3β-hydroxyandrost-5-en-17-one acetate

Endpoint summary

Description of key information

Repeated dose toxicity - oral: No reliable, key repeated dose toxicity study is available for T008506. Therefore, reliable data from the supporting substance Dehydroepiandrosterone (DHEA) is used to cover this endpoint. In a one-year, chronic toxicity study in cynomolgus monkey, an NOAEL of 10 mg/kg/d was established. This NOAEL is also considered valid for the target substance T008506. Based on the results and the CLP Regulation, the substance is not to be classified as STOT RE.

Repeated dose toxicty - inhalation: A key study is available for the oral route of exposure. According to the REACH regulation, only one route of exposure should be tested for repeated dose toxicity (column 2, annex VIII, section 8.6.1). Therefore, it is not necessary to perform a repeated dose toxicity study via the inhalation route of exposure.

Repeated dose toxicty - dermal: A key study is available for the oral route of exposure. According to the REACH regulation, only one route of exposure should be tested for repeated dose toxicity (column 2, annex VIII, section 8.6.1). Therefore, it is not necessary to perform a repeated dose toxicity study via the dermal route of exposure.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Reference 1

Endpoint:

chronic toxicity: oral

Type of information:

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

Adequacy of study:

key study

Justification for type of information:

Data from the supporting substance Dehydroepiandrosterone is used to cover this endpoint. The justification for read across is attached in IUCLID Section 13.

Reason / purpose for cross-reference:

read-across source

Key result

Dose descriptor:

NOAEL

Effect level:

10 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Assumes that the observed effects on endocrine organ weights are pharmacologic.

Remarks on result:

other:

Remarks:

This NOAEL is considered relevant for Dehydroepiandrosterone acetate. Justification for this read across approach is included in IUCLID section 13.

Key result

Critical effects observed:

no

Conclusions:

No reliable repeated dose toxicity study is available for Dehydroepiandrosterone acetate. Therefore, reliable data from the supporting substance Dehydroepiandrosterone (DHEA) is used to cover this endpoint. In a one year monkey oral toxicology study, DHEA produced no adverse effects in male and female monkeys up to 10 mg/kg/day. Changes in endocrine organ weights (ovary, uterus, vagina, pituitary in females and epididymis, testis, spleen and thymus in males) were attributed to estrogenic/androgenic effects that were assumed to be pharmacologic in nature. A NOAEL of 10 mg/kg was identified for male and female monkeys. DHEA is considered to be a worst case read-across substance for Dehydroepiandrosterone acetate. Justification for this read across approach is included in IUCLID section 13.

Reference 2

Endpoint:

chronic toxicity: oral

Type of information:

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

Adequacy of study:

supporting study

Justification for type of information:

Data from the supporting substance Dehydroepiandrosterone is used to cover this endpoint. The justification for read across is attached in IUCLID Section 13.

Reason / purpose for cross-reference:

read-across source

Key result

Dose descriptor:

LOAEL

Effect level:

10 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

female

Basis for effect level:

gross pathology

histopathology: non-neoplastic

Remarks on result:

other:

Remarks:

This LOAEL is considered relevant for Dehydroepiandrosterone acetate. Justification for this read across approach is included in IUCLID section 13.

Key result

Dose descriptor:

NOAEL

Effect level:

10 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male

Basis for effect level:

body weight and weight gain

histopathology: non-neoplastic

Remarks on result:

other:

Remarks:

This NOAEL is considered relevant for Dehydroepiandrosterone acetate. Justification for this read across approach is included in IUCLID section 13.

