Registration Dossier

Administrative data

Description of key information

The LD50 of the test item 1,3-Diiodopropane is greater than 300 mg/kg and lower than 2000 mg/kg body weight after single oral administration to Wistar rats. Thus, the substance 1,3-Diiodopropane is classified in GHS Category 4 with a LD50 cut off value 500 mg/kg body weight, after single oral administration to Wistar rats.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records
Reference
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
April - May 2020
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Version / remarks:
December 2001
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Test type:
acute toxic class method
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
female
Details on test animals or test system and environmental conditions:
Species: Wistar rats
Source: Institue of Experimental Pharmacology and Toxicology, Center of Experimental Medicine of the Slovak Academy of Sciences, Dobrá Voda, Slovak Republic
Number and Sex of Animals: 9 females (non-pregnant and nulliparous, age at first dose 8 - 12 weeks)
Animal Health: The health condition of animals was examined by a veterinarian before initiation of the study.
Acclimation: The animals were acclimated to the condition identical to the condition during the experiment at least 5 days prior to the start of treatment. The acclimation was according to standard operation procedures.
Housing Condition: The animals were housed in plastic cages suspended on stainless steel racks, up to 3 animals per cage, in a room equipped with central air-conditioning. The room temperature was maintained within the range of 22 ±2 °C. The relative humidity was 55 ±10%. The light regime was set to a 12-hour light / 12-hour dark cycle. The sanitation was performed according to standard operation procedures.
Diet: A standard laboratory food KKZ-P/M (UEFT CEM SAS) was available ad libitum.
Water: The animals received tap water for human consumption. Supply of drinking water was unlimited. The quality of drinking water is periodical monitored (including microbiological control) and recorded.
Bedding: AlpenSpan Eco, Johann Pabst Holzindustrie GmbH, Zeltweg, Austria
Animals Identification: Each animal was marked with an ID number. Each cage was affixed with a cage card containing pertinent animal and study information. The animals in cages were marked by a line on the tail with an ink marker.
Route of administration:
oral: gavage
Vehicle:
olive oil
Details on oral exposure:
Number of Animals and Dose Levels: The starting dose can be selected from the fixed dose levels of 5, 50, 300, and 2000 mg/kg body weight. Available information indicated that the test item was likely to be non-toxic regarding acute toxicity; therefore, a dose of 2000 mg of 1,3-Diiodopropane per kg body weight was used as a starting dose. In the first step, one group of 3 females was dosed. The test item in limit dose caused mortality of all three animals within 48 hours after administration. In a second step, 3 females were treated at dose of 300 mg/kg body weight. Test item-related mortality was not observed for 48 hours and therefore, in a third step, another 3 females were treated at the same dose level.
Dose Preparation: The required amount of the test item (according to the body weight and dose) was mixed with appropriate vehicle (olive oil) shortly before administration. In case of dose of 2000 mg/kg, the liquid test item was administered without the vehicle and appropriate dose was calculated according to weight of animal. Dose was recalculated to concentration 100 % of 1,3-Diiodopropane (purity of test item is ˃ 99 %).
Dose Administration: The test item was administered in a single dose by gavage using an oral gavage. Animals were fasted prior to dosing (food but not water was withheld over-night). Following the period of fasting, the animals were weighed, and the test item was administered. After the test item administration, food was withheld for further 3 - 4 hours.
Doses:
doses of 2000 mg/kg bw and 300 mg/kg bw were applied
No. of animals per sex per dose:
3 females per dose for 2000 mg/kg bw and 6 females for 300 mg/kg bw.
Control animals:
no
Details on study design:
Post exposure the following observations were performed:
Clinical Observation: The animals were observed individually immediately after the administration of the test item and then 0.5, 1, 2 and 4 hours later. Each animal was inspected daily for the next 14 days.
Observations included: changes in skin and fur, eyes and mucous membranes, and also respiratory, circulatory, autonomic and central nervous systems, and somatomotor activity and behavioural patterns. Attention was directed to observations of tremors, convulsions, salivation, diarrhoea, lethargy, sleep and coma.
Body Weight: Individual weights of animals were determined shortly before the test item administration and weekly thereafter. Weight changes after first and second week after administration were calculated and recorded.
Pathology: All test animals (including those that died during the test or were removed from the study for animal welfare reasons) were subjected to gross necropsy. All gross pathological changes were recorded for each animal. Examinations included: external body surface and orifices, the appearance of tissues and organs in the thoracic cavity (trachea, esophagus, heart, aorta, lungs with main stem bronchi, thymus, tracheobronchial lymph node) and in the abdominal cavity (liver, spleen, adrenal glands, kidneys, ovaries, uterus including cervix, urinary bladder, small intestine, large intestine, pancreas, stomach, mesenteric lymph nodes).
Statistics:
none required
Sex:
female
Dose descriptor:
LD50 cut-off
Effect level:
500 mg/kg bw
Based on:
test mat.
Mortality:
Mortality of 3/3 females at limit dose of 2000 mg/kg body weight was observed. Five out of six female animals survived, and one animal died 5 days after administration at the dose of 300 mg/kg body weight. Summary results of clinical observations are presented in Tables 1 and 2.
Clinical signs:
In the 300 mg/kg bw dose group piloerection was observed within 1 hour after administration and persisted for 2 - 3 hours as presented in Table 4.
Body weight:
The body weights of animals increased during the study. Summary results of body weights are presented in Table 3.
Gross pathology:
All animals were necropsied. In animals No 1 and 2 dosed with 2000 mg/kg body weight we observed necrosis of the stomach. No visible pathological findings were observed in animals dosed with 300 mg/kg body weight. All necropsy results are in Table 4.

