among animals from both the positive' control and test groups which was attributed to the positive control and test materials.The incidence of hyperplasia observed was comparable in positive control and treated animals. Minor focal lesions of degeneration, necrosis , fatty metamorphosis , inflammation, bile duct proliferation and cholangiofibrosis were present in the liver of control, positive control and test animals. However the severity of these Iesions was generally greater in the livers of the positive control animals than in the Iivers of control or test animals. The lesions noted in other tissues upon microscopic examination of the from control, positive control and test animals were attributed to naturally occurring disease and were considered to be nor-mal for albino rats of this age and strain. Hepatomas were present in 2/9 male and 1/19 female that survived the length of the investigation. There were no hepatomas observed in any of the treated animals that died prior to the conclusion of the study. On the basis of observations made, the no observed adverse effect level (NOAEL) for Calcozine YeIlow SPF unblended is considered to be 100 mg/Kg bw/day.

Four groups of five male and five female Wistar rats received structurally related substance Acid Red 52 (CAS 3520 -42 -1) daily by gavage at doses of 0, 100, 300 and 1000 mg/kg bw/day for 14 days (cited inTHE SCIENTIFIC COMMITTEE ON COSMETIC PRODUCTS AND NON-FOOD PRODUCTS (SCCNFP) /0803/ 23 April 2004). The test material (purity specified about 80 %, Lot. 18882) was homogenized in bi-distilled water containing 1 % Carboxymethylcellulose sodium salt (CMC). Clinical signs, food consumption and body weights were recorded periodically during pretest, and treatment period. All animals were killed, necropsied and examined post mortem. No death occurred during the 14-day treatment period. In all treated animals, violet faeces were observed until the end of the treatment period. This was considered to be a typical passive effect resulting from oral administration of dyestuff and is not considered to be a sign of toxicity. The absolute and relative kidney weights of males treated with 1000 mg/kg bw/day was lower than those of control animals. This finding was considered to be incidental. No other test substance related changes were observed, hence the No-Observable-Adverse-Effect-Level (NOAEL) of sodium 4-[3,6-bis(diethylamino)-2,7-dimethylxanthenium-9-yl]benzene-1,3-disulfonate (Acid Red 52) is considered to be 1000 mg/kg bw/day when administered by gavage over a period 14 days.

Based on the data summarized, 4,4'-carbonimidoylbis(N,N-diethylaniline) hydrochloride is not likely to be toxic upon repeated exposure by oral route. Thus, the chemical is not classified as a toxicant as per the criteria mentioned in CLP regulation.

Repeated dose toxicity: inhalation
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 4,4'-carbonimidoylbis[N,N-diethylaniline] monohydrochloride, which is reported as 0.00000000015 Pa. Thus, exposure to inhalable dust, mist and vapour of the chemical 4,4'-carbonimidoylbis[N,N-diethylaniline] monohydrochloride  is highly unlikely. Therefore this study is considered for waiver.

Repeated dse toxicity: dermal
The acute toxicity value for 4,4'-carbonimidoylbis[N,N-diethylaniline] monohydrochloride (as provided in section 7.2.3) is >2000 mg/kg body weight. Thus, it is expected that 4,4'-carbonimidoylbis[N,N-diethylaniline] monohydrochloride shall not exhibit 28 day repeated dose toxicity by the dermal route. In addition, there is no data available that suggests that 4,4'-carbonimidoylbis[N,N-diethylaniline] monohydrochloride shall exhibit repeated dose toxicity by the dermal route. Hence this end point was considered for waiver. )

Justification for classification or non-classification

Based on the data summarized, 4,4'-carbonimidoylbis(N,N-diethylaniline) monohydrochloride is not likely to be toxic upon repeated exposure by oral route. Thus, the chemical is not classified as a toxicant as per the criteria mentioned in CLP regulation.