Key result

Critical effects observed:

yes

Lowest effective dose / conc.:

10 mg/kg bw/day (nominal)

System:

female reproductive system

Organ:

ovary

uterus

vagina

Treatment related:

yes

Dose response relationship:

yes

Relevant for humans:

not specified

Key result

Critical effects observed:

yes

Lowest effective dose / conc.:

100 mg/kg bw/day (nominal)

System:

endocrine system

Organ:

adrenal glands

Treatment related:

yes

Dose response relationship:

yes

Relevant for humans:

not specified

Conclusions:

No reliable repeated dose toxicity study is available for Dehydroepiandrosterone acetate. Therefore, reliable data from the supporting substance Dehydroepiandrosterone (DHEA) is used to cover this endpoint. In a 6 month rat oral toxicology study of DHEA, estrogen/androgen related effects were observed. In females, this included minimal to slight squamous metaplasia of the glandular epithelium of the uterus at doses of 10 to 100 mg/kg. In males, this included minimal to slight diffuse vacuolation of adrenal cortical cells and reductions in body weight/body weight gain at a dose of 100 mg/kg. A NOAEL was not determined for female rats (LOAEL = 10 mg/kg), while a NOAEL of 10 mg/kg was identified for male rats. DHEA is considered to be a worst case read-across substance for Dehydroepiandrosterone acetate. Justification for this read across approach is included in IUCLID section 13.

Reference 3

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

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

Adequacy of study:

supporting study

Justification for type of information:

Data from the supporting substance Dehydroepiandrosterone is used to cover this endpoint. The justification for read across is attached in IUCLID Section 13.

Reason / purpose for cross-reference:

read-across source

Dose descriptor:

LOAEL

Effect level:

ca. 30 mg/kg bw/day (nominal)

Based on:

other: Dehydroepiandrosterone

Sex:

female

Basis for effect level:

clinical biochemistry

histopathology: non-neoplastic

other: Vaginal cytology data indicated reproductive cycle arrest in the estrus stage.

Remarks on result:

other:

Remarks:

This LOAEL is considered relevant for Dehydroepiandrosterone acetate. Justification for this read across approach is included in IUCLID section 13.

Dose descriptor:

NOAEL

Effect level:

ca. 30 mg/kg bw/day (nominal)

Based on:

other:

Remarks:

Dehydroepiandrosterone

Sex:

male

Basis for effect level:

body weight and weight gain

clinical biochemistry

clinical signs

food consumption and compound intake

histopathology: non-neoplastic

mortality

organ weights and organ / body weight ratios

other: All other endocrinologic parameters measured

Remarks on result:

other:

Remarks:

This NOAEL is considered relevant for Dehydroepiandrosterone acetate. Justification for this read across approach is included in IUCLID section 13.

Dose descriptor:

LOEL

Effect level:

ca. 150 mg/kg bw/day (nominal)

Based on:

other:

Remarks:

Dehydroepiandrosterone

Sex:

male

Basis for effect level:

body weight and weight gain

food consumption and compound intake

other: Plasma androstenedione level

Remarks on result:

other:

Remarks:

This LOEL is considered relevant for Dehydroepiandrosterone acetate. Justification for this read across approach is included in IUCLID section 13.

Conclusions:

No reliable repeated dose toxicity study is available for Dehydroepiandrosterone acetate. Therefore, reliable data from the supporting substance Dehydroepiandrosterone (DHEA) is used to cover this endpoint. The endocrinologic effects of this read-across substance was examined in adult male and female Fischer 344 rats following 28 days of daily oral treatment (gavage). Initial doses tested were 30 and 300 mg/kg/day (n=12/sex/group), which is equivalent to 104 and 1,042 µmoles/kg/day DHEA. However, due to weight loss at the high dose, this dose was lowered to 150 mg/kg/day (521 µmoles/ kg/day DHEA). Administration of DHEA resulted in dose-dependent increases in plasma DHEA and DHEA-Sulfate 1 hour after dosing in week 4. DHEA produced an estrogenic effect in female rats expressed as decreased plasma follicle stimulating hormone (FSH) and luteinizing hormone (LH), inhibition of ovulation, prolonged estrus, and increased uterine estrogen receptors. DHEA produced histologic and endocrinologic changes in reproductive tissues in female rats. Decreased corpora lutea in the ovaries was produced by DHEA in a dose-dependent fashion, which indicated that the estrus cycle was arrested in the estrus stage so that ovulation failed to occur. DHEA also increased plasma levels of androstenedione in males and females. Except for increased plasma levels of androstenedione, no other endocrinologic effects were elicited in males by DHEA administration. DHEA is considered to be a worst case read-across substance for Dehydroepiandrosterone acetate. Justification for this read across approach is included in IUCLID section 13.

