Reaction products of propane-1,2-diamine with 2-[(2-methylphenoxy)methyl]oxirane

Endpoint summary

Description of key information

The acute oral LD50 was determined to be between 300 mg/kg bw and 2000 mg/kg bw in 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:

2015-11-10 to 2016-01-26

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:

2001

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)

Version / remarks:

2008

Deviations:

no

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1100 (Acute Oral Toxicity)

Version / remarks:

2002

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:

TEST ANIMALS
- Source: Toxi-Coop Zrt. 1103 Budapest, Cserkesz u. 90
- Age at study initiation: 11 weeks old in group 1, group 2 and group 3
- Weight at study initiation: 223-226 g (first step), 221-225 g (second step), 210-233 g (third step)
- Fasting period before study: The day before treatment, food but not water was withheld overnight.
- Housing: 3 animals/sex/cage in type II polypropylene/polycarbonate cages
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 26 days in first step, 27 days in second step and 28 days in third step

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3
- Humidity (%): 30 - 70
- Air changes (per hr): above 10 air exchanges by central air-condition system.
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

oral: gavage

Vehicle:

other: sunflower oil (Helianthi annui oleum raffinatum)

Details on oral exposure:

VEHICLE
- Concentration in vehicle: The test item was applied in a concentration of 200 and 30 mg/mL.

MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg bw

CLASS METHOD
- Rationale for the selection of the starting dose: The starting dose was selected on the basis of the available information about the test item.

Doses:

2000 and 300 mg/kg bw

No. of animals per sex per dose:

3 females

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: The body weight were recorded on day 0 (shortly before the treatment), on day 7 and on day 15 on all animals. Animals were observed individually after dosing once during the first 30 minutes, then 1 h, 2 h, 3 h, 4 h, after the treatment and once per day for 14 days thereafter.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight

Statistics:

NA

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

>= 300 - <= 2 000 mg/kg bw

Based on:

test mat.

Mortality:

All female rats dosed at 2000 mg/kg bw of the test item died on the treatment day. Animal No.: 290 died 1 hour after the treatment, animal No.: 287 died 2 hours after the treatment and animal No.: 289 died 3 hours after the treatment, as well. No death occurred at 300 mg/kg bw single oral dose of the test item. All rats in step 2 and step 3 survived until the end of the 14-day observation period.

Clinical signs:

other: In group 1 treated with 2000 mg/kg bw dose clinical sign of reaction comprised of decreased activity (8 cases out of 8 observations), prone position (6/8), incoordination (6/8), crouching (5/8), closed eyes (7/8), decreased body temperature (5/8), vocaliz

Gross pathology:

All rats treated with 2000 mg/kg bw dose of the test item spontaneously died during the study. External pathological change as rectal periphery contaminated with thin faeces was found in animal No.: 287. Internal pathological change as red alteration on the mucous membrane of stomach and intestines was found in two animals (No.: 287, 290), as well as slight haemorrhages in the mucous membrane of stomach and intestines was recorded in animal No.: 289. These macroscopic changes observed were related to the effect of the test item.
All animals treated with 300 mg/kg bw dose of test item survived until the scheduled necropsy on Day 15. Moderate hydrometra was found in female No.: 309 of the group 2. Hydrometra is physiological finding and connected to the cycle of the animal. No pathological changes were found related to the effect of the test item during the macroscopic examination of animals of group 2 and 3 (300 mg/kg bw).

Interpretation of results:

Category 4 based on GHS criteria

Conclusions:

The test item was examined for its acute oral toxicity in rats according to OECD guideline 423. The LD50 was determined to be between 300 mg/kg bw and 2000 mg/kg bw.

Executive summary:

An acute oral toxicity study was carried out using the class method according to OECD guideline 423. The method was conducted using a stepwise procedure with the use of 2000 mg/kg bw as the starting dose in three female rats. The starting dose was selected on the basis of the available information about the test item. Since three female animals died the test was continued at 300 mg/kg bw dose level on further three female rats. No animal died in the second step at 300 mg/kg bw dose level, three further female rats were treated with the same (300 mg/kg bw) dose. No animal died in the third step, too, so the test was finished, the stopping criteria of Annex 2d of OECD Guideline No. 423 were met. Animals were weighed, observed for lethality and toxic symptoms for 14 days after the treatment. Gross pathological examination was carried out in animals died on the treatment day, as well as 15th day after the treatment in survivor animals.