Table 1. Clinical observation - 2000 mg/kg body weight, Animal No 1 - 3.

Observation

Time After Administration

Hour

Day

I

0.5

1

2

4

1

2

3

4

5

6

7

8

9

10

11

12

13

14

Skin and Hair**

-

1,2,3

1,2,3

1,2,3

1,2,3

3

-

-

-

-

-

-

-

-

-

-

-

-

-

Eyes

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

Mucosa

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

Respiratory

System*

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

Circulatory

System

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

CNS

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

Somatomotoric

Activity

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

Tremor

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

Spasms

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

Salivation

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

Diarrhoea

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

Lethargy

-

-

-

-

-

3

-

-

-

-

-

-

-

-

-

-

-

-

-

Sleep

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

Coma

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

Death

-

-

-

-

-

1,2

3

-

-

-

-

-

-

-

-

-

-

-

-

Sacrificed

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

Others

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-No observed signs, I - immediately. * - dyspnoe, ** - vein vasodilatation in hindlimb soles and tail

 

Summary of Table 1 observations

Sex

Dose

ID

Administration

 Result

Clinical Observation

2000 mg/kg

1

death

- piloerection ½ an hour after administration

- 1 day after: death of animal

2

death

- piloerection ½ an hour after administration

- 1 day after: death of animal

3

death

- piloerection ½ an hour after administration

- 1 day after: piloerection

- 2 days after: death of animal

 

Table 2. Clinical observation 300 mg/kg body weight, Animal No 4 - 9.

Observation

Time After Administration

Hour

Day

I

0.5

1

2

4

1

2

3

4

5

6

7

8

9

10

11

12

13

14

Skin and Hair**

-

4

7

4,5,6

7,8,9

4,5,6

7,8,9

4

8,9

8

-

-

-

-

-

-

-

-

-

-

-

-

-

Eyes

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

Mucosa

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

Respiratory

System*

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

Circulatory

System

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

CNS

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

Somatomotoric

Activity

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

Tremor

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

Spasms

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

Salivation

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

Diarrhoea

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

Lethargy

-

8

8

8,9

4

8,9

-

-

-

-

-

-

-

-

-

-

-

-

-

-

Sleep

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

Coma

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

Death

-

-

-

-

-

-

-

-

-

8

-

-

-

-

-

-

-

-

-

Sacrificed

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

Others

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-

-No observed signs, I - immediately. * - dyspnoe, ** - vein vasodilatation in hindlimb soles and tail

 

Summary of Table 2 observations

Sex

Dose

ID

Administration

Result

Clinical Observation

300

mg/kg

4

alive

piloerection was observed ½ an hour after administration and 2 hours later lethargy was observed which persisted for 2 hours

