6 alpha-Fluoro-16 alpha-methyl-21-valeryloxy-1,4,9(11)-pregnatriene-3,20-dione

Endpoint summary

Description of key information

In analogy to fluocortolone, the structurally analogue substance delta-9(11)-fluocortolone-valerate is considered to cause organ damage after repeated administration to test animals. In systemic tolerance studies with fluocortolone involving repeated administration of both subcutaneous and oral doses in rats and dogs for 4 to 80 weeks, typical glucocorticoid effects were observed: degeneration of lymphatic tissue, suppression of the adrenal cortex, impairment of the hematogenic tissue (bone marrow) (Dres et al., 1975; Günzel et al., 1976; Staben, 1979; Woodard et al., 1966, 1967, 1969).

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Reference 1

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

other information

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)

Deviations:

not applicable

Principles of method if other than guideline:

The study was conducted prior to implementation of the OECD test guidelines.

GLP compliance:

no

Limit test:

no

Species:

rat

Strain:

other: Caesarean-derived weanling albino rats

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Breeding Laboratories
- Weight at study initiation: males: 93-95 g for the preliminary study and 157 g-208 g for the dose range finder, females: 88-91g for the preliminary study and 151 - 207 g for the dose range finder
- Housing: Individually
- Diet (e.g. ad libitum): Purina Laboratory Chow (meal) ad libitum
- Water (e.g. ad libitum): Water, ad libitum
- Acclimation period: 8 d


ENVIRONMENTAL CONDITIONS
The rats were individually housed in temperature-controlled quarters.

Route of administration:

oral: feed

Details on route of administration:

A basal diet was fed to all animals for the eight-day acclimation period. The drugs were then incorporated into the diet by means of a mechanical mixer to yield concentrations
required to provide the desired daily intake of compound.

Vehicle:

not specified

Analytical verification of doses or concentrations:

no

Duration of treatment / exposure:

A. preliminary study: 10 days exposure plus 18 days post exposure time (resulting in 4 weeks test)
B. range finding study: 15 days

Frequency of treatment:

daily

Dose / conc.:

0.3 mg/kg bw/day (nominal)

Remarks:

dose range finder

Dose / conc.:

1 mg/kg bw/day (nominal)

Remarks:

dose range finder

Dose / conc.:

3 mg/kg bw/day (nominal)

Remarks:

dose range finder

Dose / conc.:

3 mg/kg bw/day (nominal)

Remarks:

Preliminary study

Dose / conc.:

9 mg/kg bw/day (nominal)

Remarks:

Preliminary study

Dose / conc.:

50 mg/kg bw/day (nominal)

Remarks:

Preliminary study

No. of animals per sex per dose:

A. preliminary study: 30/sex/dose
B. range finding study: 2/sex/dose

Control animals:

yes, concurrent vehicle

other: preliminary study: 9 mg/kg prednisolone as positive control.

Key result

Dose descriptor:

LOAEL

Effect level:

>= 0.3 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: BW gain

Critical effects observed:

not specified

A. preliminary study: 15 animals receiving fluocortolone died in second week on treatment (13 rats of high dose group, 2 rats in mid dose group). Despite the cessation of test substance on 11th day further 16 animals (12 rats of high dose group, 3 rats of mid dose group, 1 rat of low dose group) died until end of study after 4 weeks. Decrease of body weight in week 1. Reduced bw gain until end of study. Reduced food consumption.

B. range finding study: All animals survived study period. Reduced bw gain in low dose group. Bw loss in mid and high dose groups.

Conclusions:

In a preliminary 4 weeks study rats (30/sex/dose) were treated orally with 3, 9 or 50 mg/kg fluocortolone for 10 days and suviving animals were observed until end of study. 15 rats died during treatment period, additional 16 animals died in post exposure period. Animals showed decreased body weight and food consumption in week 1 and reduction of bw gain until end of study.

