Registration Dossier

Diss Factsheets

Administrative data

Description of key information

Single exposure (acute) studies indicate that EDIPA is harmful if swallowed (rat LD50 = 317), of low toxicity if absorbed through skin (rat LD0 > 2000 mg/kg), and toxic if inhaled (rat 4-hr LC50 = 2.63 mg/l)

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
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Comparable to Guideline study (GLP; ATC method, dose steps: 2000, 500 and 200 mg/kg bw, respectively, instead of 2000, 300 and 50 mg/kg bw.)
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Version / remarks:
EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method; Dec 29, 1992)
Deviations:
yes
Remarks:
dose steps: 2000, 500 and 200 mg/kg bw, respectively, instead of 2000, 300 and 50 mg/kg bw.
GLP compliance:
yes
Test type:
acute toxic class method
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: DR. K. THOMAE GMBH, Biberach, Germany
- Age at study initiation: young adult animals
- Weight at study initiation: 173 - 194 g (±20% of the mean weight)
- Fasting period before study: at least 16 h before administration, but water was available ad libitum
- Housing: single housing in stainless steel wire mesh cages, Type DK-III (Becker & Co., Castrop-Rauxel, FRG)
- Diet: KLIBA-LABORDIAET 343, Klingenthalmuehle AG, Kaiseraugst, Switzerland; ad libitum
- Water: tap water; ad libitum
- Acclimation period: at least 1 week


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24 °C
- Humidity (%): 30-70 %
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
oral: gavage
Vehicle:
olive oil
Remarks:
DAB 10
Details on oral exposure:
VEHICLE
- Justification for choice of vehicle: test substance is unsoluble in water
- Concentration in vehicle: 4.0, 10.0 and 40.0 g/100 ml, respectively for the low, mid and high dose groups
MAXIMUM DOSE VOLUME APPLIED: 5 ml

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: based on the physical and chemical characteristics of the test substance and its composition no pronounced acute oral toxicity was expected. Therefore a starting dose of 2000 mg/kg bw was chosen in a first step with 3 female animals. As all animals died, 500 mg/kg bw were used with 3 female animals in a second step. Because 100% mortality occurred, 200 mg/kg bw were tested in a third step with 3 female rats. Because no mortality occurred in this third step, 3 male animals were treated in a fourth step with the same dose (200 mg/kg bw).

Doses:
200, 500, 2000 mg/kg
No. of animals per sex per dose:
3 females (high and mid dose levels); 3 males and 3 females (low dose level)
Control animals:
no
Details on study design:
- Duration of observation period following administration: up to 14 days (depending on survival)
- Frequency of observations: clinical signs daily (several times on the day of administration, and at least once each workday); check for mortality and moribund animal twice each workday and once on Saturdays, Sundays and public holidays
- Frequency of weighing: day 0, 7 and 14
- Necropsy of survivors performed: yes; necropsy at the last day of the observation period. Withdrawal of food at least 16 hours before killing with CO2, then necropsy with gross-pathology examination. Necropsy of all animals that died before as early as possible.
- Other examinations performed: clinical signs, body weight
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 200 - < 500 mg/kg bw
Based on:
test mat.
Remarks on result:
other: no mortality occurred at 200 mg/kg bw (3 male and 3 female animals), whereas 100% mortality was observed at 500 and 2000 mg/kg bw (only females)
Sex:
male/female
Dose descriptor:
LD50
Effect level:
ca. 317 mg/kg bw
Based on:
test mat.
95% CL:
15 - 1 360
Remarks on result:
other: LD50 point estimate (re-calculated)
Mortality:
- 2000 mg/kg bw: all 3 animals died within 1 hour;
- 500 mg/kg bw: 1 animal died within 1 hour, the remaining 2 within 3 hours;
- 200 mg/kg bw: no mortality.
Clinical signs:
other: - 200 mg/kg: impaired general state (day 2), poor general state (hour 0-day 1), dyspnoea (hour 0-day 2), apathy (hour 0-day1), staggering (hour 0-hour 5), piloerection (hour 0-day 2) in all male animals. Poor general state, dyspnoea, apathy, staggering, t
Gross pathology:
Animals that died:
- 2000 mg/kg bw: glandular stomach: slight hyperemia of the glandular stomach, moderate erythema of the small intestine;
- 500 mg/kg bw: slight thickening of fore stomach and glandular stomach walls;
- 200 mg/kg bw (sacrificed animals): organs without particular findings.

