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Endpoint:
basic toxicokinetics, other
Remarks:
Statement on Toxicokinetics
Type of information:
other: Statement on Toxicokinetics
Adequacy of study:
supporting study
Study period:
2013
Reliability:
2 (reliable with restrictions)
Objective of study:
other: Assumption on toxicokinetic following the procedure indicated in the “Guidance on information requirements and chemical safety assessment chapter R.7c” of the ECHA guidance document (version 1.1, November 2012).
Principles of method if other than guideline:
Assumption on toxicokinetic following the procedure indicated in the ECHA guidance R.7c (version 1.1, November 2012).
GLP compliance:
no
Details on absorption:
Absorption is anticipated to be negligible / very low by oral, dermal and inhalation routes based on the physic-chemical properties: high molecular weight (740.31 < MW < 1232.98), low log Pow (calculated <-0.2) and slow solubility in water in an OECD TG 105 study with the saturation equilibrium not reached at 34 days.

Low absorption is confirmed by a 14 day oral gavage pilot study specifically designed to investigate potential compound uptake, distribution and excretion based on the intensive blue color of the compound.
Details on distribution in tissues:
Based on the low log Pow (<-0.2, calculated) and the slow solubility in water it is not likely that C.I. Direct Blue 264 distributes into cells. This assumption is supported by the 14 day pilot toxicity study in which no adverse effects were observed at the limit dose 1000 mg/kg bw/day. As indicated above blue color was seen only in the intestinal tract No other organ was colored blue. Furthermore, photometry of urinary samples gave no evidence that the test substance was excreted with the urine.
Based on the photometric urine analysis and the necropsy findings in this 14 day pilot study specifically designed to investigate potential compound uptake, distribution and excretion, no systemic absorption was observed.
Details on excretion:
Based on the low absorption potential of C.I. Direct Blue 264 excretion is anticipated mainly, if not exclusively, via the feces. This is supported by the 14 day pilot toxicity study. The only finding at clinical examinations was changed feces color, which was observed for all treated animals and is assumed to be due to the color of the test substance. Photometry of urinary samples gave no evidence that the test substance was excreted via urine.
Details on metabolites:
In vitro genotoxicity data do not indicate any genotoxic metabolites. C.I. Direct Blue 264 is not genotoxic in absence or presence of S9 extracts [Ames test, in-vitro micronucleus test and gene mutation assay in mammalian cells (HPRT)].
Executive summary:

Absorption of C.I. Direct Blue 264 is assumed to be low via oral, dermal and inhalation routs based on physicochemical properties. This assumption is confirmed by a 14 day oral gavage pilot study specifically designed to investigate potential compound uptake, distribution and excretion based on the intensive blue color of the compound.

In this study no adverse effects were observed at the limit dose 1000 mg/kg bw/day.

Compound related blue color was seen only in the intestinal tract. No other organ was colored blue. Furthermore, photometry of urinary samples gave no evidence that the test substance was excreted with the urine.

Based on the photometric urine analysis and the necropsy findings in this 14 day pilot study systemic absorption of C.I. Direct Blue 264 is unlikely.

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
2012
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: 14 day pilot study specifically designed to investigate potential compound uptake, distribution and excretion based on the intensive blue color of C.I. Direct Blue 264.
Objective of study:
other: 14 day pilot study specifically designed to investigate potential compound uptake, distribution and excretion based on the intensive blue color of the compound.
Qualifier:
no guideline followed
Principles of method if other than guideline:
14 day oral gavage pilot study. The aim of the study was to investigate if there is evidence that C.I. Direct Blue 264 is absorbed after oral dosing and to investigate potential toxicity after repeated oral dosing.
GLP compliance:
no
Radiolabelling:
no
Species:
rat
Strain:
Wistar
Sex:
male/female
Route of administration:
oral: gavage
Vehicle:
other: Cremophor El (2% in tapwater; v/v)
Duration and frequency of treatment / exposure:
14 days; once per day
Remarks:
Doses / Concentrations:
0, 100, 300, 1000 mg/kg bw/day
No. of animals per sex per dose:
3 males and 3 females
Control animals:
yes, concurrent vehicle
Details on absorption:
There were no toxicologically significant effects on survival, clinical examinations, body weight, food intake and water intake. The only finding at clinical examinations was blue feces color, which was observed for all treated animals and is due to the color of the test substance. Findings clearly related to the oral administration of the test compound were noticed at necropsy only in the intestinal tract in males starting at 100 mg/kg bw/day and in females starting at 500 mg/kg bw/day. Changes in content, blue, was observed in small intestine, cecum and large intestine. No other organ was colored.
Details on distribution in tissues:
Findings clearly related to the oral administration of the test compound were noticed at necropsy only in the intestinal tract in males starting at 100 mg/kg bw/day and in females starting at 500 mg/kg bw/day. Changes in content, blue, was observed in small intestine, cecum and large intestine. No other organ was colored.
Single males of this study displayed pale discoloration of the kidney. These observations are not necessarily indicative for a systemic effect on the kidneys induced by a test compound because they could have developed perimortally as a consequence of interindividual differences in the grade/status of exsanguination. Occasionally these gross observations do not have any histopathologic correlate at all or may show an equivocal histopathologic finding of the kidneys.
Details on excretion:
To investigate potential uptake and excretion of the compound the color of the urine was investigated photometrically in this study. Urine has be collected during a period of about 16 hours at room temperature from all animals of the control and high dose groups near the end of the study. The color of the urine did not differ between these groups. Furthermore, photometry of urinary samples gave no evidence that the test substance was excreted with the urine.
Metabolites identified:
no