In a second range finding study rats (2/sex/dose) were treated orally with fluocortolone (0.3, 1.0, 3.0 mg/kg). All animals survived study period. Reduced bw gain in low dose group and bw loss in mid and high dose groups was observed.

The low adverse effect level was determined at the lowest dose level of 0.3 mg/kg.

Executive summary:

In a subchronic toxicity study (similar to OECD test guideline 407 but conducted prior to implementation of the test guidelines, Fluocortolon was administered to 30 albino white rats/sex/dose for the preliminary study and 2 albino white rats/sex/dose for the range finder study in diet, at dose levels of 0, 3, 9, and 50 mg/kg bw/day (preliminary study) and 0, 0.3, 1, and 3 mg/kg bw/day (range finder study).

In the preliminary 4 weeks study rats (30/sex/dose) were treated orally with 3, 9 or 50 mg/kg fluocortolone for 10 days and surviving animals were observed until end of study. 15 rats died during treatment period, additional 16 animals died in post exposure period. Animals showed decreased body weight and food consumption in week 1 and reduction of bw gain until end of study. In the range finder study rats were treated with 0.3, 1, and 3 mg/kg bw/day. The animals showed a decreased body weight gain from 1.0 mg/kg bw/day and at 3.0 mg/kg bw/day. An increased body weight gain was only observed at 0.3 mg/kg bw/day. Thus, based on these results the LOAEL is > 0.3 mg/kg bw/day.

 

Reference 2

Endpoint:

chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

other information

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 452 (Chronic Toxicity Studies)

Deviations:

not applicable

GLP compliance:

no

Limit test:

no

Species:

rat

Strain:

other: albino rats Charles River

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: The Charles River Breeding Laboratories
- Housing: individually
- Diet (e.g. ad libitum): Purin Laboratory Chow ad libitum
- Water (e.g. ad libitum):water, ad libitum
- Acclimation period: 8 days

Route of administration:

oral: feed

Details on route of administration:

The drug was incorporated into the diet by means of a mechanical mixer to yield the required concentrations.

Vehicle:

not specified

Details on oral exposure:

DIET PREPARATION
- Mixing appropriate amounts with (Type of food): The drug was incorporated into the diet by means of a mechanical mixer to yield the required concentrations.

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

79-80 weeks

Frequency of treatment:

daily in the diet

Dose / conc.:

0.1 mg/kg bw/day (actual dose received)

Dose / conc.:

0.3 mg/kg bw/day (actual dose received)

Dose / conc.:

0.6 mg/kg bw/day (actual dose received)

No. of animals per sex per dose:

30/sex/dose

Control animals:

yes, plain diet

other: 0.6 mg/kg prednisolone as positive control

Details on study design:

- Dose selection rationale: The study was initially started at dosage levels of 50, 9.0, and 3.0 mg/kg of the test item and 9.0 mg/kg of the positive control. Due to markedly reduced body weight gains and food in take for all treated animals and deaths at the 50 and 9.0 mg/kg levels, the study was discontinued after 4 weeks. The treated rats were placed on control diet for aperiod of 19 days. Markedly reduced food intake and deaths at the 50 and 9.0 mg/kg levels continued.

Positive control:

0.6 mg/kg bw prednisolone

Mortality:

mortality observed, treatment-related

Description (incidence):

The mortality rate was remarkably low with only thirty non-surviving rats during the course of the study. Except for seven rats, all deaths occurred during the second year of study and were generally related to the normal aging of rats. Twice as many treated male rats died as did treated female rats and most deaths occurred for males receiving 0.6 mg/kg/day of SH 742

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Body weight gain was significantly depressed for male rats receiving the test item at the 0.6 and 0.3 mg/kg/day levels. Body weight gain for treated females was comparable except that a greater rate of gain was experienced by the 0.1 mg/kg/day level than by other treated groups. The food intake pattern was consistent with the growth of these rats.

Dose descriptor:

LOAEL

Effect level:

>= 0.1 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Critical effects observed:

not specified

Twice as many male rats died as females. Most deaths appeared in high dose fluocortolone and prednisolone groups.

