Registration Dossier

Based on an OECD 422 study with the source substance, the NOAEL for reproductive toxicity was determined to be 1000 mg/kg/day.

Reference

Endpoint:

screening for reproductive / developmental toxicity

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Justification for type of information:

Refer chapter 13 for detailed read across justification.

Reason / purpose for cross-reference:

read-across source

Key result

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Absence of any evidence for general systemic toxicity or effects on reproductive performance/offspring development.

Critical effects observed:

no

Key result

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

1 000 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: no adverse effects were observed

Critical effects observed:

no

Reproductive effects observed:

no

Conclusions:

It was concluded that in the absence of any evidence for general systemic toxicity or effects on reproductive performance/offspring development that the no observed adverse effect level for the read across substance was 1000 mg/kg/day.

Executive summary:

A study was conducted to assess the general systemic toxic potential of FAT 41001/H in rats, including a screen for reproductive/developmental effects. The study was designed to meet the requirements of OECD 422 guideline for testing of chemicals adopted 22 March 1996: Combined repeated dose toxicity study with the reproduction/developmental toxicity screening test. The study was conducted in accordance with the requirements of current, internationally recognised Good Laboratory Practice Standards, and the applicable sections of the United Kingdom Animals (Scientific Procedures) Act 1986, Amendment Regulations 2012 (the Act). Three groups, each comprising ten male and ten female rats received FAT 41001/H at doses of 100, 330 or 1000 mg/kg/day by oral gavage administration. Males were treated daily for two weeks before pairing up to necropsy, after a minimum of five consecutive weeks. Females were treated daily for two weeks before pairing, throughout pairing, gestation and until Day 6 of lactation. Females were killed on Day 7 of lactation. A similarly constituted Control group received the vehicle (purified water) at the same volume dose as the treated groups. The F1 generation received no direct administration of the test substance; any exposure wasin uteroor via the milk. During the study, clinical condition, detailed physical examination and arena observations, sensory reactivity, grip strength, motor activity, body weight, food consumption, haematology (peripheral blood), blood chemistry, pre-coital interval, mating performance, fertility, gestation length, organ weight, macroscopic pathology and histopathology investigations were undertaken. The clinical condition, litter size, survival, sex ratio, body weight and macropathology for all offspring were also assessed.

Results

Oral administration of FAT 41001/H at doses of 100, 330 or 1000 mg/kg/day was generally well tolerated with no mortalities related to treatment. There were no adverse effects attributed to treatment on sensory reaction, grip strength or motor activity; in addition, all of the reproductive/developmental endpoints assessed were unaffected by treatment and included, pre-coital interval, mating performance, fertility, gestation length, offspring weights, litter size, sex ratio and offspring survival. Signs in association with the administration of FAT 41001/H were restricted to rales in one male receiving 330 mg/kg/day on Day 3 of treatment. At the detailed physical examination and arena observations, signs seen in relation to treatment were confined to blue staining of various body parts at all dose levels (100, 330 or 1000 mg/kg/day), with the magnitude of incidence increasing as the dose level increased. Group mean body weight gain for males and females receiving FAT 41001/H at 100 mg/kg/day were similar to controls throughout the study and were considered unaffected by treatment. In males treated at 330 or 1000 mg/kg/day, overall group mean body weight gain was low when compared with Controls however this was predominately a result of low weight gains in Week 0-1 (males treated at 1000 mg/kg/day) and Week 4-5 (males treated at 330 or 1000 mg/kg/day). For females receiving FAT 41001/H there was no conclusive effect of treatment on body weight gain. There was no effect of treatment on food consumption in males, or in females prior to pairing. During Days 6-19 gestation, food consumption of all groups of treated females was slightly high. Throughout lactation, food consumption was slightly higher in females receiving 330 or 1000 mg/kg/day, with the increase being dose dependent.

