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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 Blue 98:

Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test, oral (gavage), rat , M/F, OECD guideline 422, GLP

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: oral
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 for cross-reference:
read-across source
Clinical signs:
no effects observed
Mortality:
mortality observed, non-treatment-related
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
no effects observed
Water consumption and compound intake (if drinking water study):
no effects observed
Ophthalmological findings:
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
no effects observed
Behaviour (functional findings):
no effects observed
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
effects observed, treatment-related
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
not examined
Key result
Dose descriptor:
NOAEL
Effect level:
100 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
female
Basis for effect level:
histopathology: non-neoplastic
Key result
Dose descriptor:
LOAEL
Effect level:
100 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male
Basis for effect level:
histopathology: non-neoplastic
Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
100 mg/kg bw/day (actual dose received)
System:
gastrointestinal tract
Organ:
pancreas
Treatment related:
yes
Dose response relationship:
yes
Relevant for humans:
not specified
Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
300 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 of Solvnet Blue 79B is predicted to be 100 mg/kg body weight/day for females. The value was established for the analogue substance Solvent Blue 98 based upon the increase in necrosis/apoptosis of pancreatic acinar cells at 300mg/kg/day. A NOAEL could not be determined for males due to an increase in necrosis/apoptosis of pancreatic acinar cells in males at all dose levels.
Executive summary:

A read across approach was used to evaluate potential toxicity effects of Solvent Blue 79B following repeated oral exposure

( Reaction mass of Reaction mass of 1,4-bis[(2-ethylhexyl)amino]-9,10-dihydroanthracene-9,10-dione and1-[(2-ethylhexyl)amino]-4-(3-[(2-ethylhexyl)oxy]propylamino)anthraquinone and 1,4 di (3-[(2-ethylhexyl)oxy]propylamino) anthraquinone

An analogue substance Solvent Blue 98 was tested according to OECD guideline 422. The analogue substance is compositionally very similar. It is also anthraquinone based, with aliphatic amine substitutions.

Where the Solvent Blue 79B contains ethylhexyl amine groups and ethylhexyl)oxy]propylamino groups, the

Solvent Blue 98 contains ethylhexyl, methyl and pentyl groups. There is therefore overlap in the compositions and the structures are very similar. Further supporting information on the readacross approach has been provided in section 13 (Read across justification document)


Based on read across to an analogue substance, The value of NOAEL (No Observed Adverse Effect Level) for repeated dose toxicity of Solvnet Blue 79B is predicted to be 100 mg/kg body weight/day for females. The value was established for the analogue substance Solvent Blue 98 based upon the increase in necrosis/apoptosis of pancreatic acinar cells at 300mg/kg/day.  A NOAEL could not be determined for males due to an increase in necrosis/apoptosis of pancreatic acinar cells in males at all dose levels.  

The analogue substance results are summarised below:

Treatment-relatedclinical observations consisted of blue skin/mucous membranes and/or blue feces in all treated animals which were attributed to the dye nature of the test material.

There were no treatment-related effects on body weight, body weight gain, or feed consumption in males or females in any treated groups compared to controls. 

There were no treatment-related effects on reproductive function in either males or females or prenatal/early neonatal growth and survival of offspring in any treated groups compared to controls.

There were no treatment-related effects on sensory evaluation, rectal temperature or grip performance in males or females from any dose group. There were no treatment-related effects on motor activity in males at any dose level or in females at dose levels
≤ 300 mg/kg/day. There was a treatment-related decrease in the total motor activity of females given 1000 mg/kg/day when compared to control females. There were no treatment-related changes in the hematology parameters of males or females in any dose group. Males given 1000 mg/kg/day had a treatment-related increase in mean prothrombin time that was interpreted to be non-adverse. Males and females given 1000 mg/kg/day had treatment-related higher mean cholesterol concentrations that were interpreted to be non-adverse. Males given 100, 300 or 1000 mg/kg/day had purple discoloration of the urine, which was attributed to the dye nature of the test material present in the urine. 

Males and females given 100, 300 or 1000 mg/kg/day had treatment-related increases in mean absolute and relative liver weights. The higher liver weights corresponded to hepatocellular hyperthophy in males and females in all dose groups. Males given
1000 mg/kg/day had treatment-related increases in mean absolute and relative thyroid gland weights. The higher thyroid gland weights corresponded to slight diffuse hypertrophy of follicular cells in males given 1000 mg/kg/day. 

All male and female rats given 100, 300 or 1000 mg/kg/day had a blue discoloration of various tissues throughout the body attributed to the presence of the test material. The blue discoloration was most prominent in adipose tissue. Limited gross pathological observations on postpartum day 4 pups revealed blue adipose tissue and stomach contents in pups from all treated groups.  This discoloration was attributed to the dye nature of the test material and demonstrated systemic exposure to the pups via the milk. 