Body weight gain was depressed and alopecia and skin lesions were detected. Furthermore the treatment led to an atrophy of the lymphoreticular tissue and the bone marrow with concurrent haematological changes. A decrease of blood leukocyte and thrombocyte counts as well as reduced haemoglobin content and an increase of extramedullar haematopoesis. Decreased adrenal weights with a concurrent atrophy of the adrenal cortex, local fibroses, and cellular necroses in the myocard and hyperplasia of the islets of Langerhans were detected. In addition, toxic effects on the liver were seen in clinical chemistry and as histologically visible vacuolization of liver cells. Toxic effects were more pronounced in male rats and predominantly in the high dose treatment groups.

Conclusions:

LOAEL: 0.1 mg/kg bw. A NOAEL could not be determined.

Executive summary:

In a study conducted comparable to OECD test guideline 452 (study performed prior to implementation of OECD guidelines) Fluocortolone was administered orally via food to rats (30/sex/group)at dose levels of 0, 0.1, 0.3, or 0.6 mg/kg body weight once daily for 79-80 weeks. The study also includes a dose group with prednisolone 0.6 mg/kg bw. A clear dose dependency of the toxic effects was detected. Twice as many male rats died as females. Most deaths appeared in high dose fluocortolone and prednisolone groups. Body weight gain was depressed and alopecia and skin lesions were detected. Furthermore, the treatment led to an atrophy of the lymphoreticular tissue and the bone marrow with concurrent haematological changes. A decrease of blood leukocyte and thrombocyte counts as well as reduced haemoglobin content and an increase of extramedullar haematopoesis. Decreased adrenal weights with a concurrent atrophy of the adrenal cortex, local fibroses, and cellular necroses in the myocard and hyperplasia of the islets of Langerhans were detected. In addition, toxic effects on the liver were seen in clinical chemistry and as histologically visible vacuolization of liver cells. Toxic effects were more pronounced in male rats and predominantly in the high dose treatment groups.  At the low dose group only 4 animals died during the whole experimental time, only one female was sacrificed due to a moribund condition. In contrast to the decrease of body weight gain in males in the high and mid dose group females of the low dose group gained more weight as compared to the control group animals. Open lesions, hematological changes, changes in clinical biochemistry, changes in organ weights or histopathological changes were only reported for the mid and the high dose group. Thus, the LOAEL was set to: 0.1 mg/kg bw. A NOAEL could not be determined.

 

Reference 3

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

other information

Study period:

1. Mar to 31. Mar 1970

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Qualifier:

equivalent or similar to guideline

Guideline:

EU Method B.7 (Repeated Dose (28 Days) Toxicity (Oral))

Deviations:

not applicable

GLP compliance:

no

Limit test:

yes

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Züchter Mus Rattus AG
- Females (if applicable) nulliparous and non-pregnant: [yes/no]
- Weight at study initiation: 146-227 g
- Housing: Individually in mcrolon cages type II
- Diet (e.g. ad libitum): Altromin R, ad libitum
- Water (e.g. ad libitum):Tap Water, ad libitum
- Acclimation period: 11 d

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23-24
- Humidity (%): 44-65
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

oral: gavage

Details on route of administration:

Test item was applied 7 days/week

Vehicle:

other: micro 20, microcrystalsuspension

Analytical verification of doses or concentrations:

no

Duration of treatment / exposure:

7 days/week for 4 to 5 weeks

Frequency of treatment:

daily

Dose / conc.:

0.01 mg/kg bw/day (actual dose received)

Dose / conc.:

0.1 mg/kg bw/day (actual dose received)

Dose / conc.:

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

No. of animals per sex per dose:

10/sex/dose

Control animals:

yes, concurrent vehicle

Dose descriptor:

NOAEL

Effect level:

>= 0.01 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Critical effects observed:

not specified

The two higher dose levels (0.1 and 1.0 mg/kg) led to reduced body weight gain, increased electrolyte excretion in the urine, and atrophy of lymphatic tissue in spleen, lymph nodes, and bone marrow. In low dose animals only an increased glycogen deposition in the liver was observed.