Reference 4

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

The dates of the study were not reported in the publication.

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

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

Remarks:

Study not performed according to GLP, but is sufficient to accept the data and is nevertheless well documented and scientifically acceptable.

Principles of method if other than guideline:

Experiment 1 (Tagliaferro, et al., 1986): The purpose of this study was to examine the effects of DHEA acetate on resting metabolism and body composition of males versus females. Five male and 5 female 15-week old Sprague-Dawley outbred rats were administered Dehydroepiandrosterone acetate (DHEA acetate) in a commercial, nonpurifed diet (6 g DHEA acetate/kg diet) for 11 weeks to examine the effects of DHEA acetate on resting metabolism and body composition of male versus female animals. Control animals (5 males and 5 females) were fed nonpurifed diet only. Food intake and body weight were recorded daily. Resting heat production of metabolic rate (RMR) was measured during weeks 0, 6 and 11 of the experiment by indirect respiration calorimetry in an open-loop system. At the end of the 12th week, animals were killed by decapitation. Blood was collected and the caudate lobe of the liver was removed and frozen in liquid nitrogen. The gastrointestinal tract was removed, washed, dried and returned to the body cavity. Blood sera, hepatic tissue and carcasses were frozen at -20 degrees C for future analyses, including body composition (total moisture, fat and nitrogen), hepatic glucose-6-phosphate dehydrogenase activity and serum triglycerides.

Experiment 2 (Tagliaferro, et al., 1986): Six adult (age not specified) male rats (strain not specified) were housed in metabolic cages equipped with feeding tunnels and urine collection trays. To establish baseline, all rats were fed nonpurified, commercial diet for one week; food and water intakes, urine volume and acetoacetate levels in 24-h urine sample were measured daily during the baseline week. For 15 weeks, 3 animals remained on the nonpurified diet, while 3 animals were fed 6 g DHEA acetate/kg diet. During weeks 1-4, the same measurements performed during baseline were made. After 15 weeks, the animals were killed by decapitation. Blood was collected to measure DHEA levels. Adrenal glands, liver, heart, skeletal muscle and interscapular brown adipose tissue were removed, homogenized in a buffered solution and frozen at -20 degrees C for future analyses, including specific activity of citrate synthase as a marker of oxidative metabolism.

Experiment 3 (Leighton, et al., 1987): This study was a follow-up study to Tagliaferro, et al., 1986. Its purpose was to examine the effectes of DHEA acetate on peroxisomal enzymes fatty acyl-CoA and catalase and on mitochondrial citrate synthase. Six male and 6 female 15-week old Wistar rats were administered Dehydroepiandrosterone acetate (DHEA acetate) in a commercial, nonpurifed diet (6 g DHEA acetate/kg diet) for 6 weeks to examine the effects of DHEA acetate on activities of peroxisomal fatty acyl-coenzyme (CoA) oxidase, catalase and mitochondrial citrate synthase. Control animals (6 males and 6 females) were fed nonpurifed diet only. After 6 weeks, the animals were killed by cervical dislocation. Livers were removed as rapidly as possible, weighed, then divided in halves. One half was used for assay of enzyme of activities, while the other half was stored in liquid nitrogen.