Mortality:

 Dose (mg/kg bw)  Gender  1 h  3 h  14 days
 200  male  0/3  0/3  0/3
 200  female  0/3  0/3  0/3
 500  female  1/3  3/3  3/3
 2000  female  3/3  3/3 3/3

Weight (g):

 Dose (mg/kg)

 Gender  day 0  day 7  day 14      
 200  male  181 243 283      
 200  female  176 210  224     
 500  female 188   -      
 2000  female  177  -  -    

There is indication that the test substance causes local irritation to the exposed tissue.

Interpretation of results:
Category 4 based on GHS criteria
Conclusions:
The LD50 value is between 200 and 500 mg/kg and calculated to be 317 mg/kg bw.

.
Executive summary:

To assess the acute oral toxicity after a single oral administration of ethyldiisopropylamine, a GLP study according to the acute toxic class method was conducted.


None of the animals (0/6, m/f) died after administration of 200 mg/kg bw. However clinical symptoms of toxicity were observed (poor general state, dyspnoea, apathy, staggering, tremor and twitching). All animals (3/3, f) died after receiving a dose of 500 mg/kg or 2000 mg/kg bw. Clinical symptoms were the same as observed for the 200 mg/kg dose group. Necropsy of the animals that died revealed hyperemia of the gastro-intestinal tract pointing to the irritating/caustic properties of the test substance. The test substance was applied in olive oil, which might have influenced the resorption properties and necropsy findings of this caustic substance to some extend.  The LD50 value is between 200 and 500 mg/kg and calculated to be 317 mg/kg bw.


.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
317 mg/kg bw

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
Deviations:
yes
Remarks:
Due to failure of the TSE temperature-humidity sensor in the exposure system, the humidity was not measured during the animal exposures.
GLP compliance:
yes (incl. QA statement)
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Research Models and Services, Germany GmbH, Sandhofer Weg 7, D-97633 Sulzfeld
- Age at study initiation: 8-9 weeks old
- Weight at study initiation: 215 to 375 g (¿: 328-375g; ¿: 215-242g)
- Fasting period before study:
- Housing: Group of 5 (by sex) in type III solid floor cages with stainless steel mesh lids
- Diet: ssniff SM R/M-Z “Autoclavable Complete Feed for Rats and Mice – Breeding and Maintenance” (ssniff Spezialdiäten GmbH, D-59494 Soest Germany; Batch: 445 8440, Expiry: May 2013), ad libitum
- Water: tap water, ad libitum
- Acclimation period: At least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3
- Humidity (%): 30 – 70
- Air changes (per hr): 15-20
- Photoperiod (hrs dark / hrs light): 12/12h

IN-LIFE DATES: From: To: 12 March 2013-03 April 2013
Route of administration:
inhalation: vapour
Type of inhalation exposure:
nose only
Vehicle:
clean air
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: TSE Rodent Exposure System (TSE Systems GmbH, Bad Homburg, Germany). This system comprises of two, concentric anodised aluminium chambers and a computer control system incorporating pressure detectors and mass flow controllers.
- Method of holding animals in test chamber: The animals were held in polycarbonate restraint tubes located around the chamber which allowed only the animal’s nares to enter the exposure port.
- Source and rate of air: The flow of air through each port was at least 0.7 L/min. This flow rate was considered adequate to minimise re-breathing of the test atmosphere as it is about twice the respiratory minute volume of a rat.
- System of generating particulates/aerosols: The test item was aerosolised using a stainless steel concentric jet nebuliser (TSE Systems GmbH, Bad Homburg, Germany) located at the top of the exposure chamber. The rate of formulation use was controlled by a syringe pump. Compressed air was supplied by means of an oil-free compressor passed through a suitable filter system prior to introduction to the nebuliser.
- Method of particle size determination: The particle size of the test atmosphere was not determined due to the test item was evaporated and were non-condensing.
- Treatment of exhaust air:
- Temperature, humidity, O2 and CO2 in air chamber: monitored continuously and recorded every minute during each exposure period by the TSE-DACO monitoring system

TEST ATMOSPHERE
- Brief description of analytical method used: The test atmosphere was sampled at regular intervals during the exposure period. Samples were taken from an unoccupied exposure port (representing the animal’s breathing zone) by pulling a suitable, known volume (56 ml injected sample or 60 L direct sample) of test atmosphere by a 60 ml syringe and then the samples were analyzed using a calibrated Miran 1A CVF gas analyser containing a 5.64 L measuring loop and recorded by a TESTO 175-S2 Data Logger.
- Samples taken from breathing zone: yes

