Isopropylamine

Endpoint summary

Description of key information

LD50(oral, rat) <172 mg/kg bw (undiluted) / mean LD50(oral, rat) = 550 - 820 mg/kg bw (diluted in water or olive oil); 
mean LC50(inh., rat) = 8.7 mg/L;
LD50(dermal, rat) > 400 mg/kg bw (diluted, 10 % in water; no animal died at this dose which already was corrosive to the skin) and a LD50 (dermal, rabbit) of 378 mg/kg has been reported in rabbits.

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:

comparable to guideline study with acceptable restrictions

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 425 (Acute Oral Toxicity: Up-and-Down Procedure)

Deviations:

yes

Remarks:

only males tested; screening

GLP compliance:

not specified

Test type:

up-and-down procedure

Limit test:

no

Species:

rat

Strain:

Wistar

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: no data
- Age at study initiation: 3 - 4 wk
- Weight at study initiation: 90 -120 g
- Fasting period before study: unfasted
- Housing: no data
- Acclimation period: no data


ENVIRONMENTAL CONDITIONS: no data

Route of administration:

oral: gavage

Vehicle:

water

Details on oral exposure:

Application by gavage through a commercial ball-end needle attached to a calibrated syringe (page 153)

Doses:

no details, dose range with spacing factor 2

No. of animals per sex per dose:

5 males

Control animals:

not specified

Statistics:

Moving average method according to Thompson (1947) und Weil (1983)

Key result

Sex:

male

Dose descriptor:

LD50

Effect level:

< 0.25 mL/kg bw

Remarks on result:

other: undiluted

Key result

Sex:

male

Dose descriptor:

LD50

Effect level:

< 172 mg/kg bw

Remarks on result:

other: undiluted; transformation from volume (ml/kg bw) to mass (mg/kg bw) on the basis of a density of 0,6871 g/cm3

Key result

Sex:

male

Dose descriptor:

LD50

Effect level:

1.07 mL/kg bw

95% CL:

>= 0.72 - <= 1.59

Remarks on result:

other: 10% solution

Key result

Sex:

male

Dose descriptor:

LD50

Effect level:

ca. 735 mg/kg bw

95% CL:

>= 495 - <= 1 092

Remarks on result:

other: 10% solution; transformation from volume (ml/kg bw) to mass (mg/kg bw) on the basis of a density of 0,6871 g/cm3

Mortality:

Time to death: 7 min. - 4d (undiluted), 4h - 14d (10% solution)

Clinical signs:

other: lethargy, labored breathing, piloerection, prostration

Gross pathology:

lung hemorrhage; kidney and adrenal congestion; gastric and intestinal hemorrhage, ulceration
Most surviving animals were without significant gross pathology (page 163)

Interpretation of results:

Category 3 based on GHS criteria

Conclusions:

Under the conditions of this study, the LD50 in male rats was < 172 mg/kg bw

Executive summary:

Five male Wistar rats per group were gavaged with the test substance in doses spaced by a factor of 2 to derive LD50 values. The animals were kept for a 14 days observation period. Under the conditions of this study, the LD50 in male rats was < 172 mg/kg bw. Gross necropsy showed lung hemorrhage, kidney and adrenal congestion, gastric and intestinal hemorrhage and ulceration.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

172 mg/kg bw

Quality of whole database:

sufficient for evaluation

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:

guideline study

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

Qualifier:

according to guideline

Guideline:

EPA OTS 798.1150 (Acute inhalation toxicity)

GLP compliance:

yes

Test type:

standard acute method

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Breeding Laboratories, Inc., Raleigh, North Carolina, USA
- Age at study initiation: males 8 - 9 wk, females 10 - 11 wk
- Weight at study initiation: males: 242 g - 335g, females: 208g - 236g
- Housing: doubly housed during acclimation period, individually housed in Plexiglass chamber (100 L) during exposure
- Diet , water: ad libitum
- Acclimation period: 1 to 3 wk

ENVIRONMENTAL CONDITIONS during acclimation period
- Temperature (°C): 19 - 24°C
- Humidity (%): 40 - 70%
- Air changes (per hr): no data
- Photoperiod: 12hrs dark / 12hrs light)