Conclusions:

Rats (10/sex/group) were treated orally with fluocortolone (0; 0.01; 0.1 and 1 mg/kg bw) once daily on 7 days/week for 4 to 5 weeks. The two higher dose levels (0.1 and 1.0 mg/kg) led to reduced body weight gain, increased electrolyte excretion in the urine, and atrophy of lymphatic tissue in spleen, lymph nodes, and bone marrow. In low dose animals only an increased glycogen deposition in the liver was observed. The no adverse effect level was determined at the lowest dose level of 0.01 mg/kg.

Executive summary:

In a subchronic toxicity study (similar to EU Method B.7 but conducted prior to implementation of the test guidelines), Fluocortolon was administered orally by gavage to 10 Wistar rats/sex/dose at 0.01, 0.1, and 1 mg/kg bw/d for 4-.5 weeks at 7 days/week.

The two higher dose levels (0.1 and 1.0 mg/kg) led to reduced body weight gain, increased electrolyte excretion in the urine, and atrophy of lymphatic tissue in spleen, lymph nodes, and bone marrow. In low dose animals only an increased glycogen deposition in the liver was observed. The no adverse effect level was determined at the lowest dose level of 0.01 mg/kg.

 

 

Reference 4

Endpoint:

chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

other information

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

comparable to guideline study

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 452 (Chronic Toxicity Studies)

Deviations:

not applicable

GLP compliance:

no

Limit test:

no

Species:

dog

Strain:

Beagle

Sex:

male/female

Route of administration:

oral: capsule

Vehicle:

other: cornstarch

Details on oral exposure:

PREPARATION OF DOSING SOLUTIONS: capsules

DIET PREPARATION
The dosage was administered in gelatin capsules, six days per week, with the high level animals receiving half their dosage in the morning and half in the afternoon about four and one-half hours apart.

Analytical verification of doses or concentrations:

no

Duration of treatment / exposure:

54 weeks

Frequency of treatment:

daily, 6 days/week

Dose / conc.:

3 mg/kg bw/day (actual dose received)

Dose / conc.:

9 mg/kg bw/day (actual dose received)

Dose / conc.:

50 mg/kg bw/day (actual dose received)

No. of animals per sex per dose:

4/sex/dose

Control animals:

yes, concurrent vehicle

Mortality:

mortality observed, treatment-related

Description (incidence):

All of the dogs on
the 50 mg/kg dosage level of SH 742 died or were sacrificed in moribund condition within 16 weeks. Except for dog No. 4448 M in the partial sacrifice at 15 weeks, all of the dogs on the 9.0 mg/kg dosage level died or were sacrificed in moribund condition within 43 weeks. Dogs 4451 M and 4499 F on the 3.0 mg/kg dosage level were in the partial sacrifice at 15 weeks. Dogs 4395 M and 4555 M on this low level died during weeks 32 and 54, respectively. The other four dogs on the 3.0 mg/kg level survived until termination of the experiment.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

All of the animals on the 50 mg/kg dosage level ofthe test compound lost from 1.2 to 6.1 kilograms of bodyweight be fore being autopsied. Two of the males and three of the females on the 9.0 mg/kg level lost from 0.9 to 4.0 kilograms of body weight before being autopsied. Dog No. 4395 M on the 3.0,mg/kg level lost 1.4 kilograms and dog NO. 4555 M lost 0.6 kilogram prior to death. Each of the four 3.0 mg/kg animals that survived gained at least 1.0 kilogram of body weight more than any of the controls.

Key result

Dose descriptor:

LOAEL

Effect level:

>= 3 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Critical effects observed:

not specified

All dogs of the highest and of the medium dose level died or were sacrificed in moribund condition within 43 weeks (medium dose group) respectively 16 weeks (highest dose group). Two dogs of the low dose group died in weeks 32 and 54.