TEST ATMOSPHERE (if not tabulated)
- Particle size distribution: not relevant for vapours
- MMAD (Mass median aerodynamic diameter) / GSD (Geometric st. dev.): not relevant for vapours
Analytical verification of test atmosphere concentrations:
yes
Duration of exposure:
4 h
Concentrations:
0.48±00.7, 2.07±0.18, 4.34±0.52 and 9.16±0.72 mg/l (analytical conc.)
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
Morbidity/Mortality:
Animals were checked hourly during exposure, one hour after exposure and twice daily (early and late in the working day) during the 14-day observation period for morbidity and/or mortality.

Clinical Signs:
All animals were observed for clinical signs at hourly intervals during exposure, as soon as practically possible following removal from restraint at the end of exposure, one hour after exposure and subsequently once daily for fourteen days.

Bodyweight:
Individual bodyweights were recorded prior to treatment on the day of exposure (Day 0), on Days 1, 3, 7, 14 and at unscheduled deaths.

Necropsy:
At the end of the fourteen day observation period, the animals were euthanised by exsanguination under anaesthesia (RELEASE 300mg/ml) and gross macroscopic examination was performed. All animals were subject to a gross necropsy which included a detailed examination of the abdominal and thoracic cavities. Special attention was given to the respiratory tract for macroscopic signs of irritancy or local toxicity.
Statistics:
The four-hour LC50 values were calculated using SPSS software and a log/probit method.
Sex:
male/female
Dose descriptor:
LC50
Effect level:
2.63 mg/L air (analytical)
Based on:
test mat.
95% CL:
2.17 - 5.23
Exp. duration:
4 h
Sex:
male/female
Dose descriptor:
other: LOAEC
Effect level:
480 mg/m³ air (analytical)
Based on:
test mat.
Exp. duration:
4 h
Remarks on result:
other: Clinical signs of respiratory tract irritation, reversible within 24h and a slight body weight loss 24 hours after exposure
Mortality:
A single four hours nose-only exposure of Ethyldiisopropylamine to CRL: (WI) rats strain rat led to the death of 0/10, 1/10, 10/10 and 4/4 rats dosed at a concentration of 0.48, 2.07, 4.15 and 9.16 mg/L, respectively.
Clinical signs:
other: Wet fur was recorded both during and for several hours after exposure whilst fur staining on whole body was recorded on removal from restraint and persisted for several days. In addition, fur staining by the test item was detected during exposure and pers
Body weight:
In all surviving animals of groups 1 and 2, a slight to moderate body weight loss was observed 24 hours after exposure (-9.6% in males and -4.4% in females of group 1 and -25% in males and -14% in females of group 2). Normal bodyweight gain was noted thereafter during the observation period for the surviving animals, with the exception of one male and one female in group 2 where slight bodyweight loss was noted during the first week of the observation period.
Gross pathology:
Dark/red discoloration of the lungs recorded for 10/10 found dead rats at a concentration 4.15 mg/L, was considered to be potentially related to the administration of the test item.
In surviving animals dosed at 0.48 and 2.07 mg/L no macroscopic observations were seen at the termination on Day 14.

The mortality data are summarised as follows:

Group
Number

Mean Achieved
(mg/L)

Male Deaths

Female Deaths

Total Deaths

0.1

9.19

2/2

2/2

4/4

1

0.48

0/5

0/5

0/10

2

2.07

0/5

1/5

1/10

3

4.15

5/5

5/5

10/10

Interpretation of results:
Category 3 based on GHS criteria
Conclusions:
The acute inhalation median lethal concentrations (4hr LC50) (and 95% confidence limits) of Ethyldiisopropylamine, in Wistar CRL:(WI) strain rats, were calculated to be 2.63 (2.17 – 5.23) mg/L (all animals).
Executive summary:

This study was performed to assess the acute inhalation toxicity of ethyldiisopropylamine. The method used was designed to meet OECD guideline 403 (07 September 2009). Group 0.1 of two male and two female and groups 1 to 3 each of five female and five male CRL: (WI) Wistar rats were exposed for four hours using a nose-only exposure system to vapours of ethyldiisopropylamine. The exposure was followed by a fourteen day observation period. Vapour concentrations were measured using a calibrated Miran 1A CVF gas analyzer. Clinical observations and bodyweights were recorded throughout the study. At deaths and the end of the scheduled period the animals were sacrificed and subjected to a gross examinationpost mortem. No control group was used in this study. The exposure of rats to 0.48, 2.07, 4.15 and 9.19 mg/L Ethyldiisopropylamine led to the death of 0/10, 1/10, 10/10 and 4/4 rats, respectively. Wet fur and fur staining were commonly recorded on the day of exposure. These observations were considered to be related to the restraint and exposure procedures and, in isolation, were considered not to be biologically significant. Slight to severe laboured respiration was noted on day of exposure in the animals exposed to 0.48 mg/L. No clinical signs were recorded in these animals from the following day after exposure. At the concentration of 2.07 mg/L, one female died during the exposure. Slight to severe laboured and noisy respiration were noted for the exposed animals on day of exposure. In addition, sneezing, decreased activity, weak condition and eyes partially closed were observed in animals during and/or shortly after the exposure. In females, slight continues tremors and prostration were noted on Day 0. All clinical signs ceased in surviving animals from Day 3. All animals exposed to 4.15 and 9.19 mg/L died during the first two hours and the first hour of the exposure, respectively. In all surviving animals exposed to 0.48 and 2.07 mg/L, a slight to moderate body weight loss was observed 24 hours after exposure (-9.6% in males and -4.4% in females at 0.48mg/L and -25% in males and -14% in females at 2.07 mg/L). Normal bodyweight gain was noted thereafter during the observation period for the surviving animals, with the exception of one male and one female exposed to 2.07 mg/L, where slight bodyweight loss was noted during the first week of the observation period. Non collapsed lung was observed in dead animals from the sighting exposure dosed at 9.16 mg/L. Dark/red discoloration of the lungs recorded for 10/10 found dead rats at a concentration 4.15 mg/L, was considered to be potentially related to the administration of the test item. In surviving animals dosed at 0.48 and 2.07 mg/L no macroscopic observations were seen at the termination on Day 14. The acute inhalation median lethal concentrations (4hr LC50) (and 95% confidence limits) of ethyldiisopropylamine, in Wistar CRL:(WI) strain rats, were calculated to be:

All animals:            2.63 (2.17 – 5.23) mg/L

Male only:              2.96 (1.64 – 9.05) mg/L

Female only:           2.46 mg/L

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LC50
Value:
2 630 mg/m³ air
Quality of whole database:
Key study

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
12 March 2012 - 06 April 2012
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
Deviations:
no
GLP compliance:
yes (incl. QA statement)
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: breeder: Janvier, Le Genest-Saint-Isle, France
- Age at study initiation: approximately 8 weeks old on the day of treatment
- Mean body weight at study initiation: . the males had a mean body weight of 357 g (range: 349 g to 372 g) and the females had a mean body weight of 228 g (range: 224 g to 236 g)
- Fasting period before study: yes, during the night before treatment
- Housing: polycarbonate cages with stainless steel lids
- Diet: SSNIFF R/M-H pelleted diet (free access)
- Water: tap water filtered with a 0.22 µm filter (free access)
- Acclimation period: the animals were acclimated to the study conditions for a period of 5 days (females) or 8 days (males) before treatment.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 2°C
- Humidity (%): 50 ± 20%
- Air changes (per hr): approximately 12 cycles/hour of filtered, non-recycled air
- Photoperiod (hrs dark / hrs light): 12 h/12 h (7:00 - 19:00)

IN-LIFE DATES: 20 March 2012 to 06 April 2012.
Type of coverage:
other: hydrophilic gauze pad
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- Area of exposure: 10% of body surface, dorsal site
- Type of wrap if used: hydrophilic gauze pad + adhesive hypoallergenic aerated semi-occlusive dressing + restraining bandage

REMOVAL OF TEST SUBSTANCE
- Removal of dressing: 24h post-exposure
- Washing: at 24h post-exposure, with a moistened cotton pad

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2000 mg/kg
- Constant volume: no
- For solids, paste formed: not applicable
Doses:
2000 mg/kg/day.
No. of animals per sex per dose:
5 animals per dose.
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Clinical observations: frequently during the hours following treatment; then, at least once a day.
- Body weight: just before treatment on day 1; then on days 8 and 15.
- Necropsy of survivors performed: yes (macroscopic).
Sex:
male/female
Dose descriptor:
LD0
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No unscheduled deaths occurred during the study.
Clinical signs:
other: No clinical signs indicative of systemic toxicity were observed in any animal.
Gross pathology:
At necropsy, 14 days after dermal application of the test item to rats at 2000 mg/kg/day, no changes that could be related to treatment were observed.
Other findings:
Very slight to well-defined erythema was observed on the application site of all females and 4/5 males between days 2 and 5.
Scabs were recorded on the application site of 2/5 females and 4/5 males between days 3 and 13.