GLP compliance:

no

Specific details on test material used for the study:

EXPERIMENTS 1, 2 & 3: Dehydroepiandrosterone acetate

SOURCE OF TEST MATERIAL (Dehydroepiandrosterone acetate; DHEA acetate)
- Source: Sigma Chemical Co., St. Louis, Missouri, USA
- Purity: Not specified

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of the test material: Not specified
- Solubility and stability of the test substance in the solvent/vehicle: Not specified

FORM AS APPLIED IN TEST
- DHEA acetate was mixed with nonpurified diet (6 g DHEA acetate/kg diet) and fed to animals ad libitum

Species:

rat

Strain:

other: Experiment 1: Sprague-Dawley outbred Experiment 2: strain not specified Experiment 3: Wistar

Details on test animals or test system and environmental conditions:

EXPERIMENT 1

TEST ANIMALS
- Source: Charles River (Wilmington, Massachusetts, USA)
- Age: 15 weeks
- Weight: 469 +/- 9.9 g (males); 283 +/- 6.1 g (females)
- Housing: Animals were housed individually in stainless steel cages equipped with feeding tunnels.
- Diet: Ad libitum; commercial, nonpurified diet (Ralston-Purina #5001, St. Louis, Missori, USA)
- Water: Ad libitum; tap water

ENVIRONMENTAL CONDITIONS
- Temperature: 26 degrees C
- Humidity (%): not specified
- Photoperiod (hrs dark / hrs light): 12-hr light-dark cycle (0800-2000)

EXPERIMENT 2

TEST ANIMALS
- Source: not specified
- Age: not specified
- Weight: not specified
- Housing: Animals were housed individually in metabolic cages equipped with feeding tunnels and collection trays for urine.
- Diet: Ad libitum; commercial, nonpurified diet (Ralston-Purina #5001, St. Louis, Missori, USA)
- Water: Ad libitum; tap water

ENVIRONMENTAL CONDITIONS
- Temperature: not specified
- Humidity (%): not specified
- Photoperiod (hrs dark / hrs light): not specified

EXPERIMENT 3

TEST ANIMALS
- Source: Batin and Kingman (Hull, United Kingdom)
- Age: 15 weeks
- Weight: 349 +/- 6 g (males); 216 +/- 5 g (females)
- Housing: Animals were housed in pairs in 41 x 56 cm wire-mesh cages.
- Diet: Ad libitum; commercial powdered nonpurified diet (S.D.S. Witham, Essex, United Kingdom)
- Water: Ad libitum; tap water

ENVIRONMENTAL CONDITIONS
- Temperature: 22 degrees C
- Humidity (%): not specified
- Photoperiod (hrs dark / hrs light): Lights on 0600-2000

Route of administration:

oral: feed

Details on route of administration:

EXPERIMENTS 1, 2 & 3:
- Method: Animals were fed nonpurified diet mixed with DHEA acetate (6 g/kg diet)
- Frequency: Animals were fed ad libitum

Vehicle:

not specified

Details on oral exposure:

EXPERIMENTS 1, 2 & 3:
- Animals were fed nonpurified diet mixed with DHEA acetate (6 g/kg diet) ad libitum

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

Experiment 1: 11 weeks
Experiment 2: 6 weeks
Experiment 3: 15 weeks

Frequency of treatment:

Animals were fed nonpurified diet mixed with DHEA acetate (6 g/kg diet) ad libitum

Dose / conc.:

0 mg/kg diet

Remarks:

Control Group

Dose / conc.:

6 000 mg/kg diet

Remarks:

Dose Group 1

No. of animals per sex per dose:

Experiment 1: 5 males/5 females
Experiment 2: 3 males
Experiment 3: 6 males/6 females

Control animals:

yes, plain diet

Details on study design:

- Dose selection rationale: No information was provided in the publication on dose selection.

- Rationale for animal assignment: Animals were assigned randomly to either the DHEA-treated or the control group.

Positive control:

No

Observations and examinations performed and frequency:

Experiment 1 (Tagliaferro, et al., 1986):
CAGE SIDE OBSERVATIONS: Not specified.