A treatment-related histopathologic effect in the liver consisted of very slight to slight hypertrophy of hepatocytes with increased cytoplasmic eosinophilia. The hypertrophy was present in the centrilobular/midzonal regions of the hepatic lobule in the male 100 and
300 mg/kg/day groups and all treated female groups.  In some males from the
300 mg/kg/day group and all males in the 1000 mg/kg/day group, the hypertrophy was panlobular. The hepatocellular hypertrophy was interpreted to be an adverse effect in the male and female 1000 mg/kg/day groups because the corresponding increases in mean relative liver weights were at least 25% higher than the control group mean.

A treatment-related histopathologic effect occurred in the thyroid glands of males given
1000 mg/kg/day and consisted of a slight hypertrophy of the follicular epithelial cells. This was interpreted to be a non-adverse adaptive response likely secondary to the induction of liver microsomal enzymes.

Treatment-related histopathologic effects in the pancreas involved the exocrine tissue, not the islets of Langerhans, and consisted of a slight increase in apoptosis/necrosis of acinar cells and in individual autophagic/vacuolated acinar cells. These treatment-related effects were present in all male dose groups and in the female 300 and 1000 mg/kg/day dose groups. The apoptosis/necrosis of pancreatic acinar cells was interpreted to be an adverse effect.

A treatment-related histopathologic effect in the kidneys consisted of a slight increase in the accumulation of hyaline protein droplets in the cytoplasm of tubular epithelial cells of the proximal convoluted tubules in males given 1000 mg/kg/day. This observation was interpreted to be a non-adverse effect because it was not accompanied by degeneration or necrosis of the tubular epithelial cells and because hyaline droplet nephropathy is a male rat specific lesion with no significant relevance to humans.

Results for thePig-aassay showed no significant change in the frequency of RETCD59-or RBCCD59-in animals treated with the test material. Therefore, C.I. Solvent Blue 98 (3 Amine) was negative in thisin vivogene mutationPig-aassay.

A no-observed-effect level (NOEL) for general toxicity could not be determined for male or female rats due to the occurrence of treatment-related effects at all dose levels. A no-observed-adverse-effect level (NOAEL) could not be determined for males because of the increase in necrosis/apoptosis of pancreatic acinar cells in males from all treated groups. The NOAEL for females was 100 mg/kg/day based upon the increase in necrosis/apoptosis of pancreatic acinar cells at 300 mg/kg/day. The NOEL for neurological toxicity was
300 mg/kg/day in females and 1000 mg/kg/day in males, the highest dose level tested. The NOEL for reproductive toxicity or for effects on prenatal/neonatal growth and survival was 1000 mg/kg/day, the highest dose level tested.

 

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LOAEL
100 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
good
System:
gastrointestinal tract
Organ:
pancreas

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 evaluate potential toxicity effects of Solvent Blue 79B following repeated oral exposure

( Reaction mass of Reaction mass of 1,4-bis[(2-ethylhexyl)amino]-9,10-dihydroanthracene-9,10-dione and1-[(2-ethylhexyl)amino]-4-(3-[(2-ethylhexyl)oxy]propylamino)anthraquinone and 1,4 di (3-[(2-ethylhexyl)oxy]propylamino) anthraquinone

An analogue substance Solvent Blue 98 was tested according to OECD guideline 422. The analogue substance is compositionally very similar. It is also anthraquinone based, with aliphatic amine substitutions.

Where the Solvent Blue 79B contains ethylhexyl amine groups and ethylhexyl)oxy]propylamino groups, the

Solvent Blue 98 contains ethylhexyl, methyl and pentyl groups. There is therefore overlap in the compositions and the structures are very similar. Further supporting information on the readacross approach has been provided in section 13 (Read across justification document)


Based on read across to an analogue substance, The value of NOAEL (No Observed Adverse Effect Level) for repeated dose toxicity of Solvent Blue 79B is predicted to be 100 mg/kg body weight/day for females. The value was established for the analogue substance Solvent Blue 98 based upon the increase in necrosis/apoptosis of pancreatic acinar cells at 300mg/kg/day.  A NOAEL could not be determined for males due to an increase in necrosis/apoptosis of pancreatic acinar cells in males at all dose levels.  

The analogue substance results are summarised below:

Treatment-relatedclinical observations consisted of blue skin/mucous membranes and/or blue feces in all treated animals which were attributed to the dye nature of the test material.

There were no treatment-related effects on body weight, body weight gain, or feed consumption in males or females in any treated groups compared to controls. 

There were no treatment-related effects on reproductive function in either males or females or prenatal/early neonatal growth and survival of offspring in any treated groups compared to controls.