There were no toxicologically significant effects on survival, clinical examinations, body weight, food intake and water intake. The only finding at clinical examinations was blue feces color, which was observed for all treated animals and is due to the color of the test substance. Findings clearly related to the oral administration of the test compound were noticed at necropsy only in the intestinal tract in males starting at 100 mg/kg bw/day and in females starting at 500 mg/kg bw/day. Changes in content, blue, was observed in small intestine, cecum and large intestine. No other organ was colored. Single males of this study displayed pale discoloration of the kidney. These observations are not necessarily indicative for a systemic effect on the kidneys induced by a test compound because they could have developed perimortally as a consequence of interindividual differences in the grade/status of exsanguination. Occasionally these gross observations do not have any histopathologic correlate at all or may show an equivocal histopathologic finding of the kidneys. To investigate potential uptake and excretion of the compound the color of the urine was investigated photometrically in this study. Urine has be collected during a period of about 16 hours at room temperature from all animals of the control and high dose groups near the end of the study. The color of the urine did not differ between these groups. Furthermore, photometry of urinary samples gave no evidence that the test substance was excreted with the urine.

 

Based on the photometric urine analysis and the necropsy findings in this 14 day pilot study specifically designed to investigate potential compound uptake, distribution and excretion, no systemic absorption was observed.

Executive summary:

A 14 day oral gavage pilot study was performed to investigate potential compound uptake, distribution and excretion based on the intensive blue color of C.I. Direct Blue 264.

In this study no adverse effects were observed at the limit dose 1000 mg/kg bw/day.

Compound related blue color was seen only in the intestinal tract.No other organ was colored blue. Furthermore, photometry of urinary samples gave no evidence that the test substance was excreted with the urine.

Based on the photometric urine analysis and the necropsy findings in this 14 day pilot study systemic absorption of C.I. Direct Blue 264 is unlikely.

Description of key information

Absorption is anticipated to be negligible / very low by oral, dermal and inhalation routes based on the physic-chemical properties: high molecular weight (740.31 < MW < 1232.98), low log Pow (calculated <-0.2) and slow solubility in water in an OECD TG 105 study with the saturation equilibrium not reached at 34 days.

Low absorption is confirmed by a 14-day oral gavage pilot study specifically designed to investigate potential compound uptake, distribution and excretion based on the intensive blue color of the compound.

Based on the low log Pow (<-0.2, calculated) and the slow solubility in water it is not likely that C.I. Direct Blue 264 distributes into cells. This assumption is supported by the 14-day pilot toxicity study in which no adverse effects were observed at the limit dose 1000 mg/kg bw/day. As indicated above blue color was seen only in the intestinal tract No other organ was colored blue. Furthermore, photometry of urinary samples gave no evidence that the test substance was excreted with the urine.

Based on the photometric urine analysis and the necropsy findings in this 14-day pilot study specifically designed to investigate potential compound uptake, distribution and excretion, no systemic absorption was observed.

Based on the low absorption potential of C.I. Direct Blue 264 excretion is anticipated mainly, if not exclusively, via the feces. This is supported by the 14-day pilot toxicity study. The only finding at clinical examinations was changed feces color, which was observed for all treated animals and is assumed to be due to the color of the test substance. Photometry of urinary samples gave no evidence that the test substance was excreted via urine.

Key value for chemical safety assessment

Bioaccumulation potential:
low bioaccumulation potential

Additional information

Potential absorption and bioavailability:

 

Study results on C.I. Direct Blue 264:

No adverse effects were reported in a non-guideline pilot study where the C.I. Direct Blue 264 was administered orally by gavage to 3 male and 3 female rats per group, in daily doses of 0, 100, 500 or 1000 mg/kg bw/day for 14 days. There were no toxicologically significant effects on survival, clinical examinations, body weight, food intake and water intake. The only finding at clinical examinations was blue feces color, which was observed for all treated animals and is due to the color of the test substance. Findings clearly related to the oral administration of the test compound were noticed at necropsy only in the intestinal tract in males starting at 100 mg/kg bw/day and in females starting at 500 mg/kg bw/day. Changes in content, blue, was observed in small intestine, cecum and large intestine. No other organ was colored. Single males of this study displayed pale discoloration of the kidney. These observations are not necessarily indicative for a systemic effect on the kidneys induced by a test compound because they could have developed perimortally as a consequence of interindividual differences in the grade/status of exsanguination. Occasionally these gross observations do not have any histopathologic correlate at all or may show an equivocal histopathologic finding of the kidneys. To investigate potential uptake and excretion of the compound the color of the urine was investigated photometrically in this study. Urine has be collected during a period of about 16 hours at room temperature from all animals of the control and high dose groups near the end of the study. The color of the urine did not differ between these groups. Furthermore, photometry of urinary samples gave no evidence that the test substance was excreted with the urine. Based on the photometric urine analysis and the necropsy findings in this 14 day pilot study specifically designed to investigate potential compound uptake, distribution and excretion, no systemic absorption was observed.