3-(m-tert-butylphenyl)-2-methylpropionaldehyde

Toxicity to reproduction: other studies

Administrative data

Endpoint:

toxicity to reproduction: other studies

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP, Draft guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2009

Report date:

2009

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

other: Draft OECD Guideline for the Testing of Chemicals; The Hershberger Bioassay in Rats: A Short-term Screening Assay for (Anti)Androgenic Properties

GLP compliance:

yes (incl. QA statement)

Type of method:

in vivo

Test material

Test material information

Constituent 1

Reference substance name:

3-(m-tert-butylphenyl)-2-methylpropionaldehyde

EC Number:

263-580-6

EC Name:

3-(m-tert-butylphenyl)-2-methylpropionaldehyde

Cas Number:

62518-65-4

Molecular formula:

C14H20O

IUPAC Name:

3-(3-tert-butylphenyl)-2-methylpropanal

Details on test material:

- Name of test material (as cited in study report): V4 m-Lysmeral Destillation Fr. 6
- Physical state: liquid/colorless, clear
- Analytical purity: 99.22 Area %
- Impurities (identity and concentrations):p-Lysmeral 55 mg/kg
- Storage condition of test material: ambient (room temperature); under Argon

The stability of the test substance in Olive Oil Ph. Eur. at room temperature for a period of 7
days was demonstrated.

Test animals

Species:

rat

Strain:

Wistar

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories; Germany
- Age: 45 +1 days at castration, 52 +1 days at test substance administration
- Housing: 3 animals per cage
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: approx 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24
- Humidity (%): 30-70
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

olive oil

Analytical verification of doses or concentrations:

yes

Duration of treatment / exposure:

10 days

Frequency of treatment:

daily

Duration of test:

10 days

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 50, 150, 450 mg/kg bw/d
Basis:

No. of animals per sex per dose:

6

Control animals:

other: vehicle control without TP; vehicle control with TP; Flutamide control with TP

Details on study design:

EXPERIMENTAL PROCEDURE
On day -7 of the study all animals were castrated. The test substance was administered daily for 10 days. The Antagonist groups were treated
with Testosterone-Propionate (0.4 mg/kg bw/day) subcutaneously. Control animals received the vehicle, Testosterone-Propionate (TP) or Testosterone-Propionate+Flutamide (TP+FL). All animals were sacrificed after a fasting period (withdrawal of food) of at least 16 hours.

Mortality:
checked twice daily on working days and once daily on Saturdays, Sundays and public holidays. If animals were in a moribund state, they were sacrificed and necropsied.
Clinical observations:
checked daily before and after the administration for any clinically abnormal signs.
Food consumption:
determined on day 5 and 9, calculated as mean food consumption in grams per animal and day.
Water consumption:
observed daily by visual inspection of the water bottles for any overt changes in volume.
Body weight:
determined before the start of the administration period in order to randomize the animals; daily during the administration period.
Food efficiency
calculated based upon individual values for body weight and food consumption.
Necropsy:
Animals were sacrificed by decapitation under Isoflurane anesthesia. The exsanguinated animals were necropsied and assessed by gross pathology.
Organ weights:
fresh (unfixed) weights were determined in all animals after they were carefully trimmed of excess adhering tissue and fat. Each tissue was weighed without blotting (sex accessory tissues, kidneys and adrenal glands to the nearest 0.1 mg, liver and anesthetized animals to the nearest 0.1 g).
1. Anesthetized animals
2. Ventral prostate (VP)
3. Seminal vesicle together with coagulation gland (SVCG)
4. Musc. levator ani together with Musc. bulbocavernosus (LABC)
5. Bulbo-urethral gland (COW)
6. Adrenal glands
7. Glans penis (GP)
8. Liver
9. Kidneys

TEST GROUPS AND DOSES:
Negative control group:
0. vehicle control
1. vehicle control + testosteron propionate (0.4 mg/kg bw/d)
Positive control:
2. Flutamide (3 mg/kg bw/d) + testosteron propionate (0.4 mg/kg bw/d)
Antagonist groups:
3. m-Lysmeral (50 mg/kg bw/d) + testosteron propionate (0.4 mg/kg bw/d)
4. m-Lysmeral (150 mg/kg bw/d) + testosteron propionate (0.4 mg/kg bw/d)
5. m-Lysmeral (450 mg/kg bw/d) + testosteron propionate (0.4 mg/kg bw/d)
Agonist groups:
6. m-Lysmeral (50 mg/kg bw/d)
7. m-Lysmeral (150 mg/kg bw/d)
8. m-Lysmeral (450 mg/kg bw/d)

Statistics:

Body weight, body weight change: DUNNETT's test (two-sided)

Weight parameters (VP, SVCG, LABC, COW, GP): DUNNETT’s test (one-sided) for TS treated groups; Student’s t-test (one-sided) for the neg/ pos control group comparison.

