1-(4-tert-butylphenyl)-3-(4-methoxyphenyl)propane-1,3-diol

Endpoint summary

Description of key information

No test for acute oral toxicity is available for Avodiol. However, an oral LD50 value of >16000 mg/kg bw in the rat is available for a structurally similar compound.

Therefore, based on this read-across, it can be concluded that the oral LD50 value of Avodiol is > 2000 mg/kg bw.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Reference 1

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Comparable to guideline study with acceptable restrictions.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

yes

Remarks:

: limit dose of 16000 mg/kg bw

GLP compliance:

no

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: W. Gassner, Sulzfeld, Germany
- Weight at study initiation: 90-115g
- Fasting period before study: 16h
- Housing: 5 animals per Makrolon Type III cage with autoclaved sawdust as bedding
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22±1°C
- Humidity (%): 55±5%
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

oral: gavage

Vehicle:

other: 4% w/v aqueous gum arabic solution

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 40% w/v as suspension
- Amount of vehicle (if gavage): 40 mL/kg bw

Doses:

limit dose of 16000 mg/kg bw

No. of animals per sex per dose:

10 males and 10 females

Control animals:

yes

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: frequently on the day of dosing and daily thereafter
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, histopathology (5 males and 5 females of the treated group and all organs with abnormal macroscopic appearance)

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 16 000 mg/kg bw

Remarks on result:

other: all animals survived at this dose

Mortality:

There were no mortalities in either the treated or control group.

Clinical signs:

Signs of reaction to treatment, observed shortly after dosing included pitoerection (only in control animals) and abnormal body carriage (hunched posture). These signs were accompanied by slight lethargy immediately after dosing in male rats only.
Recovery, as judged by external appearance and behaviour, was apparently complete within 5 days after treatment.

Body weight:

Bodyweight gains in all treated rats were comparable with those of the control animals throughout the two week observation period.

Gross pathology:

Autopsy findings for rats killed at termination were considered to be normal.

Other findings:

HISTOPATHOLOGY:
The marked loss of sperm as well as the accumulation of cellular debris in the epididymal tubules of the 5 males examined and the slight vacuolation of hepatocytes (3 male and 2 female animals) may be attributable to treatment with butyl methoxydibenzoylmethane (BMDBM). The testes of all examined animals appeared normal.
Hemosiderin deposits occur commonly in the spleen of rats whereas hemopoiesis in the same organ occurs at a time of stress. Furthermore, the spleen is a hemopoietic organ in the embryo and up some weeks after birth. So indications of spleen hemopoiesis could also be remains of animal development. Unfortunately, no data of control animals were provided for comparison, so that attributing these findings uniquely to BMDBM treatment is not justified. Peribronchial lymphoid hyperplasia and focal interstitial pneumonitis are stages of evolution of chronic murine pneumonia. Small round infiltrates in the liver and focal interstitial nephritis may be considered as a bacterial infection.
Mitotic cells in kidneys, liver, stomach, duodenum, pancreas, adrenals, and epididymis are signs of growing organs.

Table 2: Acute toxicity signs as reaction to treatment with BMDBM

Day	Control Males	Control Females	16000 mg/kg bw Males	16000 mg/kg bw Females
1	15A	15A	15A / 21A / 1A	15B / 21A
	15A	15A	15A	15B
	15A	15A	15A	15B
2	15A	15A	15A	15B
3	15A	15A	15A	15B
4	N	N	N	15A
5	N	N	N	N
6-14	N	N	N	N

Signs of toxicity coding: 1. Lethargy, 15. Piloerection, 21. Hunched posture

Degree of reaction: A = slight, B = Moderate, C = Severe, N = No abnormalities detected

 

Table 3: Body weight gains of rates dosed once with BMDBM

Group	Sex	Bodyweight [g]^a)			Bodyweight gain [g]
		Day 1	Day 8	Day 15
Control	Male	108	167	214	106
	Female	99	152	178	79
16000 mg/kg bw	Male	106	166	218	112
	Female	101	151	175	74

^a)Average of 10 animals per group per sex

 

Table 4: Autopsy findings after acute oral toxicity study with BMDBM

Group	Sex	Organs examined	Autopsy findings
Control	Male	As listed in table 1	Within normal limits
	Female	As listed in table 1	Within normal limits
16000 mg/kg bw	Male	As listed in table 1	Within normal limits
	Female	As listed in table 1	Within normal limits

Interpretation of results:

practically nontoxic

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

After oral administration of 16,000 mg/kg bw of BMDBM as suspension in 4% gum arabic in water w/v to male and female rats, no mortality was observed. The test item BMDBM can therefore be classified as practically nontoxic according to OECD GHS.

Executive summary:

Oral application of a suspension containing 16,000 mg/kg bw by gavage to male and female rats resulted in no mortality within 14 days of post-observation. Also vehicle-treated animals showed no mortality. Both groups exhibited clinical signs in the first 4 days after treatment of which the most abundant was piloerection; the animals treated with BMDBM but not the controls showed signs of lethargy and hunched posture. Body weights and gross necropsy were in normal limits in all animals. Histopathological changes were observed mainly in the epididymes and spleen of treated animals, but no causal connection could be developed as animals suffered from a bacterial infection and pneumonia.

Taken together, the test item BMDBM has a LD50 (rat, oral) of >16,000 mg/kg bw and can therefore be classified as practically nontoxic according to OECD GHS.

Reference 2

Endpoint:

acute toxicity: oral

Type of information:

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

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study

Justification for type of information:

For this endpoint information from a structural similar compound is available. This study for this similar compound was performed according to GLP and the methods applied are fully compliant with OECD TG 423. See chapter 13 report for a more detailed justification.

Reason / purpose for cross-reference:

read-across source

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Interpretation of results:

GHS criteria not met

Conclusions:

For this endpoint information from a structural similar compound is available. This study for this similar compound was performed according to GLP and the methods applied are fully compliant with OECD TG 423.
See chapter 13 report for a more detailed justification.
From this justification it can be concluded that the oral LD50 value is higher than 2000 mg/kg after single oral administration in rats.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

16 000 mg/kg bw

Quality of whole database:

The study is sufficiently described and well documented. A justification for the analogue approach is provided.

Justification for classification or non-classification

Based on a read-across approach, the substance must not be classified with regard to acute oral toxicity.