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Description of key information

Repeated dose toxicity: Oral

Based on the observations made, the No Observed Adverse Effect Level (NOAEL) for the test chemical Benzene-1,4-diammonium sulphate (CAS no 16245 -77 -5) is considered to be 25 mg/kg/day when F344 rats were exposed to the test chemical.

Repeated dose toxicity: Inhalation

Benzene-1,4-diammonium sulphate (CAS no.: 16245-77-5) has very low vapour pressure (0.000413 Pa =3.097754308e-6 mmHg), so the potential for the generation of inhalable vapours is very low. Also the normal conditions of use of this substance will not result in aerosols, particles or droplets of an inhalable size, so exposure to humans via the inhalatory route will be highly unlikely and therefore the end point for repeated dose toxicity by dermal route was considered for waiver.

Repeated dose toxicity: Dermal

The acute dermal toxicity value for Benzene-1,4-diammonium sulphate (CAS no.: 16245-77-5) (as provided in section 7.2.3) is >2000 mg/kg body weight. The substance was also found to be not irritating to the skin.  Considering this, the end point for repeated dermal toxicity is considered as 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:
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 of read across substances
Justification for type of information:
Data for the target chemical is summarized based on the structurally similar read across chemicals
Reason / purpose:
read-across source
Related information:
Composition 1
Reason / purpose:
read-across source
Related information:
Composition 1
Reference:
Composition 0
Qualifier:
according to
Guideline:
other: Refer below principle
Principles of method if other than guideline:
WoE derived based on the experimental data from structurally and functionally similar read across chemicals
GLP compliance:
not specified
Limit test:
no
Test material information:
Composition 1
Species:
rat
Strain:
Fischer 344
Details on species / strain selection:
No data
Sex:
male/female
Details on test animals and environmental conditions:
1. TEST ANIMALS- Source: Charles River Japan, Inc., Kanagawa, Japan- Age at study initiation: 6 weeks- Weight at study initiation: No data- Fasting period before study: No data- Housing: Rats were housed in plastic cages- Diet (e.g. ad libitum): Oriental M powdered diet (Oriental Yeast Co., Tokyo, Japan)- Water (e.g. ad libitum): Tap water ad libitum- Acclimation period: No dataENVIRONMENTAL CONDITIONS- Temperature (°C): 24˚C- Humidity (%):No data- Air changes (per hr): No data- Photoperiod (hrs dark / hrs light): No dataIN-LIFE DATES: From: To: No data2. TEST ANIMALS- Source: Charles River Laboratories Japan, Inc.(Atsugi, Japan)- Age at study initiation: 6 weeks- Weight at study initiation: No data- Fasting period before study: No data- Housing: No data- Diet (e.g. ad libitum): pelleted chow food (CRF-1, Oriental Yeast, Co., Ltd) ad libitum- Water (e.g. ad libitum): tap water ad libitum- Acclimation period: 7 daysENVIRONMENTAL CONDITIONS- Temperature (°C): No data- Humidity (%):No data- Air changes (per hr): No data- Photoperiod (hrs dark / hrs light): No dataIN-LIFE DATES: From: To: No data
Route of administration:
other: 1. Feed; 2. Gavage
Details on route of administration:
No data
Vehicle:
other: 1. Feed; 2. 1% CMC
Details on oral exposure:
1. PREPARATION OF DOSING SOLUTIONS: The test chemical was mixed with feed at dose levels of 0, 25 or 50 mg/Kg/dayDIET PREPARATION- Rate of preparation of diet (frequency): No data- Mixing appropriate amounts with (Type of food): No data- Storage temperature of food: No dataVEHICLE- Justification for use and choice of vehicle (if other than water): No data- Concentration in vehicle: 0, 25 or 50 mg/Kg/day- Amount of vehicle (if gavage): No data- Lot/batch no. (if required): No data- Purity: No data2. PREPARATION OF DOSING SOLUTIONS: The test chemical was mixed with 1% CMC at dose levels of 0 or 100 mg/Kg/dayDIET PREPARATION- Rate of preparation of diet (frequency): No data- Mixing appropriate amounts with (Type of food): No data- Storage temperature of food: No dataVEHICLE- Justification for use and choice of vehicle (if other than water): No data- Concentration in vehicle: 0 or 100 mg/Kg/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:
1. 80 weeks2. 28 days
Frequency of treatment:
Daily
Remarks:
0, 25 or 50 mg/Kg/day / 1
Remarks:
0 or 100 mg/Kg/day / 2
No. of animals per sex per dose:
1. 0 mg/Kg/day: 24-25 rats25 mg/Kg/day: 63-66 rats50 mg/Kg/day: 63-66 rats2. Total: 80 mg/Kg/day: 4 male rats100 mg/Kg/day: 4 male rats
Control animals:
yes, concurrent vehicle
Details on study design:
1. - Dose selection rationale: The concentrations of p-phenylenediamine used were decided from the results of the subacute toxicity test. - Rationale for animal assignment (if not random): No data- Rationale for selecting satellite groups: No data- Post-exposure recovery period in satellite groups: No data- Section schedule rationale (if not random): No data2. - Dose selection rationale: The administration dose for each chemical was set around their minimum carcinogenic doses for carcinogens or maximum tolerable doses based on the information in NTP and CCRIS database as well as other literatures for non-carcinogens.- Rationale for animal assignment (if not random): No data- Rationale for selecting satellite groups: No data- Post-exposure recovery period in satellite groups: No data- Section schedule rationale (if not random): No data
Positive control:
No data
Observations and examinations performed and frequency:
1. CAGE SIDE OBSERVATIONS: No data- Time schedule: No data- Cage side observations checked in table [No.?] were included. No dataDETAILED CLINICAL OBSERVATIONS: No data- Time schedule: No dataBODY WEIGHT: Yes- Time schedule for examinations: weeklyFOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes, weekly- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes - Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No dataFOOD 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 dataWATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data- Time schedule for examinations: No dataOPHTHALMOSCOPIC EXAMINATION: No data- Time schedule for examinations: No data- Dose groups that were examined: No dataHAEMATOLOGY: Yes- Time schedule for collection of blood: All animals surviving in week 80 were subjected to hematological analysis.- Anaesthetic used for blood collection: No data - Animals fasted: No data - How many animals: All animals surviving in week 80- Parameters checked in table [No.?] were examined. No dataCLINICAL 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 dataURINALYSIS: 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 dataNEUROBEHAVIOURAL 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 dataOTHER: No data2. CAGE SIDE OBSERVATIONS: No data- Time schedule: No data- Cage side observations checked in table [No.?] were included. No dataDETAILED CLINICAL OBSERVATIONS: No data- Time schedule: No dataBODY WEIGHT: No data- Time schedule for examinations: No dataFOOD 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 dataFOOD 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 dataWATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data- Time schedule for examinations: No dataOPHTHALMOSCOPIC EXAMINATION: No data- Time schedule for examinations: No data- Dose groups that were examined: No dataHAEMATOLOGY: 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 dataCLINICAL 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 dataURINALYSIS: 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 dataNEUROBEHAVIOURAL 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 dataOTHER: No data
Sacrifice and pathology:
1. GROSS PATHOLOGY: Yes, Animals were killed after 80 weeks or when they became moribund and were necropsied after death. All organs were examinedMacroscopically.HISTOPATHOLOGY: Yes, All organs were examined macroscopically, and then fixed in 10% buffered formalin and sections were prepared for histological examination.2. GROSS PATHOLOGY: Yes, Rats were humanly sacrificed with CO2-O2 (4:1) gas inhalation at 3, 14 or 28 days after administration. The livers were immediately excised and weighedHISTOPATHOLOGY: Yes, A portion of the left lateral lobe was also taken for histopathology. Tissues were fixed in 10% neutral-buffered formalin, and subsequently sectioned and stained with hematoxylin and eosin.
Other examinations:
No data
Statistics:
No data
Clinical signs:
not specified
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
1. There was no relation between the average body weight and the concentration of p-phenylenediamine in male rats, but the body weight of female rats given 0.1% p-phenylenediamine was less than that of the controls.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
1. The food consumption of male and female rats in the experimental groups was not significantly different from those of the controls.
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):
1. The number of red and white blood cells and the hematocrit and hemoglobin values were not significantly different in different groups.
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:
effects observed, treatment-related
Description (incidence and severity):
1. In females in group 1, given 0.1% p-phenylenediamine, the mean weights of the body and spleen were less than those of the control, and in females in group 2, given 0.05%, the mean weight of the spleen was less than that of the control.
Gross pathological findings:
not specified
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
effects observed, non-treatment-related
Description (incidence and severity):
1. The incidences of non-neoplastic lesions, including hemorrhage of the pituitary gland, fatty degeneration of the liver, fibrosis of the pancreas and pneumonia, were also not significantly different in different groups. No marked changes of the thyroid gland were observed in any rats.
Histopathological findings: neoplastic:
effects observed, non-treatment-related
Description (incidence and severity):
1. The first tumor (a pheochromocytoma) was observed in a male rat that died of pneumonia in week 60. In both sexes the highest incidence of neoplastic lesions was that of pheochromocytomas of the adrenal gland. These lesions were observed in 10 (27.8%) of 36 male rats given 0.1% p-phenylenediamine, 8 (22.9%) of 35 male rats given 0.05% p-phenylenediamine and 6 (31.6%) of 19 males in the control group, but there was no significant difference in their incidences in different groups. In females, pheochromocytomas were also found in all experimental groups, although at lower incidences than in males. Other neoplastic lesions were as follows: hyperplasia of the forestomach in males, a fibroadenoma of the mammary gland in a female, a fibroma of the skin in a male, lymphomas in females and ductal hyperplasia of the pancreas in a female. The incidences of these neoplastic lesions were not significantly different in different groups.
Other effects:
not specified
Dose descriptor:
NOAEL
Remarks:
1
Effect level:
25 mg/kg bw (total dose)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: No significat effects were noted at the mentioned dose level
Dose descriptor:
NOAEL
Remarks:
2
Effect level:
50 mg/kg bw (total dose)
Based on:
test mat.
Sex:
male
Basis for effect level:
other: No significant alterations were noted at the mentioned dose level
Dose descriptor:
NOAEL
Remarks:
2
Effect level:
100 mg/kg bw (total dose)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No significant effects were noted at the mentioned dose level
Critical effects observed:
not specified
Conclusions:
The No Observed Adverse Effect Level (NOAEL) for the test chemical Benzene-1,4-diammonium sulphate (CAS no 16245 -77 -5) is considered to be 25 mg/kg/day when F344 rats were exposed to the test chemical.
Executive summary:

Data available for the test chemicals was reviewed to determine the mutagenic nature of Benzene-1,4-diammonium sulphate (CAS no 16245 -77 -5). The studies are as mentioned below:

Combined repeated dose & carcinogenicity study was performed to determine the toxic nature of the test chemical. The study was performed using 6 week old male F344 rats in a 80 weeks study. The test chemical was mixed with feed and used at dose level of 0, 25 or 50 mg/Kg/day.The animals were observed for changes in body weight and food consumption, hematology, organ weight changed and were subjected to gross and histopathology. There was no relation between the average body weight and the concentration of p-phenylenediamine in male rats, but the body weight of female rats given 0.1% p-phenylenediamine was less than that of the controls. The food consumption of male and female rats in the experimental groups was not significantly different from those of the controls. The number of red and white blood cells and the hematocrit and hemoglobin values were not significantly different in different groups. In females in group 1, given 0.1% p-phenylenediamine, the mean weights of the body and spleen were less than those of the control, and in females in group 2, given 0.05%, the mean weight of the spleen was less than that of the control. The first tumor (a pheochromocytoma) was observed in a male rat that died of pneumonia in week 60. In both sexes the highest incidence of neoplastic lesions was that of pheochromocytomas of the adrenal gland. These lesions were observed in 10 (27.8%) of 36 male rats given 0.1% p-phenylenediamine, 8 (22.9%) of 35 male rats given 0.05% p-phenylenediamine and 6 (31.6%) of 19 males in the control group, but there was no significant difference in their incidences in different groups. In females, pheochromocytomas were also found in all experimental groups, although at lower incidences than in males. Other neoplastic lesions were as follows: hyperplasia of the forestomach in males, a fibroadenoma of the mammary gland in a female, a fibroma of the skin in a male, lymphomas in females and ductal hyperplasia of the pancreas in a female. The incidences of these neoplastic lesions were not significantly different in different groups. The incidences of non-neoplastic lesions, including hemorrhage of the pituitary gland, fatty degeneration of the liver, fibrosis of the pancreas and pneumonia, were also not significantly different in different groups. No marked changes of the thyroid gland were observed in any rats. Based on the observations made, the No Observed Adverse Effect Level (NOAEL) for the test chemical is considered to be 25 mg/kg/day when F344 rats were exposed to the test chemical for 80 weeks.

In another study, combined repeated dose & carcinogenicity study was performed to determine the toxic nature of the test chemical. The study was performed using 6 week old male F344 rats in a 28 days study. The test chemical was mixed with 1% CMC and used at dose level of 0 or 100 mg/Kg/day. Rats were humanly sacrificed with CO2-O2 (4:1) gas inhalation at 3, 14 or 28 days after administration. The livers were immediately excised and weighed. Tissues were fixed in 10% neutral-buffered formalin, and subsequently sectioned and stained with hematoxylin and eosin. No histological abnormalities were noted due to test chemical treatment. The No Observed Adverse Effect Level (NOAEL) for the test chemical is considered to be 100 mg/kg/day when F344 rats were exposed for 28 days by oral gavage route.