Toxic effects were seen after 3 weeks (high dose) or later (17-29 weeks for the low dose) with a distinct dose dependency. Increased mortality, decreased body weight and food consumption, slight to moderate polyuria and polydipsia, swollen neck lymph nodes, fat deposition in the subcutis, alopecia, (bloody) diarrhoea, vomiting, neurological effects, lowering of the body temperature, dehydration, head muscle degeneration and disturbance of the electrolyte balance occurred.

Atrophy of the lymphoreticular tissue was predominant with a concurrent decrease in blood leukocyte count and haemoglobin concentration and bone marrow hypocellularity. Serum alkaline phosphatase values were elevated proportional to dose.

Increased liver weight was correlated with an increased deposition of glycogen and pigment. The kidney, the adrenal glands, and the cartilages were likewise affected by degenerative and atrophic changes.

Conclusions:

Dogs (4 males and 4 females per group) received fluocortolone orally at dose levels of 0, 3.0, 9.0 or 50 mg/kg body weight once daily for 54 weeks. All dogs of the highest and of the medium dose level died or were sacrificed in moribund condition within 43 weeks (medium dose group) respectively 16 weeks (highest dose group). Two dogs of the low dose group died in weeks 32 and 54.
Toxic effects were seen after 3 weeks (high dose) or later (17-29 weeks for the low dose) with a distinct dose dependency.
The LOAEL was determined at 3.0 mg/kg body weight, a NOAEL was not determined.

Executive summary:

In a study conducted comparable to OECD test guideline 452 (study performed prior to implementation of OECD guidelines) female and male Beagle dogs (4 males and 4 females per group) received fluocortolone orally at dose levels of 0, 3.0, 9.0 or 50 mg/kg body weight once daily for 54 weeks; 6 days/week. All dogs of the highest and of the medium dose level died or were sacrificed in moribund condition within 43 weeks (medium dose group) respectively 16 weeks (highest dose group). Two dogs of the low dose group died in weeks 32 and 54.

Toxic effects were seen after 3 weeks (high dose) or later (17-29 weeks for the low dose) with a distinct dose dependency. Increased mortality, decreased body weight and food consumption, slight to moderate polyuria and polydipsia, swollen neck lymph nodes, fat deposition in the subcutis, alopecia, (bloody) diarrhoea, vomiting, neurological effects, lowering of the body temperature, dehydration, head muscle degeneration and disturbance of the electrolyte balance occurred.

Atrophy of the lymphoreticular tissue was predominant with a concurrent decrease in blood leukocyte count and haemoglobin concentration and bone marrow hypocellularity. Serum alkaline phosphatase values were elevated proportional to dose.

Increased liver weight was correlated with an increased deposition of glycogen and pigment. The kidney, the adrenal glands, and the cartilages were likewise affected by degenerative and atrophic changes.

The LOAEL was determined at 3.0 mg/kg body weight, a NOAEL could not be determined.

 

Reference 5

Endpoint:

chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

other information

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

comparable to guideline study

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 452 (Chronic Toxicity Studies)

Deviations:

not applicable

GLP compliance:

no

Limit test:

no

Species:

dog

Strain:

Beagle

Sex:

male/female

Route of administration:

oral: gavage

Vehicle:

other: cornstarch

Details on oral exposure:

PREPARATION OF DOSING SOLUTIONS:
The dosage was administered in gelatin capsules six days per week. All animals were dosed in the morning about one and one-half hours after feeding. Dogs receiving the test item were given a dilution of one part of test compound to 49 parts of cornstarch. The cornstarch was mixed with a weighed quantity of compound and sieved several times. The appropriate amount of cornstarch was then added and the mixture was blended in a Twin Shell Blender for 10 minutes. Control dogs received 50 mg/kg of cornstarch six days per week.