On two occasions during treatment, a marked increase in water consumption was observed amongst animals receiving 1000 mg/kg/day when compared with controls. Haematological examination during Week 2 of treatment, prior to pairing, and the examination of the clotting parameters in Week 4 of treatment for the males and on gestation Day 17 for the females, revealed no significant response to treatment with FAT 41001/H. Biochemical examination of the blood plasma in Week 2 of treatment revealed low bile acid concentrations amongst all treated groups of males and females when compared with the control animals. Cholesterol concentration was high in animals receiving 330 or 1000 mg/kg/day and creatinine concentration was high in females at all dose levels. Glucose concentrations were low in males receiving 1000 mg/kg/day. High calcium concentration was evident in all treated male groups when compared with the control group; there was no similar effect in the females. At routine examination of the offspring, signs that were observed in relation to treatment with FAT 41001/H were limited to dark areas on the lower ventral abdomen at 100, 330 and 1000 mg/kg/day and blue staining was observed in offspring at 330 and 1000 mg/kg/day; this was considered to be related to the colour of the test item. After five weeks of treatment, absolute and body weight adjusted kidney weights of F0 males and females receiving 1000 mg/kg/day were marginally higher than Controls. Absolute testes weights were also high in these males and in males receiving 330 mg/kg/day. On Day 7 of lactation, absolute and body weight adjusted adrenal weights for all treated groups of F0 females were low when compared with controls. Macroscopic examination performed in F0 males after five weeks of treatment and in F0 females on Day 7 of lactation, did not reveal any treatment-related findings for animals receiving FAT 41001/H at 100 mg/kg/day. Findings observed at macroscopic examination of the males and females treated at 330 or 1000 mg/kg/day were confined to blue or dark coloration (including some blue or dark colouration of the contents) in a variety of tissues; this was considered to be due to the coloured nature of the compound and was not representative of any pathological change. At macroscopic examination of the offspring, findings observed in relation to treatment were confined to dark contents of the gastrointestinal tract at 1000 mg/kg/day. In addition, one litter at 1000 mg/kg/day were observed to have blue skin. Microscopic examination revealed treatment related changes within the kidneys, mesenteric and left axillary lymph nodes, stomach of both sexes and epididymides of the males. Renal cortical tubular vacuolation was recorded in males and females treated with 330 or 1000 mg/kg/day, accompanied by hyaline droplets in the males at both dose levels. Vacuolated macrophages were recorded in the mesenteric and left axillary lymph nodes of most males and females given 1000 mg/kg/day. Foveolar hyperplasia was recorded in the stomach of both sexes given 1000 mg/kg/day. Epithelial vacuolation of the epididymides was recorded in all males treated with 1000 mg/kg/day.

Conclusion

It was concluded that in the absence of any evidence for general systemic toxicity or effects on reproductive performance/offspring development that the no observed adverse effect level (NOAEL) was 1000 mg/kg/day.

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

High quality GLP study

Endpoint conclusion:

no study available

Endpoint conclusion:

no study available

A study was conducted to assess the general systemic toxic potential of the source substance, FAT 41001/H (a blue textile dye) in rats, including a screen for reproductive/developmental effects. Three groups, each comprising ten male and ten female rats received FAT 41001/H at doses of 100, 330 or 1000 mg/kg/day by oral gavage administration. Males were treated daily for two weeks before pairing up to necropsy, after a minimum of five consecutive weeks. Females were treated daily for two weeks before pairing, throughout pairing, gestation and until Day 6 of lactation. Females were killed on Day 7 of lactation. A similarly constituted control group received the vehicle (purified water) at the same volume dose as the treated groups. The F1 generation received no direct administration of the test substance; any exposure wasin uteroor via the milk. During the study, clinical condition, detailed physical examination and arena observations, sensory reactivity, grip strength, motor activity, body weight, food consumption, haematology (peripheral blood), blood chemistry, pre-coital interval, mating performance, fertility, gestation length, organ weight, macroscopic pathology and histopathology investigations were undertaken. The clinical condition, litter size, survival, sex ratio, body weight and macropathology for all offspring were also assessed.