see Executive summary

Interpretation of results:
not classified
Conclusions:
The dermal LD0 of the test item, ETHYLDIISOPROPYLAMINE (EDIPA), was higher than 2000 mg/kg in rats.
Executive summary:

The potential toxicity of the test item, ETHYLDIISOPROPYLAMINE (EDIPA) was evaluated following a single dermal application to rats. The study was based on the OECD No. 402 (24th February 1987) and Commission Regulation (EC) (No. 440/2008, B.3, 30 May 2008) guidelines. The study was conducted in compliance with the principles of Good Laboratory Practice.

ETHYLDIISOPROPYLAMINE (EDIPA), was applied in its original form to the skin of five female then five male Sprague-Dawley rats at the dose-level of 2000 mg/kg. The application site was covered with a hydrophilic gauze pad for 24 hours. Each animal was observed at least once a day for mortality and clinical signs for 15 days. From day 2, any local reactions at the treatment site were also noted. Body weight was recorded on day 1 and then on days 8 and 15. On completion of the observation period, the animals were sacrificed and then submitted for a macroscopic post-mortem examination. No tissues were preserved. Macroscopic lesions were preserved and no microscopic examination was performed.

No unscheduled deaths occurred during the study. No clinical signs indicative of systemic toxicity were observed in any animal. Lower body weight gain was recorded in 2/5 females and all males during the first week of observation period, and in 1/5 male during the last week of observation period. Very slight to well-defined erythema was observed on the application site of all females and 4/5 males between days 2 and 5.

Scabs were recorded on the application site of 2/5 females and 4/5 males between days 3 and 13. At necropsy, 14 days after dermal application of the test item to rats at 2000 mg/kg/day, no changes that could be related to treatment were observed.

The dermal LD0 of the test item, ETHYLDIISOPROPYLAMINE (EDIPA), was higher than 2000 mg/kg in rats.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
discriminating dose
Value:
2 000 mg/kg bw

Additional information

Acute oral toxicity

To assess the acute oral toxicity after a single oral administration of ethyldiisopropylamine, a GLP study according to the acute toxic class method was conducted (BASF, 1997). None of the animals (0/6, m/f) died after administration of 200 mg/kg bw. However clinical symptoms oftoxicity were observed (poor general state, dyspnoea, apathy, staggering, tremor and twitching).All animals (3/3, f) died after receiving a dose of 500 mg/kg or 2000 mg/kg bw. Clinical symptoms were the same as observed for the 200 mg/kg dose group. Necropsy of the animals that died revealed hyperemia of the gastro-intestinal tract pointing to the irritating/caustic properties of the test substance. The test substance was applied in olive oil, which might have influenced the resorption properties and necropsy findings of this caustic substance to some extend. The LD50 value is between 200 and 500 mg/kg and calculated to be 317 mg/kg bw.

The acute oral toxicity of ethyldiisopropylamine (EDIPA) was evaluated in rats according to OECD no. 423 guideline. 100% mortality was observed for 2000 mg/kg group on day 1; after administration animals showed hypoactivity, piloerection, dyspnea prior to death. After administration of 200 mg/kg, hypoactivity and piloerection, together with tremors and dyspnea in females were observed in all animals on day 1. Recovery was complete on day 2. Under these experimental conditions, the oral LD50 of the test item in rat is between 200 and 2000 mg/kg (Klein 2004).

 

Acute inhalation toxicity

 