Analytical verification of doses or concentrations:

no

Duration of treatment / exposure:

56 weeks

Frequency of treatment:

daily, 6 days/week

Dose / conc.:

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

No. of animals per sex per dose:

3/sex

Control animals:

yes, concurrent vehicle

other: positive control: 9 mg/kg prednisolone

Key result

Dose descriptor:

LOAEL

Effect level:

>= 1 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Critical effects observed:

not specified

Occasionally dryness of the skin, polydipsia, slight hair loss, slow response to neurological stimulus and a slight increase in serum alkaline phosphatase was detected. Enlarged livers with increased glycogen content and pigmented Kupffer cells. Atrophy of adrenal cortex and slight irregularity and reduced activity of proliferating cartilage occurred in the bone marrow.

All animals of control and test substance group survived until termination. Three animals of positiv control were sacrificed in moibund condition during weeks 40, 41 and 48. two females died during week 44 and 56.

Conclusions:

LOAEL: 1 mg/kg bw; NOAEL was not identified.

Executive summary:

In a study conducted comparable to OECD test guideline 452 (study performed prior to implementation of OECD guidelines) female and male Beagle dogs (3 males and 3 females per group) received fluocortolone orally at dose levels of 0, 1.0 mg/kg body weight once daily for 56 weeks; 6 days/week. Mortality was not observed at the 1.0 mg/kg bw dose group.

Effects seen in the fluorocotolon dose groups were predominantly mild and of transient character. Occasionally dryness of the skin, polydipsia, slight hair loss, slow response to neurological stimulus and a slight increase in serum alkaline phosphatase was detected. The enlarged livers showed an increased glycogen content and pigmented Kupffer cells. Atrophy was detected in the adrenal cortex and slight irregularity and reduced activity of proliferating cartilage occurred in the bone marrow.

The LOAEL was determined at > 1.0 mg/kg body weight, a NOAEL could not be determined.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LOAEL

0.1 mg/kg bw/day

Study duration:

chronic

Species:

rat

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

For delta-9(11)-fluocortolone-valerate (CAS No. 66233-43-0) no repeated dose toxicity data are available. Therefore, repeated dose toxicity data of fluocortolone (CAS No. 152-97-6) were used since these data are regarded as representative as most likely ester cleavage of delta-9(11)-fluocortolone-valerate occurs under physiological conditions.

In a preliminary 4-week study rats (30/sex/dose) were treated orally with 3, 9 or 50 mg/kg fluocortolone for 10 days and suviving animals were observed until end of study. 15 rats died during treatment period, additional 16 animals died in post exposure period. Animals showed decreased body weight and food consumption in week 1 and reduction of bw gain until end of study. In a second range finding study rats (2/sex/dose) were treated orally with fluocortolone (0.3, 1.0, 3.0 mg/kg). All animals survived study period. Reduced bw gain in low dose group and bw loss in mid and high dose groups was observed. The low adverse effect level was determined at the lowest dose level of 0.3 mg/kg (Woodard et al., 1967).

Rats (10/sex/group) were treated orally with fluocortolone (0; 0.01; 0.1 and 1 mg/kg bw) once daily on 7 days/week for 4 to 5 weeks. The two higher dose levels (0.1 and 1.0 mg/kg) led to reduced body weight gain, increased electrolyte excretion in the urine, and atrophy of lymphatic tissue in spleen, lymph nodes, and bone marrow. In low dose animals only an increased glycogen deposition in the liver was observed. The no adverse effect level was determined at the lowest dose level of 0.01 mg/kg (Dres et al., 1975).

 

Rats (10/sex/group) were treated subcutaneously with fluocortolone at a dose level of 0.02 mg/kg once daily for 6 weeks. Findings were reduced food consumption in females, reduced lymphocytes count in blood (males) and bone marrow, thymus involution or reduced thymus weight mainly in males, changes in lipid concentration in zona fasciculata in adrenal gland. The LOAEL was identified at 0.02 mg/kg bw, no NOAEL could be identified (Günzel et al., 1976).