5

alive

piloerection was observed 1 hour after administration and persisted for 2 hours

6

alive

piloerection was observed 1 hour after administration and persisted for 2 hours

7

alive

piloerection was observed 1 hour after administration and persisted for 2 hours

8

death

- lethargy was observed ½ an hour after administration and persisted for 4 hours, piloerection was observed ½ an hour after administration and persisted for 24 hours

- 5 day after: death of animal

9

alive

piloerection was observed 1 hour after administration and persisted for 3 hours

 

Table 3. Body Weight

Sex

Dose

ID

Body Weight (g)

Body Weight Difference (g)

Initial

Week 1

Week 2

Week 1 - Initial

Week 2 - Initial

Week 2 - Week 1

2000 mg/kg

1

203

-

-

-

-

-

2

204

-

-

-

-

-

3

194

-

-

-

-

-

300 mg/kg

4

170

190

196

20

26

6

5

211

244

257

33

46

13

6

202

225

244

23

42

19

7

190

195

201

5

11

6

8

183

-

-

-

-

-

9

184

205

231

21

47

26

 

Table 4. NecropsyResults

Sex

Dose

ID

Result

2000 mg/kg

1

Empty gastrointestinal tract and excessive erythema of the liver and gastrointestinal tract.

2

Empty gastrointestinal tract and excessive erythema of the liver and gastrointestinal tract.

3

Autolytic changes

300 mg/kg

4

no findings

5

no findings

6

no findings

7

no findings

8

Fresh blood draining from the anus was observed and intestinal bleeding of the distal colon and rectum was found.

9

no findings

 

Interpretation of results:
Category 4 based on GHS criteria
Conclusions:
The LD50 of the test item 1,3-Diiodopropane is greater than 300 mg/kg and lower than 2000 mg/kg body weight after single oral administration to Wistar rats.
Based on Annex 2d Test Procedure with a Starting Dose of 2000 mg/kg body weight of OECD Guideline 423 it can be concluded that the test item 1,3-Diiodopropane is classified in GHS Category 4 with a LD50 cut off value 500 mg/kg body weight, after single oral administration to Wistar rats.
Executive summary:

The purpose of the study was to evaluate the potential toxic effect of the test item “1,3-Diiodopropane” when administered as a single oral dose to Wistar rats.

The procedure according to OECD Guideline 423 Acute Toxic Class (ATC) method was used and a limit dose of 2000 mg/kg body weight was used as a starting dose.

In the first step, one group of 3 females was dosed. The test item in limit dose caused mortality of all animals within 48 hours after administration. In a second step, 3 females were treated with dose of 300 mg/kg body weight. The test item in dose 300 mg/kg did not cause death and therefore another 3 females were treated at the same dose level.

The test item 1,3-Diiodopropane administered to 3 females Wistar rats at a limit dose of 2000 mg/kg did not cause immediate strong reaction, but rather slight piloerection after 30 min from administration and persisted till next day. 24 hours after administration two animals died. 48 hours following administration the third animal died. During necropsy we observed empty gastrointestinal tract and excessive erythema of the liver and gastrointestinal tract. No necrosis was observed.

The dose of 300 mg/kg of body weight caused death of animal No 8. No other death at this dose was observed. Animals manifested piloerection after 30 minutes from administration and lethargy was seen in animals No 4, 8, 9. During necropsy of animal No 8 fresh blood draining from the anus was observed and intestinal bleeding of the distal colon and rectum was found. No macroscopic findings were observed in surviving animals at this dose level.

The LD50 of the test item 1,3-Diiodopropane is greater than 300 mg/kg and lower than 2000 mg/kg body weight after single oral administration to Wistar rats.

Based on Annex 2d Test Procedure with a Starting Dose of 2000 mg/kg body weight of OECD Guideline 423 it can be concluded that the test item 1,3-Diiodopropane is classified in GHS Category 4 with a LD50 cut off value 500 mg/kg body weight, after single oral administration to Wistar rats.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
discriminating dose
Value:
500 mg/kg bw

Acute toxicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Acute toxicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Justification for classification or non-classification

Based on Annex 2d Test Procedure with a Starting Dose of 2000 mg/kg body weight of OECD Guideline 423 it can be concluded that the test item 1,3-Diiodopropane is classified in GHS Category 4 with a LD50 cut off value 500 mg/kg body weight, after single oral administration to Wistar rats.