ENVIRONMENTAL CONDITIONS during exposure
- Temperature (°C): 21 - 26°C
- Humidity (%): 46 - 65%
- Air flow rate: 20 L/min (= complete air change every 5 min)

Route of administration:

inhalation: vapour

Type of inhalation exposure:

whole body

Vehicle:

other: unchanged (no vehicle)

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Plexiglass exposure chamber with glass front
- Exposure chamber volume: 100 L
- Method of holding animals in test chamber: individually
- Source and rate of air: 20 L/min, the air exchange was about once per every 5 min.
- Method of conditioning air: by passing air through a midget impinger containing the TS
- System of generating particulates/aerosols:
- Temperature: actual 21-26°C
- Relative humidity: 64-65%
- pressure: no information given

TEST ATMOSPHERE
- Brief description of analytical method used: MIRAN Ambient Air Analyser; test atmosphere was drawn through Balston DFU filter via Teflon line into the Analyser
- Samples taken from breathing zone: yes (hourly sampling)

- Particle size measurements were performed at hourly intervals

Analytical verification of test atmosphere concentrations:

yes

Duration of exposure:

4 h

Concentrations:

5.3, 2.8, 5.1, and 6.5 mg/L (analytical) [7.1, 3.4, 5.9, and 7.2 mg/L (nominal)], no aerosol

The nominal concentration was calculated from the consumption of TS from the reservoir divided by the total amount of air.

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days; detailed observations once daily for survivers; Assessment of viability twice daily
- Necropsy of survivors performed: yes (at post-exposure day 15)
- Examinations of dead and surviving animals of nasal passages, trachea, orifices, cranial cavity, brain and spinal cord, viscera, cervical tissues and organs

Statistics:

Calculation of median lethal concentration, 95% CL (method according to Litchfield and Wilcoxon)

Key result

Sex:

male/female

Dose descriptor:

LC50

Effect level:

ca. 8.7 mg/L air (analytical)

95% CL:

>= 6.5 - <= 12

Exp. duration:

4 h

Key result

Sex:

male/female

Dose descriptor:

LC50

Effect level:

ca. 3 540 ppm

Exp. duration:

4 h

Remarks on result:

other: calculated from formula 1 ppm = 2.46mg/m^3

Key result

Sex:

female

Dose descriptor:

LC50

Effect level:

7.7 mg/L air (analytical)

Exp. duration:

4 h

Key result

Sex:

male

Dose descriptor:

LC50

Effect level:

ca. 9.4 mg/L air (analytical)

Exp. duration:

4 h

Mortality:

see table below

Clinical signs:

other: Labored breathing, lacrimation, nasal discharge, reduced activity, closed eyes. Respiratory distress and nasal discharge persisted the first week of post-exposure, but moist and dry rales were observed in most of the survivors throughout 14 d.

Body weight:

Transient losses were prominent.

Gross pathology:

Nasal tubinates and lungs were reddened and swollen with lung emphysema present in a few animals.

Group   Mean Exposure  Nominal [mg/L]        Mortality
  
    
    
    
    
    
    
    
    

tration   Concentration     No.dead/No.exposed























----------------------------------------------------------------
I*         5.3             7.1           5/5    2/5     7/10           
II         2.8             3.4           0/5    0/5     0/10
III        5.1             5.9           2/5    0/5     2/10
IV         6.5             7.2           1/5    2/5     3/10
 ================================================================
* Group I was excluded from evaluation due to technical problems 
  during exposure

The LD50 of 8.7 mg/L (95% C.I. = 6.5 - 12 mg/L) is the combined 
extrapolated value.  
 -----------------

Interpretation of results:

Category 3 based on GHS criteria

Conclusions:

Under the conditions of this study, the mean LC50 in male and female rats was 8.7 mg/L (8700 mg/m3)

Executive summary:

The study was designed to assess the acute inhalation toxicity (median lethal concentration). Groups of 5 rats per sex were exposed to 5.3, 2.8, 5.1, and 6.5 mg/L (analytical) [7.1, 3.4, 5.9, and 7.2 mg/L (nominal)] of test substance vapour for 4 h. The post-exposure observation period was 14 days. The LC50 for combined sexes was 8.7 mg/L. Clinical signs during exposure were laboured breathing, lacrimation, nasal discharge, reduced  activity, closed eyes. Respiratory distress and nasal discharge persisted  the first week of post-exposure, but moist and dry rales were observed in  most of the survivors  throughout 14 d. Significant body weight losses were evident following exposure, but recovery occured over time. No clear treatment-related postmortem findings were observed.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LC50