Weight parameters (terminal body weight, liver, kidney, adrenal gland): DUNNETT’s test (two-sided) for TS treated groups; Student’s t-test (two-sided) for the neg/ pos control group comparison.

Results and discussion

Effect levels

Dose descriptor:

NOAEL

Remarks:

anti-androgenic or androgenic

Effect level:

450 mg/kg bw/day

Sex:

male

Basis for effect level:

other: no effects on reproductive organs observed

Observed effects

Negative control groups:
0. vehicle control
Clinical Examinations: No adverse findings
Pathology: No adverse findings

1. vehicle control + testosteron propionate (0.4 mg/kg bw/d)
Clinical Examinations: No adverse findings
Pathology:
Weights of adrenal glands significantly reduced compared to test group 0
Weights of seminal vesicle together with coagulation gland (SVCG), bulbo-urethral gland (COW), ventral prostate (VP), glans penis (GP) and muscles levbator ani together with bulbocavernosus (LABS) significantly increased compared to test group 0
No other substance related adverse findings

Positive control group:
2. Flutamide (3 mg/kg bw/d) + testosteron propionate (0.4 mg/kg bw/d)
Clinical Examinations: No adverse findings
Pathology:
Weights of seminal vesicle together with coagulation gland (SVCG), bulbo-urethral gland (COW), ventral prostate (VP), glans penis (GP) and muscles levbator ani together with bulbocavernosus (LABS) significantly reduced compared to test group 1


Antagonist groups:
3. m-Lysmeral (50 mg/kg bw/d) + testosteron propionate (0.4 mg/kg bw/d)
Clinical Examinations: No substance related adverse findings
Pathology (reproductive organs): No substance related adverse findings

4. m-Lysmeral (150 mg/kg bw/d) + testosteron propionate (0.4 mg/kg bw/d)
Clinical Examinations: No substance related adverse findings
Pathology (reproductive organs): No substance related adverse findings
Absolute/ relative weights of bulbo-urethral gland were significantly reduced compared to the controls. Finding is not considered as adverse or as hormonal (anti-androgenic) action, due to lack of dose-response relationship, negligible magnitude of effect compared to Flutamide treated controls and lack of significant alterations in other examined androgen-dependent organs/tissues in this group.

5. m-Lysmeral (450 mg/kg bw/d) + testosteron propionate (0.4 mg/kg bw/d)
Clinical Examinations: No substance related adverse findings
Pathology (reproductive organs): No substance related adverse findings

Agonist groups:
6. m-Lysmeral (50 mg/kg bw/d)
Clinical Examinations: No substance related adverse findings
Pathology (reproductive organs): No substance related adverse findings

7. m-Lysmeral (150 mg/kg bw/d)
Clinical Examinations: No substance related adverse findings
Pathology (reproductive organs): No substance related adverse findings

8. m-Lysmeral (450 mg/kg bw/d)
Clinical Examinations: No substance related adverse findings
Pathology (reproductive organs): No substance related adverse findings

Any other information on results incl. tables

Other statistically significant organ weight changes:

Kidney: increase of absolute/relative weights (vs ctrl):

test group 4 (150 mg/kg bw/day + TP): 117%/ 115%

test group 5 (450 mg/kg bw/day + TP): 116%/ 117%

test group 8 (450 mg/kg bw/day): 114%/ 116%

Liver: increase of absolute/relative weights (vs ctrl):

test group 4 (150 mg/kg bw/day + TP): 127%/ 125%

test group 5 (450 mg/kg bw/day + TP): 161%/ 162%

test group 7 (150 mg/kg bw/day): 118%/ 118%

test group 8 (450 mg/kg bw/day): 160%/ 163%

The weight increase of livers is a substance-related effect. A treatment-related increase of kidney weights seems unlikely, but no histomorphological investigation was carried out. The increase of liver weights is comparable to the repeated dose 28-day toxicity study in Wistar rats (BASF 2009; 30S0875/08053). Histomorphological examination in the 28- day toxicity study revealed a centrilobular hypertrophy of hepatocytes and it was regarded as an adaptive, detoxifying (cytochrome P450 enzyme induction) response to treatment. Since there is no histopathology in this study, no final assessment can be provided.

Gross lesions:

Enlargement of liver in all animals of test group 5 (450 mg/kg bw/day + TP) and test group 8 (450 mg/kg bw/day), being considered as substance related effect.