DETAILED CLINICAL OBSERVATIONS: Not specified.

BODY WEIGHT: Body weight was recorded daily.

FOOD CONSUMPTION: Food intake was recorded daily.

OTHER:
- Resting heat production of metabolic rate (RMR): RMR was measured during weeks 0, 6 and 11 of the experiment by indirect respiration calorimetry in an open-loop system.
- Carcass was evaluated for body composition (total moisture, fat and nitrogen).
- Hepatic tissue was evaluated for hepatic glucose-6-phosphate dehydrogenase activity.
- Blood sera was evaluated for serum triglycerides.


Experiment 2 (Tagliaferro, et al., 1986):
CAGE SIDE OBSERVATIONS: Not specified.

DETAILED CLINICAL OBSERVATIONS: Not specified.

BODY WEIGHT: Not specified.

FOOD CONSUMPTION: Food intake was recorded daily.

WATER CONSUMPTION: Water intake was recorded daily.

OTHER:
- Urine volume: Measured daily (24-h urine sample).
- Acetoacetate levels in 24-h urine sample were measured daily.
- Adrenal glands, liver, heart, skeletal muscle and interscapular brown adipose tissue were removed, homogenized in a buffered solution and frozen at -20 degrees C for future analyses, including specific activity of citrate synthase as a marker of oxidative metabolism.
- DHEA was measured in the blood collected at 15 weeks.

Experiment 3 (Leighton, et al., 1987):
CAGE SIDE OBSERVATIONS: Not specified.

DETAILED CLINICAL OBSERVATIONS: Not specified.

BODY WEIGHT: Body weight measurements were taken, but the schedule was not specified. Initial and final body weights were reported in the publication, but no body weights for other intervals.

FOOD CONSUMPTION: Not specified.

ORGAN WEIGHTS: Livers were weighed after terminal sacrifice.

OTHER:
- Enzyme activities of peroxisomal fatty acyl-coenzyme (CoA) oxidase, catalase and mitochondrial citrate synthase were measured in treated and untreated animal livers.

Sacrifice and pathology:

Experiment 1 (Tagliaferro, et al., 1986):
SACRIFICE
- Animals were killed by decapitation.

GROSS PATHOLOGY
- Not specified.

CLINICAL BIOCHEMISTRY
- Blood sera was analyzed for serum triglycerides.

ORGAN WEIGHTS
- Hepatic lobe weight (caudate lobe)

HISTOPATHOLOGY
- Not specified.

OTHER
- The gastrointestinal tract was removed, washed, dried and returned to the body cavity.
- Carcasses were frozen at -20 degrees C for future analyses, including body composition (total moisture, fat and nitrogen).

Experiment 2 (Tagliaferro, et al., 1986):
SACRIFICE
- Animals were killed by decapitation.

GROSS PATHOLOGY
- Not specified.

HAEMATOLOGY/CLINICAL BIOCHEMISTRY
- Blood was collected to measure DHEA levels.

ORGAN WEIGHTS
- Not specified.

HISTOPATHOLOGY
- Not specified.

OTHER
- Adrenal glands, liver, heart, skeletal muscle and interscapular brown adipose tissue were removed, homogenized in a buffered solution and frozen at -20 degrees C for future analyses, including specific activity of citrate synthase as a marker of oxidative metabolism.

Experiment 3 (Leighton, et al., 1987):
SACRIFICE
- Animals were killed by cervical dislocation.

OTHER
- Livers were removed as rapidly as possible, weighed, then divided in halves. One half was used for assay of enzyme activities of peroxisomal fatty acyl-coenzyme (CoA) oxidase, catalase and mitochondrial citrate synthase. The other half of the liver was stored in liquid nitrogen.

Clinical signs:

not examined

Mortality:

no mortality observed

Description (incidence):

No mortality was described for any of the three experiments.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Experiment 1: Inhibitory effects of DHEA treatment on weight gain were observed with two weeks following beginning of treatment. DHEA-treated animals weighed significantly less than controls after six weeks and continued to the end of treatment. Paired comparisons between groups indicated that only the difference between male groups was statistically significant.