Value:

8 700 mg/m³ air

Quality of whole database:

sufficient for evaluation

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

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Deviations:

yes

Remarks:

only one dose level tested

GLP compliance:

yes

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: Animals of comparable weight (200 - 300 g)
- Housing: singly in stainless stell wire mesh cages, Type DK-III
- Diet: KLIBA-Labordiaet 343, Klingenthalmuehle AG, Switzerland, ad libitum
- Water: 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

Type of coverage:

semiocclusive

Vehicle:

other: aqua bidest

Details on dermal exposure:

TEST SITE
- Area of exposure: 50 cm2
- Type of wrap if used: Four layers of absorbent gauze


REMOVAL OF TEST SUBSTANCE
- Washing (if done): rinsing with warm water
- Time after start of exposure: 24 h


TEST MATERIAL
- Concentration (if solution): 10 %

Duration of exposure:

24 h

Doses:

400 mg/kg bw

No. of animals per sex per dose:

5

Control animals:

not specified

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Several times at the day of application and at least once daily therafter.
- Frequency of weighing: Shortly before application, weekly thereafter and at the end of the study
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 400 mg/kg bw

Based on:

act. ingr.

Remarks:

(10% dilution in water because of corrosivity)

Key result

Sex:

male/female

Dose descriptor:

LD0

Effect level:

400 mg/kg bw

Based on:

act. ingr.

Remarks:

(10% dilution in water because of corrosivity)

Mortality:

No mortality occurred.

Clinical signs:

other: On the day of application the animals showed the following syptoms: dyspnoea, apathy, staggering, spastic gait, tremor, piloerection, exophthalmos and poor general state.

Gross pathology:

Sacrificed animals:
Organs: no pathologic findings noted.
Skin: full thickness necrosis (4 males/4 females), superficial necrosis (1 female), superficial crust formation (1 male)

The acute dermal LD50 of the test material was found to be greater than 400 mg/kg bw for the male und female animals.

Interpretation of results:

GHS criteria not met

Conclusions:

Under the conditions of this study, the mean LD50 in male and female rats was > 400 mg/kg bw

Executive summary:

Acute dermal toxicity was investigate in male and female Wistar rats (5 animals per sex). Application of 400 mg/kg test item (applied as 10% dilution in water) for 24 hours under semi-occlusive conditions did not cause lethal effects. On the day of application animals showed dyspnoea, apathy, staggering, spastic gait, tremor, piloerection, exophthalmos and poor general state. The diluted test material caused full thickness necrosis in 4/4 females and 4/4 males.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

discriminating dose

Value:

400 mg/kg bw

Quality of whole database:

sufficient for evaluation

Additional information

Oral route

Undiluted isopropylamine administered by gavage to male Wistar rats (5 per group) resulted in an LD₅₀of <172 mg/kg bw, with deaths occurring between 7 minutes and 4 days (Myers and Ballantyne, 1997). Clinical signs included lethargy, labored breathing, piloerection and prostration. There were no significant findings in survivors at necropsy.

In another study, male and female rats (strain not specified) were administered a single gavage dose of 14, 55, 218, 346, 548, 869 or 3457 mg/kg bw isopropylamine (BASF, 1960). There was 1 rat exposed at 14 and 55 mg/kg bw; 5 rats exposed at 218 and 869 mg/kg bw; 10 rats exposed at 346 and 548 mg/kg bw and 2 rats exposed at 3457 mg/kg bw (sex not specified). Clinical signs were as follows by dose group: 3457 mg/kg bw: 1 animal showed 2 minute post-application dyspnea, convulsions, and gasping and the second animal showed intermittent respiration and slight abdominal position; at 869 mg/kg bw, staggering, slightly accelerated respiration, and slight abdominal position, followed on the next morning with lacrimation, ruffled fur, and blood crusted eyes; at 548 mg/kg bw, 24 hours post application showed ruffled fur; and at 346 mg/kg bw, intermittent respiration, blood crusted noses and ruffled fur. At necropsy, surviving animals dosed at 548 mg/kg bw group showed adhesion of the stomach with the peritoneum and fluffy-yellowish stomach content (residual test substance). The acute oral LD₅₀was 552 mg/kg bw (combined sexes).

