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Administrative data

Description of key information

Read Across approach used to analogue substance. Assumption that target substance will have the same properties. Available data for the source subtance Solvent Red 19E:

Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test, oral (gavage), rat (Wistar Han) M/F, OECD guideline 422, GLP: NOAEL <160 mg/kg bw/day

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:
short-term repeated dose toxicity: oral
Remarks:
combined repeated dose and reproduction / developmental screening
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
REPORTING FORMAT FOR THE ANALOGUE APPROACH : Please see attached Read Across supporting document in Section 13 which includes the following:
1. HYPOTHESIS FOR THE ANALOGUE APPROACH
2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
3. ANALOGUE APPROACH JUSTIFICATION
4. DATA MATRIX
Reason / purpose:
read-across source
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
A Read across approach to an analogue substances is being used. See Source substance for details of clinical observations.
Mortality:
no mortality observed
Description (incidence):
A Read across approach to an analogue substances is being used. See Source substance for details of clinical observations.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
A Read across approach to an analogue substances is being used. See Source substance for details of clinical observations.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
A Read across approach to an analogue substances is being used. See Source substance for details of clinical observations.
Food efficiency:
no effects observed
Description (incidence and severity):
A Read across approach to an analogue substances is being used. See Source substance for details of clinical observations.
Water consumption and compound intake (if drinking water study):
effects observed, treatment-related
Description (incidence and severity):
A Read across approach to an analogue substances is being used. See Source substance for details of clinical observations.
Ophthalmological findings:
not examined
Description (incidence and severity):
A Read across approach to an analogue substances is being used. See Source substance for details of clinical observations.
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
A Read across approach to an analogue substances is being used. See Source substance for details of clinical observations.
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
A Read across approach to an analogue substances is being used. See Source substance for details of clinical observations.
Urinalysis findings:
effects observed, treatment-related
Description (incidence and severity):
A Read across approach to an analogue substances is being used. See Source substance for details of clinical observations.
Behaviour (functional findings):
no effects observed
Description (incidence and severity):
A Read across approach to an analogue substances is being used. See Source substance for details of clinical observations.
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
A Read across approach to an analogue substances is being used. See Source substance for details of clinical observations.
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
A Read across approach to an analogue substances is being used. See Source substance for details of clinical observations.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
A Read across approach to an analogue substances is being used. See Source substance for details of clinical observations.
Histopathological findings: neoplastic:
no effects observed
Description (incidence and severity):
A Read across approach to an analogue substances is being used. See Source substance for details of clinical observations.
Key result
Dose descriptor:
NOAEL
Effect level:
< 160 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
haematology
clinical biochemistry
histopathology: non-neoplastic
Remarks on result:
other: NOAEL for Read across Source substance
Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
160 mg/kg bw/day (actual dose received)
System:
hepatobiliary
Organ:
liver
Treatment related:
yes
Dose response relationship:
yes
Relevant for humans:
not specified
Conclusions:
Based on read across to an analogue substance, The value of NOAEL (No Observed Adverse Effect Level) for repeated dose toxicity is predicted to be
<160 mg/kg body weight/day for both males and females. For the purposes or risk assessment a LOAEL of 160mg/kg bw will be used. The value was established on the analogue substance based on haematology (decreased values of RBC, haematocrit, haemoglobin and prothrombin time,
increased values of CPTT and fibrinogen) and biochemistry blood parameters (increased activity of ALP in both sexes) and microscopical examination of organs (vacuolation of hepatocytes in males).
Executive summary:

A read across approach was used to predict the subacute oral toxicity properties of Solvent Red 19T ( 1-({2-methyl-4-[(2-methylphenyl)diazenyl]phenyl}diazenyl)-N-tridecylnaphthalen-2-amine).

The analogue source substance was Solvent Red 19E, which has the same structure, but where the tridecyl group has been replaced with a 2 -ethyl hexyl group. This material was assessed for repeated dose toxicity according to guideline OECD 422. Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test.