Based on the observations made, the No Observed Adverse Effect Level (NOAEL) for the test chemical Benzene-1,4-diammonium sulphate (CAS no 16245 -77 -5) is considered to be 25 mg/kg/day when F344 rats were exposed to the test chemical.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
25 mg/kg bw/day
Study duration:
chronic
Species:
rat
Quality of whole database:
Data is from peer reviewed 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

Mode of Action Analysis / Human Relevance Framework

Additional information

Repeated dose toxicity: Oral

Data available for the test chemicals was reviewed to determine the mutagenic nature of Benzene-1,4-diammonium sulphate (CAS no 16245 -77 -5). The studies are as mentioned below:

Combined repeated dose & carcinogenicity study was performed to determine the toxic nature of the test chemical. The study was performed using 6 week old male F344 rats in a 80 weeks study. The test chemical was mixed with feed and used at dose level of 0, 25 or 50 mg/Kg/day.The animals were observed for changes in body weight and food consumption, hematology, organ weight changed and were subjected to gross and histopathology. There was no relation between the average body weight and the concentration of p-phenylenediamine in male rats, but the body weight of female rats given 0.1% p-phenylenediamine was less than that of the controls. The food consumption of male and female rats in the experimental groups was not significantly different from those of the controls. The number of red and white blood cells and the hematocrit and hemoglobin values were not significantly different in different groups. In females in group 1, given 0.1% p-phenylenediamine, the mean weights of the body and spleen were less than those of the control, and in females in group 2, given 0.05%, the mean weight of the spleen was less than that of the control. The first tumor (a pheochromocytoma) was observed in a male rat that died of pneumonia in week 60. In both sexes the highest incidence of neoplastic lesions was that of pheochromocytomas of the adrenal gland. These lesions were observed in 10 (27.8%) of 36 male rats given 0.1% p-phenylenediamine, 8 (22.9%) of 35 male rats given 0.05% p-phenylenediamine and 6 (31.6%) of 19 males in the control group, but there was no significant difference in their incidences in different groups. In females, pheochromocytomas were also found in all experimental groups, although at lower incidences than in males. Other neoplastic lesions were as follows: hyperplasia of the forestomach in males, a fibroadenoma of the mammary gland in a female, a fibroma of the skin in a male, lymphomas in females and ductal hyperplasia of the pancreas in a female. The incidences of these neoplastic lesions were not significantly different in different groups. The incidences of non-neoplastic lesions, including hemorrhage of the pituitary gland, fatty degeneration of the liver, fibrosis of the pancreas and pneumonia, were also not significantly different in different groups. No marked changes of the thyroid gland were observed in any rats. Based on the observations made, the No Observed Adverse Effect Level (NOAEL) for the test chemical is considered to be 25 mg/kg/day when F344 rats were exposed to the test chemical for 80 weeks.

In another study, combined repeated dose & carcinogenicity study was performed to determine the toxic nature of the test chemical. The study was performed using 6 week old male F344 rats in a 28 days study. The test chemical was mixed with 1% CMC and used at dose level of 0 or 100 mg/Kg/day. Rats were humanly sacrificed with CO2-O2 (4:1) gas inhalation at 3, 14 or 28 days after administration. The livers were immediately excised and weighed. Tissues were fixed in 10% neutral-buffered formalin, and subsequently sectioned and stained with hematoxylin and eosin. No histological abnormalities were noted due to test chemical treatment. The No Observed Adverse Effect Level (NOAEL) for the test chemical is considered to be 100 mg/kg/day when F344 rats were exposed for 28 days by oral gavage route.

Based on the observations made, the No Observed Adverse Effect Level (NOAEL) for the test chemical Benzene-1,4-diammonium sulphate (CAS no 16245 -77 -5) is considered to be 25 mg/kg/day when F344 rats were exposed to the test chemical.

Repeated dose toxicity: Inhalation

Benzene-1,4-diammonium sulphate (CAS no.: 16245-77-5) has very low vapour pressure (0.000413 Pa =3.097754308e-6 mmHg), so the potential for the generation of inhalable vapours is very low. Also the normal conditions of use of this substance will not result in aerosols, particles or droplets of an inhalable size, so exposure to humans via the inhalatory route will be highly unlikely and therefore the end point for repeated dose toxicity by dermal route was considered for waiver.

Repeated dose toxicity: Dermal

The acute dermal toxicity value for Benzene-1,4-diammonium sulphate (CAS no.: 16245-77-5) (as provided in section 7.2.3) is >2000 mg/kg body weight. The substance was also found to be not irritating to the skin.  Considering this, the end point for repeated dermal toxicity is considered as waiver.

Based on the data available for the test chemical and applying the weight of evidence approach, Benzene-1,4-diammonium sulphate (CAS no 16245 -77 -5) is not likely to be toxic as per the criteria mentioned in CLP regulation.

Justification for classification or non-classification

Based on the data available for the test chemical and applying the weight of evidence approach, Benzene-1,4-diammonium sulphate (CAS no 16245 -77 -5) is not likely to be toxic as per the criteria mentioned in CLP regulation.