Another study of sufficient reliability reported an oral LD50 of 820 mg/kg bw (range 670 -1070 mg/kg bw) isopropylamine in male rats (Smyth et al., 1951 and further publications).

Inhalation route

In a study conducted according to EPA OPPTS 798.1150 (Acute inhalation toxicity), groups of 5 male and 5 female Sprague-Dawley rats were exposed by whole body vapor inhalation for four hours to concentrations of 2.3, 2.8, 5.1, and 6.5 mg/L (measured) (Hoffman and Newton, 1990). Clinical signs included labored breathing, lacrimation, nasal discharge, reduced activity and closed eyes. Respiratory distress and nasal discharge persisted the first week post-exposure, but moist and dry rales were observed in most of the survivors throughout 14 d. Transient body weight losses were noted. At gross necropsy, the nasal turbinates and lungs were reddened and swollen with lung emphysema present in a few animals. Group I (5.3 mg/L) was excluded from evaluation due to technical problems during exposure. The acute inhalation LC₅₀was = 8.7 mg/L (combined sexes).

In a study performed similar to OECD Guideline 403, groups of 5 male and 5 female Charles River Crl:CD BR VAF/PLUS rats/group were exposed to isopropylamine for 6 min (13,700, 16,400, 16,600, 17,300 and 19,100 ppm); 20 min (5,180, 6,160, 7,050, 7,110, 8,060 and 9,580 ppm) or 60 min (2,750, 3,360, 4,200, 4,780, 4,810 and 5,090 ppm) by whole body vapor inhalation (IRDC, 1992). Death, gasping, labored breath, rales and corneal opacity was observed in all exposure groups. The 60 minute LC₅₀was 4770 ppm. Based on a molecular weight of 59.11, this value corresponds to 11,73 mg/L (at 20 °C). This data cannot be used for classification due to the short exposure duration.

Another study reported an inhalation LC50 of > 9.8 - < 19.6 mg isopropylamine/L air (Smyth et al., 1951 and further publications). No LC50 was calculated. However, the data point to a slightly higher LC50 than in the key study and are in agreement with the observations of the key study.

Dermal route

In a study conducted according to OECD Guideline 402 (Acute Dermal Toxicity) 5 male and 5 female Wistar rats were exposed for 24 hours to 400 mg/kg bw isopropylamine (purity 99.9%) with a semi-occlusive coverage (BASF AG, 1993). There were no mortalities. Clinical signs included dyspnea, apathy, staggering, spastic gait, tremor, piloerection, exophthalmos and poor general state. Body weights were not affected by treatment. There were no findings at necropsy except full skin thickness necrosis (4 males/4 females), superficial necrosis (1 female), and superficial crust formation (1 male). No LD₅₀ can be derived from this study (combined sexes) as no mortality occurred.

Another study reported a dermal LD50 of 378 mg/kg bw for isopropylamine (Smyth et al., 1951 and further publications) in 4 male rabbits. Exposure was for 24 h under occlusive conditions. No information on local effects were provided.

A further study reported a dermal LD50 > 1000 mg/kg bw (Bioresearch, 1975). However, the reliability of this data is restricted due to major methodological deficiencies.

The acute dermal study in rats (BASF, 1993), which was performed under GLP conditions, was selected as key study as a sufficient number of animals was exposed to a dose of 400 mg/kg of a high purity substance for 24 h under semi-occlusive conditions. No animal died under these conditions which already caused necrosis, therefore no testing of higher doses was possible. The results of the rabbit study, which was performed under occlusive conditions before GLP came into place and which revealed a LD 50 of 378 mg/kg bw/d, points to a classification for acute dermal toxicity Cat. 3. Taking into consideration the occlusive conditions in the rabbit study the results of both studies seem to be in good agreement. Therefore, in a conservative manner a classification for acute dermal toxicity Cat. 3 is suggested.

Justification for classification or non-classification

Based on the experimental findings and according to Regulation (EC) No 1272/2008 the substance should be classified for acute oral toxicity Category 3 after oral (H301), dermal (H311) and inhalation (H331) exposure.