Food consumption and compound intake (if feeding study):

no effects observed

Description (incidence and severity):

Experiments 1 and 2: Food intake was found not to change from baseline levels and was not significantly different between treated and control animals.

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

no effects observed

Description (incidence and severity):

Experiment 2: Water intake was found not to change from baseline levels and was not significantly different between treated and control animals.

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

effects observed, treatment-related

Description (incidence and severity):

Experiment 1: Serum triglyceride levels were lower in the DHEA-treated group.

Urinalysis findings:

no effects observed

Description (incidence and severity):

Experiment 2: Urine volume and urinary ketone levels were found not to change from baseline levels and were not significantly different from controls.

Behaviour (functional findings):

not examined

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

Experiment 1: Hepatic caudal lobes of DHEA-treated animals were heavier than controls when expressed on a relative weight basis.
Experiment 3: Mean liver weights (g/kg body weight) of the treated male and female groups were significantly heavier by 20 and 65%, respectively, than those of the control animals.

Gross pathological findings:

not examined

Neuropathological findings:

not examined

Histopathological findings: neoplastic:

not examined

Other effects:

effects observed, treatment-related

Description (incidence and severity):

Experiment 1:
- Resting heat production of metabolic rate (RMR): At the end of weeks 6 and 11, the RMR of both treated males and females was higher than the controls (ANOVA, p < 0.01).
- Body composition (total moisture, fat and nitrogen): No statistically significant differences in body water content was observed between DHEA-treated and control animals within sex groups. DHEA decreased both total and relative body fat in males and females, but the finding was statistically significant only in females. Relative content of body protein was increased in both treated males and females, but significantly more so for females than males. Relative ash content was increased in both treated males and females, but this finding was statistically significant only in the treated females. DHEA decreased total carcass energy in both sexes, but the finding was statistically significant only in females.
- Hepatic glucose-6-phosphate dehydrogenase activity: Specific activity of G6PDH was suppressed in animals.

Experiment 2:
- Citrate synthase activity (marker of oxidative metabolism) in adrenal glands, liver, heart, skeletal muscle and interscapular brown adipose tissue: The specific activity of citrate synthase was not affected significantly by DHEA treatment.

Experiment 3:
- Enzyme activities of peroxisomal fatty acyl-coenzyme (CoA) oxidase, catalase and mitochondrial citrate synthase: Specific activity of peroxisomal enzymes fatty acyl-CoA oxidase and catalase was significantly higher in the liver tissue of DHEA-treated groups than in control groups. There were no differences in citrate synthase activity. Catalase activity on only treated females was significantly higher (30%) than controls.

Dose descriptor:

LOEL

Effect level:

6 000 mg/kg diet

Based on:

test mat.

Sex:

male/female

Basis for effect level:

body weight and weight gain

clinical biochemistry

organ weights and organ / body weight ratios

other: Increased resting heat production, lower hepatic glucose-6-phosphate dehydrogenase activity, lower body fat, increased body water, increased protein and ash, increased peroxisomal fatty acyl-CoA oxidase and catalase activities

Conclusions:

In the three experiments undertaken for this study, DHEA acetate treatment resulted in increased resting heat production, reduced body weights (statistically significant only in males) without an effect on food intake, reduced serum triglycerides, increased liver weights (significant in males and females), lower body fat (significant only in females), higher body protein and ash (significant in females only), and significantly higher specific activity of the peroxisomal enzymes fatty acyl-CoA oxidase and catalase in the liver tissue of DHEA-treated animals. The study authors conclude that DHEA acetate treatment affects body weight, body composition and utilization of dietary energy by impairing fat synthesis and promoting fat-free tissue deposition and resting heat production. The results also support the hypothesis that the inhibitory effect of DHEA on energy storage as fat is mediated in part by increased beta-oxidation of fatty acids in peroxisomes.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

10 mg/kg bw/day

Study duration:

chronic

Species:

monkey

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: inhalation

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

other:

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - local effects

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: inhalation

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

other:

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: dermal

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

other:

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: dermal

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

other:

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Repeated dose toxicity: oral

Four publications of repeated dose toxicity studies are considered: 1 study with the target substance T008506 and 3 with the supporting substance DHEA.