Wistar rats were dosed at 160, 400, 1000 mg/kg of body weight /day.

Repeated oral administration of Solvent Red 19E to rats by gavage at the dose levels 160,400 and 1000 mg/kg/day did not cause any mortality.

At 160 mg/kg/day, no effect on growth of animals was detected in both sexes only slight changes of food conversion and consumption were detected. The animals’ heath condition was good during the whole study. During functional examination slight decrease of upstanding in males were recorded. Changes of haematological parameters (significantly decreased value of RBC, with the haematocrit, haemoglobin and prothrombin time, significantly increased value of fibrinogen in males), biochemical parameter (significantly increased value of glucose - above historical control limits in males), urinalysis in males (presence of leucocytes) and biometry of organs (significantly decreased absolute and relative weight of kidneys and significantly decreased relative weight of ovaries in females) were detected.

Occurrence of macroscopic changes in males and females (mainly reddish colouring of some organs and/or tissues in both sexes) and microscopic changes in prostate gland in males and ovaries, vagina, mammary gland and uterus in females were detected at the dose level 160 mg/kg/day. These microscopic changes in reproductive organs did not relate to the test substance treatment.

 

At 400 mg/kg/day, no effect on growth of animals was detected in both sexes only slight changes of food conversion and consumption were detected. Changes of clinical status in animals (red colouring of excrement), haematological parameters (significantly decreased value of prothrombin time in males and females, in males it was under historical control limits), biochemical parameters (significantly increased value of glucose in males and significantly decreased value of sodium ions in females), urinalysis in males (change of colour, presence of leucocytes) and biometry of organs (significantly increased absolute and relative weight of liver in males and significantly decreased absolute and relative weight of pituitary gland and significantly decreased relative weight of ovaries in females) were detected.

Occurrence of macroscopic changes in males and females (mainly red colouring of some organs and/or tissues by the test substance in both sexes and marked structure in liver in males) and microscopic changes of liver, lungs and prostate gland in males and ovaries, vagina and uterus in females were detected at the dose level 400 mg/kg/day. These microscopic changes in reproductive organs did not relate to the test substance treatment.

 

At 1000 mg/kg/day, no effect on growth of animals was detected in both sexes only slight changes of food conversion and consumption were detected. Clinical status of animals after application was influenced by the test substance treatment (red colouring of excrement and shavings, gait on toes, raised tail, nuzzling in the shavings and disquiet after application). Tail of animals was contaminated by coloured excrement. During functional examination increase of upstanding in satellite females were recorded.

Changes of haematological parameters (irreversible significantly decreased value of RBC, haematocrit and haemoglobin, significantly decreased value of prothrombin time, significantly increased value of fibrinogen in males and irreversible significantly increased value of WBC, delayed significantly decreased value of granulocytes in females), blood biochemical parameters (delayed significantly decreased value of bilirubin total and calcium ions in both sexes and delayed significantly increased activity of AST in females), urinalysis in males (change of colour, presence of leucocytes), biometry of organs (delayed significantly decreased absolute and relative weight of thymus, significantly increased relative weight of liver in males and significantly decreased absolute and relative weight of ovaries, significantly decreased relative weight of kidneys and significantly increased relative weight of spleen in females), gross examination of organs and tissues (mainly irreversible red colouring of some organs and/or tissues in males and females, marked structure in liver in males and dark colouring of spleen in females) and histological examination of organs and tissues (mainly vacuolation of hepatocytes in liver, nonpurulent pneumonitis in lungs in males and accumulation of lipophages and/or pigmentophages in uterus, haemorrhage in uterus and degeneration of tertiary follicles in ovaries in females) at the dose level 1000 mg/kg/day were recorded. These microscopic changes in reproductive organs did not relate to the test substance treatment.