There were no treatment-related effects on sensory evaluation, rectal temperature or grip performance in males or females from any dose group. There were no treatment-related effects on motor activity in males at any dose level or in females at dose levels
≤ 300 mg/kg/day. There was a treatment-related decrease in the total motor activity of females given 1000 mg/kg/day when compared to control females. There were no treatment-related changes in the hematology parameters of males or females in any dose group. Males given 1000 mg/kg/day had a treatment-related increase in mean prothrombin time that was interpreted to be non-adverse. Males and females given 1000 mg/kg/day had treatment-related higher mean cholesterol concentrations that were interpreted to be non-adverse. Males given 100, 300 or 1000 mg/kg/day had purple discoloration of the urine, which was attributed to the dye nature of the test material present in the urine. 

Males and females given 100, 300 or 1000 mg/kg/day had treatment-related increases in mean absolute and relative liver weights. The higher liver weights corresponded to hepatocellular hyperthophy in males and females in all dose groups. Males given
1000 mg/kg/day had treatment-related increases in mean absolute and relative thyroid gland weights. The higher thyroid gland weights corresponded to slight diffuse hypertrophy of follicular cells in males given 1000 mg/kg/day. 

All male and female rats given 100, 300 or 1000 mg/kg/day had a blue discoloration of various tissues throughout the body attributed to the presence of the test material. The blue discoloration was most prominent in adipose tissue. Limited gross pathological observations on postpartum day 4 pups revealed blue adipose tissue and stomach contents in pups from all treated groups.  This discoloration was attributed to the dye nature of the test material and demonstrated systemic exposure to the pups via the milk. 

A treatment-related histopathologic effect in the liver consisted of very slight to slight hypertrophy of hepatocytes with increased cytoplasmic eosinophilia. The hypertrophy was present in the centrilobular/midzonal regions of the hepatic lobule in the male 100 and
300 mg/kg/day groups and all treated female groups.  In some males from the
300 mg/kg/day group and all males in the 1000 mg/kg/day group, the hypertrophy was panlobular. The hepatocellular hypertrophy was interpreted to be an adverse effect in the male and female 1000 mg/kg/day groups because the corresponding increases in mean relative liver weights were at least 25% higher than the control group mean.

A treatment-related histopathologic effect occurred in the thyroid glands of males given
1000 mg/kg/day and consisted of a slight hypertrophy of the follicular epithelial cells. This was interpreted to be a non-adverse adaptive response likely secondary to the induction of liver microsomal enzymes.

Treatment-related histopathologic effects in the pancreas involved the exocrine tissue, not the islets of Langerhans, and consisted of a slight increase in apoptosis/necrosis of acinar cells and in individual autophagic/vacuolated acinar cells. These treatment-related effects were present in all male dose groups and in the female 300 and 1000 mg/kg/day dose groups. The apoptosis/necrosis of pancreatic acinar cells was interpreted to be an adverse effect.

A treatment-related histopathologic effect in the kidneys consisted of a slight increase in the accumulation of hyaline protein droplets in the cytoplasm of tubular epithelial cells of the proximal convoluted tubules in males given 1000 mg/kg/day. This observation was interpreted to be a non-adverse effect because it was not accompanied by degeneration or necrosis of the tubular epithelial cells and because hyaline droplet nephropathy is a male rat specific lesion with no significant relevance to humans.

Results for thePig-aassay showed no significant change in the frequency of RETCD59-or RBCCD59-in animals treated with the test material. Therefore, C.I. Solvent Blue 98 (3 Amine) was negative in thisin vivogene mutationPig-aassay.

A no-observed-effect level (NOEL) for general toxicity could not be determined for male or female rats due to the occurrence of treatment-related effects at all dose levels. A no-observed-adverse-effect level (NOAEL) could not be determined for males because of the increase in necrosis/apoptosis of pancreatic acinar cells in males from all treated groups. The NOAEL for females was 100 mg/kg/day based upon the increase in necrosis/apoptosis of pancreatic acinar cells at 300 mg/kg/day. The NOEL for neurological toxicity was
300 mg/kg/day in females and 1000 mg/kg/day in males, the highest dose level tested. The NOEL for reproductive toxicity or for effects on prenatal/neonatal growth and survival was 1000 mg/kg/day, the highest dose level tested.

 

Justification for classification or non-classification

Based on read across to the analogue source substance solvent blue 98, classification for repeat dose toxicity is not justified. Although an adverse effect was observed in the pancreas, it was interpreted to be insufficient in severity to warrant classification. The functioning of the pancreas was not impacted, and there were no other observations indicating that the organ had been damaged to an extent that it could not perform its biological functions.

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