6, 11 or 15 weeks dosing of T008506 in rat (Tagliaferro et al., 1986; Leighton et al., 1987)

DHEA acetate (or T008506) was dosed to rats at 6000mg/kg/day via diet for 6, 11 or 15 weeks. The study concluded that DHEA acetate treatment affects body weight, body composition and utilization of dietary energy by impairing fat synthesis and promoting fat-free tissue deposition and resting heat production. These results also support the hypothesis that the inhibitory effects of DHEA on energy storage as fat is mediated in part by increased beta-oxidation of fatty acids in peroxisomes. An LOEL of 6000 mg/kg/d was established.

28-day repeated dose toxicity study in rat (Brown et al., 2003) with DHEA

The endocrinologic effects of DHEA were examined in adult male and female Fischer 344 rats following 28 days of daily oral treatment (gavage) with 30 or 300 mg/kg/day. DHEA produced an estrogenic effect in female rats expressed as decreased plasma FSH and LH, inhibition of ovulation, prolonged estrus and increased uterine estrogen receptors. DHEA produced histologic and endocrinologic changes in reproductive tissues in female rats. Decreased corpora lutea in the ovaries were observed in a dose-dependent fashion, which indicated that the estrus cycle was arrested in the estrus stage so that ovulation failed to occur.

6-month repeated dose toxicity in rat with DHEA

Male and female rats were dosed with 10 or 100 mg/kg/d DHEA via oral gavage during 6 months. Estrogen/androgen related effects were observed. In females, this included minimal to slight squamous metaplasia of the glandular epithelium of the uterus at doses of 10 to 100 mg/kg/day. In males, this included minimal to slight diffuse vacuolation of adrenal cortical cells and reductions in body weight/body weight gain at a dose of 100 mg/kg/d. An NOAEL was not determined for female rats (LOAEL = 10 mg/kg), while an NOAEL of 10 mg/kg was identified for male rats.

1-year chronic toxicity study in rat with DHEA

Male and female cynomolgus monkey were dosed daily with 2 or 10 mg/kg/d during 1 year via oral gavage. DHEA produced no adverse effects in male and female monkeys up to 10 mg/kg/d. Changes in endocrine organ weights (ovary, uterus, vagina, pituitary in females and epididymides, testis, spleen, and thymus in males) were attributed to estrogenic/androgenic effects that were assumed to be pharmacologic in nature. A NOAEL of 10 mg/kg/d was identified for male and female monkeys.

In conclusion, DHEA is considered to be a worst-case read-across substance for T008506. Based on the results described above, the chronic toxicity study in cynomolgus monkey with NOAEL = 10 mg/kg/day is considered the key study and key value.

Repeated dose toxicity: inhalation

A key study is available for the oral route of exposure. According to the REACH Regulation, only one route of exposure should be tested for repeated dose toxicity (column 2, annex VIII, section 8.6.1). Therefore, it is not necessary to perform a repeated dose toxicity study via the inhalation route of exposure.

Repeated dose toxicity: dermal

A key study is available for the oral route of exposure. According to the REACH Regulation, only one route of exposure should be tested for repeated dose toxicity (column 2, annex VIII, section 8.6.1). Therefore, it is not necessary to perform a repeated dose toxicity study via the dermal route of exposure.

Justification for classification or non-classification

Based on the results of the repeated dose toxicity via the oral route and the criteria of the CLP Regulation, T008506 should not be classified as STOT repeated exposure.