 

Rats (10/sex/group) were treated subcutaneously with fluocortolone at a dose level of 0, 0.002, 0.02, or 0.2 mg/kg once daily for 4-5 weeks. Findings were mainly reduced body weight gain, effects on thymus, adrenal gland and spleen. In addition haemorrhages around the location of application were detected. LOAEL: 0.002 mg/kg bw. NOAEL could not be identified (Staben, 1979).

 

Fluocortolone was administered orally to rats (30/sex/group) at dose levels of 0, 0.1, 0.3, or 0.6 mg/kg body weight once daily for 79-80 weeks. The study also includes a dose group with prednisolone 0.6 mg/kg bw. A clear dose dependency of the toxic effects was detected. Body weight gain was depressed and alopecia and skin lesions were detected. Furthermore the treatment led to an atrophy of the lymphoreticular tissue and the bone marrow with concurrent haematological changes. A decrease of blood leukocyte and thrombocyte counts as well as reduced haemoglobin content and an increase of extramedullar haematopoesis. Decreased adrenal weights with a concurrent atrophy of the adrenal cortex, local fibroses, and cellular necroses in the myocard and hyperplasia of the islets of Langerhans were detected. In addition, toxic effects on the liver were seen in clinical chemistry and as histologically visible vacuolization of liver cells. Toxic effects were more pronounced in male rats and predominantly in the high dose treatment groups. LOAEL: 0.1 mg/kg bw. A NOAEL could not be determined (Woodard et al., 1967).

 

Dogs (4 males and 4 females per group) received fluocortolone orally at dose levels of 0, 3.0, 9.0 or 50 mg/kg body weight once daily for 54 weeks. All dogs of the highest and of the medium dose level died or were sacrificed in moribund condition within 43 weeks (medium dose group) respectively 16 weeks (highest dose group). Two dogs of the low dose group died in weeks 32 and 54. Toxic effects were seen after 3 weeks (high dose) or later (17-29 weeks for the low dose) with a distinct dose dependency. Increased mortality, decreased body weight and food consumption, slight to moderate polyuria and polydipsia, swollen neck lymph nodes, fat deposition in the subcutis, alopecia, (bloody) diarrhoea, vomiting, neurological effects, lowering of the body temperature, dehydration, head muscle degeneration and disturbance of the electrolyte balance occurred. Atrophy of the lymphoreticular tissue was predominant with a concurrent decrease in blood leukocyte count and haemoglobin concentration and bone marrow hypocellularity. Serum alkaline phosphatase values were elevated proportional to dose. Increased liver weight was correlated with an increased deposition of glycogen and pigment. The kidney, the adrenal glands, and the cartilages were likewise affected by degenerative and atrophic changes. The LOAEL was determined at 3.0 mg/kg body weight, a NOAEL was not determined (Woodard et al., 1966).

 

Dogs (3/sex/group) were orally dosed to 0 (control) or 1.0 mg/kg 6 days/week for 56 weeks. The study also contains a group dosed with 9.0 mg/kg prednisolone as positve control. Effects seen in the fluorocotolon dose groups were predominantly mild and of transient character. Occasionally dryness of the skin, polydipsia, slight hair loss, slow response to neurological stimulus and a slight increase in serum alkaline phosphatase was detected. The enlarged livers showed an increased glycogen content and pigmented Kupffer cells. Atrophy was detected in the adrenal cortex and slight irregularity and reduced activity of proliferating cartilage occurred in the bone marrow. LOAEL: 1 mg/kg bw; NOAEL was not identified (Woodard et al., 1969).

Justification for classification or non-classification

Due to the results of repeated dose toxicity studies in rats and dogs with the structurally analogue substance fluocortolone the following self classification of delta-9(11)-fluocortolone-valerate is recommended according to Regulation (EC) No. 1272/2008 (CLP):

STOT Rep. Exp. 1 (H372: Causes damage to organs through prolonged or repeated exposure)