 

The test substance, Solvent Red 19E, during Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test showed effect on clinical status (red colouring of excrements and shavings, gait on toes, raised tail, nuzzling in the shavings, disquiet after application), haematological parameters (decreased values of RBC, haematocrit, haemoglobin and prothrombin time, increased value of APTT and fibrinogen), biochemical parameters (changes of bilirubin, glucose in males, bilirubin, calcium ions, sodium ions in females and ALT, ALP and AST activity), biometry of organs (decreased weight of thymus, kidneys and ovaries and increased weight of liver and spleen) and urine parameters (change of colour urine and occurrence of leucocytes) mainly at the middle and highest dose level.

The test substance had an influence on macroscopic structure of some organs and tissues (red colouring of liver, lymph nodes, the whole GIT, body fat in both sexes and ovaries in females) and microscopic structure of liver in males (vacuolation of hepatocytes).

The value of NOAEL (No Observed Adverse Effect Level) for repeated dose toxicity was established as lower than 160 mg/kg body weight/day both for males and females. The value was established on the basis of haematology (decreased values of RBC, haematocrit, haemoglobin and prothrombin time, increased value of APTT and fibrinogen) and biochemistry blood parameters (increased activity of ALP in both sexes) and microscopic examination of organs (vacuolation of hepatocytes in males).

 

Based on the similarity in structure and manufacturing process, Solvent Red 19T would be expected to have the same properties, and the same NOAEL. (<160mg/kg). Based on the Read Across approach, the material should also be classified with respect toRepeated Dose Toxicity (Oral) as STOT RE 2 (H373; May cause damage to organs (liver) through prolonged or repeated exposure). For the purposes or risk assessment a LOAEL of 160mg/kg bw will be used.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LOAEL
160 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
The study is GLP compliant and has Klimisch score 1. The quality of the database is therefore considered to be good.
System:
hepatobiliary
Organ:
liver

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

A read across approach was used to predict the subacute oral toxicity

properties of Solvent Red 19T ( 1-({2-methyl-4-[(2-methylphenyl)diazenyl]phenyl}diazenyl)-N-tridecylnaphthalen-2-amine).

The analogue source substance was Solvent Red 19E, which has the same structure, but where the tridecyl group has been replaced with a 2 -ethyl hexyl group. This material was assessed for repeated dose toxicity according to guideline OECD 422. Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test.

Wistar rats were dosed at 160, 400, 1000 mg/kg of body weight /day.

Repeated oral administration of Solvent Red 19E to rats by gavage at the dose levels 160,400 and 1000 mg/kg/day did not cause any mortality.

At 160 mg/kg/day, no effect on growth of animals was detected in both sexes only slight changes of food conversion and consumption were detected. The animals’ heath condition was good during the whole study. During functional examination slight decrease of upstanding in males were recorded. Changes of haematological parameters (significantly decreased value of RBC, with the haematocrit, haemoglobin and prothrombin time, significantly increased value of fibrinogen in males), biochemical parameter (significantly increased value of glucose - above historical control limits in males), urinalysis in males (presence of leucocytes) and biometry of organs (significantly decreased absolute and relative weight of kidneys and significantly decreased relative weight of ovaries in females) were detected.

Occurrence of macroscopic changes in males and females (mainly reddish colouring of some organs and/or tissues in both sexes) and microscopic changes in prostate gland in males and ovaries, vagina, mammary gland and uterus in females were detected at the dose level 160 mg/kg/day. These microscopic changes in reproductive organs did not relate to the test substance treatment.

 

At 400 mg/kg/day, no effect on growth of animals was detected in both sexes only slight changes of food conversion and consumption were detected. Changes of clinical status in animals (red colouring of excrement), haematological parameters (significantly decreased value of prothrombin time in males and females, in males it was under historical control limits), biochemical parameters (significantly increased value of glucose in males and significantly decreased value of sodium ions in females), urinalysis in males (change of colour, presence of leucocytes) and biometry of organs (significantly increased absolute and relative weight of liver in males and significantly decreased absolute and relative weight of pituitary gland and significantly decreased relative weight of ovaries in females) were detected.

