Registration Dossier

Administrative data

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.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1980
Report Date:
1980

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
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

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): BMDBM
- Substance type: light yellowish powder
- Physical state: solid

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals 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

Administration / exposure

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)

Results and discussion

Effect levels
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.

Any other information on results incl. tables

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

Applicant's summary and conclusion

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.