Oral administration of FAT 41001/H at doses of 100, 330 or 1000 mg/kg/day was generally well tolerated with no mortalities related to treatment. There were no adverse effects attributed to treatment on sensory reaction, grip strength or motor activity; in addition all of the reproductive/developmental endpoints assessed were unaffected by treatment and included, pre-coital interval, mating performance, fertility, gestation length, offspring weights, litter size, sex ratio and offspring survival. Signs in association with the administration of FAT 41001/H were restricted to rales in one male receiving 330 mg/kg/day on Day 3 of treatment. At the detailed physical examination and arena observations, signs seen in relation to treatment were confined to blue staining of various body parts at all dose levels (100, 330 or 1000 mg/kg/day), with the magnitude of incidence increasing as the dose level increased. Group mean body weight gain for males and females receiving FAT 41001/H at 100 mg/kg/day were similar to controls throughout the study and were considered unaffected by treatment. In males treated at 330 or 1000 mg/kg/day, overall group mean body weight gain was low when compared with Controls however this was predominately a result of low weight gains in week 0-1 (males treated at 1000 mg/kg/day) and week 4-5 (males treated at 330 or 1000 mg/kg/day). For females receiving FAT 41001/H there was no conclusive effect of treatment on body weight gain. There was no effect of treatment on food consumption in males, or in females prior to pairing. During Days 6-19 gestation, food consumption of all groups of treated females was slightly high. Throughout lactation, food consumption was slightly higher in females receiving 330 or 1000 mg/kg/day, with the increase being dose dependent. On two occasions during treatment, a marked increase in water consumption was observed amongst animals receiving 1000 mg/kg/day when compared with controls. Haematological examination during Week 2 of treatment, prior to pairing, and the examination of the clotting parameters in week 4 of treatment for the males and on gestation Day 17 for the females, revealed no significant response to treatment with FAT 41001/H. Biochemical examination of the blood plasma in Week 2 of treatment revealed lowbile acid concentrations amongst all treated groups of males and females when compared with the control animals. Cholesterol concentration was high in animals receiving 330 or 1000 mg/kg/day and creatinine concentration was high in females at all dose levels. Glucose concentrations were low in males receiving 1000 mg/kg/day. High calcium concentration was evident in all treated male groups when compared with the control group; there was no similar effect in the females. At routine examination of the offspring, signs that were observed in relation to treatment with FAT 41001/H were limited to dark areas on the lower ventral abdomen at 100, 330 and 1000 mg/kg/day and blue staining was observed in offspring at 330 and 1000 mg/kg/day; this was considered to be related to the colour of the test item. After five weeks of treatment, absolute and body weight adjusted kidney weights of F0 males and females receiving 1000 mg/kg/day were marginally higher than Controls. Absolute testes weights were also high in these males and in males receiving 330 mg/kg/day. On Day 7 of lactation, absolute and body weight adjusted adrenal weights for all treated groups of F0 females were low when compared with Controls. Macroscopic examination performed in F0 males after five weeks of treatment and in F0 females on Day 7 of lactation, did not reveal any treatment-related findings for animals receiving FAT 41001/H at 100 mg/kg/day. Findings observed at macroscopic examination of the males and females treated at 330 or 1000 mg/kg/day were confined to blue or dark coloration (including some blue or dark colouration of the contents) in a variety of tissues; this was considered to be due to the coloured nature of the compound and was not representative of any pathological change. At macroscopic examination of the offspring, findings observed in relation to treatment were confined to dark contents of the gastrointestinal tract at 1000 mg/kg/day. In addition, one litter at 1000 mg/kg/day were observed to have blue skin. Microscopic examination revealed treatment related changes within the kidneys, mesenteric and left axillary lymph nodes, stomach of both sexes and epididymides of the males. Renal cortical tubular vacuolation was recorded in males and females treated with 330 or 1000 mg/kg/day, accompanied by hyaline droplets in the males at both dose levels. Vacuolated macrophages were recorded in the mesenteric and left axillary lymph nodes of most males and females given 1000 mg/kg/day. Foveolar hyperplasia was recorded in the stomach of both sexes given 1000 mg/kg/day. Epithelial vacuolation of the epididymides was recorded in all males treated with 1000 mg/kg/day.

It was concluded that in the absence of any evidence for general systemic toxicity or effects on reproductive performance/offspring development that the no observed adverse effect level for the read across substance was 1000 mg/kg/day.

Based on an OECD 422 study with the source substance, the NOAEL for developmental toxicity was determined to be 1000 mg/kg/day.