Occurrence of macroscopic changes in males and females (mainly red colouring of some organs and/or tissues by the test substance in both sexes and marked structure in liver in males) and microscopic changes of liver, lungs and prostate gland in males and ovaries, vagina and uterus in females were detected at the dose level 400 mg/kg/day. These microscopic changes in reproductive organs did not relate to the test substance treatment.

 

At 1000 mg/kg/day, no effect on growth of animals was detected in both sexes only slight changes of food conversion and consumption were detected. Clinical status of animals after application was influenced by the test substance treatment (red colouring of excrement and shavings, gait on toes, raised tail, nuzzling in the shavings and disquiet after application). Tail of animals was contaminated by coloured excrement. During functional examination increase of upstanding in satellite females were recorded.

Changes of haematological parameters (irreversible significantly decreased value of RBC, haematocrit and haemoglobin, significantly decreased value of prothrombin time, significantly increased value of fibrinogen in males and irreversible significantly increased value of WBC, delayed significantly decreased value of granulocytes in females), blood biochemical parameters (delayed significantly decreased value of bilirubin total and calcium ions in both sexes and delayed significantly increased activity of AST in females), urinalysis in males (change of colour, presence of leucocytes), biometry of organs (delayed significantly decreased absolute and relative weight of thymus, significantly increased relative weight of liver in males and significantly decreased absolute and relative weight of ovaries, significantly decreased relative weight of kidneys and significantly increased relative weight of spleen in females), gross examination of organs and tissues (mainly irreversible red colouring of some organs and/or tissues in males and females, marked structure in liver in males and dark colouring of spleen in females) and histological examination of organs and tissues (mainly vacuolation of hepatocytes in liver, nonpurulent pneumonitis in lungs in males and accumulation of lipophages and/or pigmentophages in uterus, haemorrhage in uterus and degeneration of tertiary follicles in ovaries in females) at the dose level 1000 mg/kg/day were recorded. These microscopic changes in reproductive organs did not relate to the test substance treatment.

 

The test substance, Solvent Red 19E, during Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test showed effect on clinical status (red colouring of excrements and shavings, gait on toes, raised tail, nuzzling in the shavings, disquiet after application), haematological parameters (decreased values of RBC, haematocrit, haemoglobin and prothrombin time, increased value of APTT and fibrinogen), biochemical parameters (changes of bilirubin, glucose in males, bilirubin, calcium ions, sodium ions in females and ALT, ALP and AST activity), biometry of organs (decreased weight of thymus, kidneys and ovaries and increased weight of liver and spleen) and urine parameters (change of colour urine and occurrence of leucocytes) mainly at the middle and highest dose level.

The test substance had an influence on macroscopic structure of some organs and tissues (red colouring of liver, lymph nodes, the whole GIT, body fat in both sexes and ovaries in females) and microscopic structure of liver in males (vacuolation of hepatocytes).

The value of NOAEL (No Observed Adverse Effect Level) for repeated dose toxicity was established as lower than 160 mg/kg body weight/day both for males and females. The value was established on the basis of haematology (decreased values of RBC, haematocrit, haemoglobin and prothrombin time, increased value of APTT and fibrinogen) and biochemistry blood parameters (increased activity of ALP in both sexes) and microscopic examination of organs (vacuolation of hepatocytes in males).

 

Based on the similarity in structure and manufacturing process, Solvent Red 19T would be expected to have the same properties, and the same NOAEL. (160mg/kg). Based on the Read Across approach, the material should also be classified

with respect toRepeated Dose Toxicity (Oral) as STOT RE 2 (H373; May cause damage to organs (liver) through prolonged or repeated exposure).

Justification for classification or non-classification

In accordance with the criteria for classification as defined in Annex I, Regulation (EC) No 1272/2008, the substance does require classification with respect to Repeated Dose Toxicity (Oral) as STOT RE 2 (H373; May cause damage to organs (liver) through prolonged or repeated exposure).