All of three animals treated with 2000 mg/kg bw of the test item died on the treatment day. One animal died 1 hour after the treatment, one animal died 2 hours after the treatment and one animal died 3 hours after the treatment, as well. No lethality was noted at single oral dose of 300 mg/kg bw. In the first step at a dose level of 2000 mg/kg bw, CNS - and emotion symptom (decreased activity, crouching, closed eyes, vocalisation, tonic convulsion, clonic convulsion), decreased reflex- and muscular tension (righting reflex, grip- and limb tone), disturbances of the coordination (prone position, incoordination, abnormal gait) and disturbances of the autonomic functions (decreased body temperature, piloerection, dyspnoea) were observed in animals on the treatment day between 30 minutes and 3 hours after the treatment. In the second and third step at a dose level of 300 mg/kg bw no clinical symptoms were observed on the day of the treatment and during the 14-day observation period, the general state and behaviour of experimental animals were normal. The body weight development was normal in all survivor animals. Altogether 3 animals died, and 6 animals were sacrificed scheduled during the study. External finding as rectal periphery contaminated with thin faeces and internal findings as red alteration on the mucous membrane of stomach and intestines and slight haemorrhages in the mucous membrane of stomach and intestines were recorded in animals treated with 2000 mg/kg bw dose. These alterations were connected with the test item effect. All organs of the animals treated with 300 mg/kg bw dose proved to be free of treatment related gross pathological changes.

The method used is not intended to allow for the calculation of a precise LD50 value. However for this acute oral toxicity study with the test item in rats the determined LD50 is between 300 and 2000 mg/kg bw.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

discriminating dose

Value:

300 mg/kg bw

Quality of whole database:

GLP-conform study according to guideline.

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

An acute oral toxicity study was carried out using the class method according to OECD guideline 423. The method was conducted using a stepwise procedure with the use of 2000 mg/kg bw as the starting dose in three female rats. The starting dose was selected on the basis of the available information about the test item. Since three female animals died the test was continued at 300 mg/kg bw dose level on further three female rats. No animal died in the second step at 300 mg/kg bw dose level, three further female rats were treated with the same (300 mg/kg bw) dose. No animal died in the third step, too, so the test was finished, the stopping criteria of Annex 2d of OECD Guideline No. 423 were met. Animals were weighed, observed for lethality and toxic symptoms for 14 days after the treatment. Gross pathological examination was carried out in animals died on the treatment day, as well as 15th day after the treatment in survivor animals.

All of three animals treated with 2000 mg/kg bw of the test item died on the treatment day. One animal died 1 hour after the treatment, one animal died 2 hours after the treatment and one animal died 3 hours after the treatment, as well. No lethality was noted at single oral dose of 300 mg/kg bw. In the first step at a dose level of 2000 mg/kg bw, CNS - and emotion symptom (decreased activity, crouching, closed eyes, vocalisation, tonic convulsion, clonic convulsion), decreased reflex- and muscular tension (righting reflex, grip- and limb tone), disturbances of the coordination (prone position, incoordination, abnormal gait) and disturbances of the autonomic functions (decreased body temperature, piloerection, dyspnoea) were observed in animals on the treatment day between 30 minutes and 3 hours after the treatment. In the second and third step at a dose level of 300 mg/kg bw no clinical symptoms were observed on the day of the treatment and during the 14-day observation period, the general state and behaviour of experimental animals were normal. The body weight development was normal in all survivor animals. Altogether 3 animals died, and 6 animals were sacrificed scheduled during the study. External finding as rectal periphery contaminated with thin faeces and internal findings as red alteration on the mucous membrane of stomach and intestines and slight haemorrhages in the mucous membrane of stomach and intestines were recorded in animals treated with 2000 mg/kg bw dose. These alterations were connected with the test item effect. All organs of the animals treated with 300 mg/kg bw dose proved to be free of treatment related gross pathological changes.

The method used is not intended to allow for the calculation of a precise LD50 value. However for this acute oral toxicity study with the test item in rats the determined LD50 is between 300 and 2000 mg/kg bw.

Justification for classification or non-classification

Classification, Labelling, and Packaging Regulation (EC) No 1272/2008

The available experimental test data are reliable and suitable for classification purposes under Regulation (EC) No 1272/2008. As a result the substance is considered to be classified as acute oral toxicity category 4 and labelled with H302 (Harmful if swallowed.), as amended for the fifteenth time in Regulation (EU) 2020/1182.