Reference

Endpoint:

developmental toxicity

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Justification for type of information:

Refer chapter 13 for detailed read across justification.

Reason / purpose for cross-reference:

read-across source

Key result

Dose descriptor:

NOAEL

Effect level:

> 1 000 mg/kg bw/day (actual dose received)

Based on:

test mat.

Basis for effect level:

other: developmental toxicity

Abnormalities:

not specified

Key result

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Remarks on result:

not determinable due to absence of adverse toxic effects

Abnormalities:

not specified

Developmental effects observed:

not specified

Conclusions:

It was concluded that in the absence of any evidence for general systemic toxicity or effects on reproductive performance/offspring development that the no observed adverse effect level was 1000 mg/kg/day.

Executive summary:

A study was conducted to assess the general systemic toxic potential of FAT 41001/H in rats, including a screen for reproductive/developmental effects. The study was designed to meet the requirements of OECD 422 guideline for testing of chemicals adopted 22 March 1996: Combined repeated dose toxicity study with the reproduction/developmental toxicity screening test. The study was conducted in accordance with the requirements of current, internationally recognised Good Laboratory Practice Standards, and the applicable sections of the United Kingdom Animals (Scientific Procedures) Act 1986, Amendment Regulations 2012 (the Act). Three groups, each comprising ten male and ten female rats received FAT 41001/H at doses of 100, 330 or 1000 mg/kg/day by oral gavage administration. Males were treated daily for two weeks before pairing up to necropsy, after a minimum of five consecutive weeks. Females were treated daily for two weeks before pairing, throughout pairing, gestation and until Day 6 of lactation. Females were killed on Day 7 of lactation. A similarly constituted Control group received the vehicle (purified water) at the same volume dose as the treated groups. The F1 generation received no direct administration of the test substance; any exposure wasin uteroor via the milk. During the study, clinical condition, detailed physical examination and arena observations, sensory reactivity, grip strength, motor activity, body weight, food consumption, haematology (peripheral blood), blood chemistry, pre-coital interval, mating performance, fertility, gestation length, organ weight, macroscopic pathology and histopathology investigations were undertaken The clinical condition, litter size, survival, sex ratio, body weight and macropathology for all offspring were also assessed.

Results

Oral administration of FAT 41001/H at doses of 100, 330 or 1000 mg/kg/day was generally well tolerated with no mortalities related to treatment. There were no adverse effects attributed to treatment on sensory reaction, grip strength or motor activity; in addition, all of the reproductive/developmental endpoints assessed were unaffected by treatment and included, pre-coital interval, mating performance, fertility, gestation length, offspring weights, litter size, sex ratio and offspring survival. Signs in association with the administration of FAT 41001/H were restricted to rales in one male receiving 330 mg/kg/day on Day 3 of treatment. At the detailed physical examination and arena observations, signs seen in relation to treatment were confined to blue staining of various body parts at all dose levels (100, 330 or 1000 mg/kg/day), with the magnitude of incidence increasing as the dose level increased.

Group mean body weight gain for males and females receiving FAT 41001/H at 100 mg/kg/day were similar to controls throughout the study and were considered unaffected by treatment. In males treated at 330 or 1000 mg/kg/day, overall group mean body weight gain was low when compared with Controls however this was predominately a result of low weight gains in Week 0-1 (males treated at 1000 mg/kg/day) and Week 4-5 (males treated at 330 or 1000 mg/kg/day). For females receiving FAT 41001/H there was no conclusive effect of treatment on body weight gain. There was no effect of treatment on food consumption in males, or in females prior to pairing. During Days 6-19 gestation, food consumption of all groups of treated females was slightly high. Throughout lactation, food consumption was slightly higher in females receiving 330 or 1000 mg/kg/day, with the increase being dose dependent.