A study was performed to assess the acute inhalation toxicity of ethyldiisopropylamine (Nagy, 2013). The method used was designed to meet OECD guideline 403 (07 September 2009). Group 0.1 of two male and two female and groups 1 to 3 each of five female and five male CRL: (WI) Wistar rats were exposed for four hours using a nose-only exposure system to vapours of ethyldiisopropylamine. The exposure was followed by a fourteen day observation period. Vapour concentrations were measured using a calibrated Miran 1A CVF gas analyzer. Clinical observations and bodyweights were recorded throughout the study. At deaths and the end of the scheduled period the animals were sacrificed and subjected to a gross examinationpost mortem. No control group was used in this study. The exposure of rats to 0.48, 2.07, 4.15 and 9.19 mg/L Ethyldiisopropylamine led to the death of 0/10, 1/10, 10/10 and 4/4 rats, respectively. Wet fur and fur staining were commonly recorded on the day of exposure. These observations were considered to be related to the restraint and exposure procedures and, in isolation, were considered not to be biologically significant. Slight to severe laboured respiration was noted on day of exposure in the animals exposed to 0.48 mg/L. No clinical signs were recorded in these animals from the following day after exposure. At the concentration of 2.07 mg/L, one female died during the exposure. Slight to severe laboured and noisy respiration were noted for the exposed animals on day of exposure. In addition, sneezing, decreased activity, weak condition and eyes partially closed were observed in animals during and/or shortly after the exposure. In females, slight continues tremors and prostration were noted on Day 0. All clinical signs ceased in surviving animals from Day 3. All animals exposed to 4.15 and 9.19 mg/L died during the first two hours and the first hour of the exposure, respectively. In all surviving animals exposed to 0.48 and 2.07 mg/L, a slight to moderate body weight loss was observed 24 hours after exposure (-9.6% in males and -4.4% in females at 0.48mg/L and -25% in males and -14% in females at 2.07 mg/L). Normal bodyweight gain was noted thereafter during the observation period for the surviving animals, with the exception of one male and one female exposed to 2.07 mg/L, where slight bodyweight loss was noted during the first week of the observation period. Non collapsed lung was observed in dead animals from the sighting exposure dosed at 9.16 mg/L. Dark/red discoloration of the lungs recorded for 10/10 found dead rats at a concentration 4.15 mg/L, was considered to be potentially related to the administration of the test item. In surviving animals dosed at 0.48 and 2.07 mg/L no macroscopic observations were seen at the termination on Day 14. The acute inhalation median lethal concentrations (4hr LC50) (and 95% confidence limits) of ethyldiisopropylamine, in Wistar CRL:(WI) strain rats, were calculated to be 2.63 (2.17 – 5.23) mg/L (all animals).

 

Acute dermal toxicity

 

The potential toxicity of the test item, ethyldiisopropylamine (EDIPA) was evaluated following a single dermal application to rats (Gerbeix, 2012). The study was based on the OECD No. 402 (24th February 1987) and Commission Regulation (EC) (No. 440/2008, B.3, 30 May 2008) guidelines. The study was conducted in compliance with the principles of Good Laboratory Practice. Ethyldiisopropylamine, was applied in its original form to the skin of five female then five male Sprague-Dawley rats at the dose-level of 2000 mg/kg. The application site was covered with a hydrophilic gauze pad for 24 hours. Each animal was observed at least once a day for mortality and clinical signs for 15 days. From day 2, any local reactions at the treatment site were also noted. Body weight was recorded on day 1 and then on days 8 and 15. On completion of the observation period, the animals were sacrificed and then submitted for a macroscopicpost-mortemexamination. No tissues were preserved. Macroscopic lesions were preserved and no microscopic examination was performed. No unscheduled deaths occurred during the study. No clinical signs indicative of systemic toxicity were observed in any animal.Lower body weight gain was recorded in 2/5 females and all males during the first week of observation period, and in 1/5 male during the last week of observation period.Very slight to well-defined erythema was observed on the application site of all females and 4/5 males between days 2 and 5. Scabs were recorded on the application site of 2/5 females and 4/5 males between days 3 and 13. At necropsy, 14 days after dermal application of the test item to rats at 2000 mg/kg/day, no changes that could be related to treatment were observed. The dermal LD0of ethyldiisopropylamine, was higher than 2000 mg/kg in rats.


Justification for selection of acute toxicity – oral endpoint
Key study

Justification for selection of acute toxicity – dermal endpoint
Key study

Justification for classification or non-classification

Acute oral toxicity:


The oral LD50of EDIPA was 317 mg/kg in rats. On the basis of this study and in accordance with Regulation (EC) No 1272/2008 and with Annex VI of Commission Directive 2001/59/EC, EDIPA shall be classified as Acute Tox. 4 (Hazard statement: H302; Harmful if swallowed).


Acute inhalation toxicity:


The 4 -h LC50 of EDIPA was 2.63 mg/L in rats. On the basis of this study and in accordance with Regulation (EC) No 1272/2008, EDIPA shall be classified as Acute Tox. 3 (Hazard statement: H331.Toxic if inhaled).


Acute dermal toxicity:


The percutaneous LD0 of EDIPA was higher than 2000 mg/kg in rats. On this basis and in accordance with Regulation (EC) No 1272/2008 no classification is warranted.