On two occasions during treatment, a marked increase in water consumption was observed amongst animals receiving 1000 mg/kg/day when compared with controls. Haematological examination during Week 2 of treatment, prior to pairing, and the examination of the clotting parameters in Week 4 of treatment for the males and on gestation Day 17 for the females, revealed no significant response to treatment with FAT 41001/H. Biochemical examination of the blood plasma in Week 2 of treatment revealed low bile acid concentrations amongst all treated groups of males and females when compared with the control animals. Cholesterol concentration was high in animals receiving 330 or 1000 mg/kg/day and creatinine concentration was high in females at all dose levels. Glucose concentrations were low in males receiving 1000 mg/kg/day. High calcium concentration was evident in all treated male groups when compared with the control group; there was no similar effect in the females. At routine examination of the offspring, signs that were observed in relation to treatment with FAT 41001/H were limited to dark areas on the lower ventral abdomen at 100, 330 and 1000 mg/kg/day and blue staining was observed in offspring at 330 and 1000 mg/kg/day; this was considered to be related to the colour of the test item. After five weeks of treatment, absolute and body weight adjusted kidney weights of F0 males and females receiving 1000 mg/kg/day were marginally higher than cControls. Absolute testes weights were also high in these males and in males receiving 330 mg/kg/day. On Day 7 of lactation, absolute and body weight adjusted adrenal weights for all treated groups of F0 females were low when compared with controls. Macroscopic examination performed in F0 males after five weeks of treatment and in F0 females on Day 7 of lactation, did not reveal any treatment-related findings for animals receiving FAT 41001/H at 100 mg/kg/day. Findings observed at macroscopic examination of the males and females treated at 330 or 1000 mg/kg/day were confined to blue or dark coloration (including some blue or dark colouration of the contents) in a variety of tissues; this was considered to be due to the coloured nature of the compound and was not representative of any pathological change. At macroscopic examination of the offspring, findings observed in relation to treatment were confined to dark contents of the gastrointestinal tract at 1000 mg/kg/day. In addition, one litter at 1000 mg/kg/day were observed to have blue skin.Microscopic examination revealed treatment related changes within the kidneys, mesenteric and left axillary lymph nodes, stomach of both sexes and epididymides of the males. Renal cortical tubular vacuolation was recorded in males and females treated with 330 or 1000 mg/kg/day, accompanied by hyaline droplets in the males at both dose levels. Vacuolated macrophages were recorded in the mesenteric and left axillary lymph nodes of most males and females given 1000 mg/kg/day. Foveolar hyperplasia was recorded in the stomach of both sexes given 1000 mg/kg/day. Epithelial vacuolation of the epididymides was recorded in all males treated with 1000 mg/kg/day.

Conclusion

It was concluded that in the absence of any evidence for general systemic toxicity or effects on reproductive performance/offspring development that the no observed adverse effect level (NOAEL) was 1000 mg/kg/day.

The study was designed to meet the requirements of OECD 422 guideline for testing of chemicals adopted 22 March 1996: Combined repeated dose toxicity study with the reproduction/developmental toxicity screening test.

The study was conducted in accordance with the requirements of current, internationally recognised Good Laboratory Practice Standards, and the applicable sections of the United Kingdom Animals (Scientific Procedures) Act 1986, Amendment Regulations 2012 (the Act).

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

High quality GLP study

Endpoint conclusion:

no study available

Endpoint conclusion:

no study available

In the OECD 422 study with the source substance (FAT 41001/H), clinical signs with offsprings were limited to dark areas on the lower ventral abdomen at 100, 330 and 1000 mg/kg/day and blue staining was observed in offsprings at 330 and 1000 mg/kg/day; this was considered to be related to the colour of the test item. Litter size, offspring survival and sex ratio were considered to be unaffected by parental exposure to FAT 41001/H. For sex ratio (%M), the group mean Control data were atypically low; consequently the apparent changes from Control for these parameters were considered to be of natural biological variation and not a response to treatment. There was no effect of treatment on offspring body weight on Day 1 of age; growth thereafter was also considered to be unaffected by treatment with FAT 41001/H. At macroscopic examination, findings observed in relation to treatment were confined to dark contents of the gastrointestinal tract of offspring at 1000 mg/kg/day. Hence, based on the findings of the study, the NOAEL for developmental toxicity was also determined to be 1000 mg/kg/day.

Based on the absence of adverse effects in the combined repeated dose and reproductive/develpomental screening study with the source substance, the target substance does not warrant classification for reproductive toxicity under the CLP (1272/2008) classification.