Ethyl [2-(4-phenoxyphenoxy)ethyl]carbamate

Endpoint summary

Description of key information

- Oral: LD50 > 10000 mg/kg bw, males/females, rat, according to OECD TG 401, Ullmann, 1982

- Inhalation: LC50 > 4434 mg/m3, males/female, rat, according to OECD TG 403, Hartmann 1992

- Dermal: LD50 > 2000 mg/kg bw, males/females, rat, equivalent to OECD TG 402, Kynoch 1981

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:

10 Mar 1982 to 31 Mar 1982

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Version / remarks:

May 1981

Qualifier:

according to guideline

Guideline:

EPA OPP 81-1 (Acute Oral Toxicity)

Version / remarks:

Aug 1978

GLP compliance:

yes

Test type:

standard acute method

Limit test:

no

Species:

rat

Strain:

Wistar

Remarks:

KFM-HAN

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: approximately 9 weeks
- Weight at study initiation: 198 - 234 g for males and 173 – 206 g for females
- Diet: Ad libitum (defined for acceptable contaminant levels)
- Water: tap water ad libitum (Quality according to the requirements of the Schweiz, lebensmittelbuch)
- Acclimation period: 1 week under test conditions

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 2
- Humidity (%): 55 ± 10
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: 10 Mar 1982 to 31 Mar 1992

Route of administration:

oral: gavage

Vehicle:

polyethylene glycol

Remarks:

PEG 400

Details on oral exposure:

VEHICLE
- Amount of vehicle: 20 mL/kg bw

Doses:

3000, 5000, 8000 and 10000 mg/kg

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Animals were observed five times at day 1 and than daily for the nature onset severity and duration of all gross or visible toxic or pharmacological effects as well as rare and time of death.
- The animals were weighed at the day of dosing and day 7 and 14 after the administration.
- All test animals were subjected to a complete necropsy following their sacrifice or spontaneous death. All organs abnormalities were recorded. From the following organ of all animals histopathological evaluation was made: heart, lung, liver, kidneys, spleen.

Statistics:

The Logit Model could not be applied to the observed rates of death. The LD50 was estimated without use of a statistic model.

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 10 000 mg/kg bw

Based on:

test mat.

Mortality:

2/5 females given 10000 mg/kg bw were found dead on day 2 after treatment. No further mortality occurred.

Clinical signs:

other: In all dose groups, rats showed sedation, dyspnoea, ventral or curved body position, latero-abdominal position, diarrhoea and ruffled fur. Rats given 5000 mg/kg or higher doses showed exophtalmos and slight spasms. Rats given 8000 and 10000 mg/kg showed s

Gross pathology:

In all dose groups, lesions in the lungs, liver and kidney were noted which are commonly seen in rats of this strain and age. Splenic haemopoiesis was seen in nearly all animals. Gastric ulcer was noted in one high-dose male. In the two females that died during the study, slight to moderate unicellular and multicellular necrosis of the liver was observed.

Other findings:

SYMPTOMS
The main symptoms observed in the different dose groups were:
3000 mg/kg bw: sedation, dyspnoea ventral-, latero-abdominal-, curved body position, diarrhoea ruffled fur.
5000 mg/kg bw: sedation, dyspnoea, exophthalmos, ventral-, latero­ abdominal- curved body position, spasms, diarrhoea ruffled fur.
8000 mg/kg bw: sedation, coma, dyspnoea, exophthalmos, ventral-, latero-abdominal-, curved body position, spasms, tremor, diarrhoea, ruffled fur.
10000 mg/kg bw: sedation, dyspnoea, exophthalmos, latero-abdominal, curved body position, spasms, tremor, loss of weight, diarrhoea ruffled fur.
 The above mentioned symptoms were more pronounced in the higher dose groups. The surviving animals had recovered within 7 to 9 observation days.
 
NECROPSY
In two high-dose animals that died two days after the application, slight to moderate, unicellular and multicellular necrosis was noted in the liver.
Gastric ulcer was noted in one high-dose male.
Splenic haemopoiesis was noted in most animals of all groups,
A few other lesions observed in this study are commonly seen in rats of this strain and age.

Interpretation of results:

GHS criteria not met

Conclusions:

The acute oral LD50 of the test substance was found to be greater than 10000 mg/kg bw in both male and female rats.

Executive summary:

Groups of 5 male and 5 female Wistar KFM-HAN rats received a single oral dose of 3000, 5000, 8000 and 10000 mg/kg bw of the test substance in a study performed according to OECD TG 401 following GLP principles. The animals were assessed daily for the following 14 days for any signs of systemic toxicity and their body weights were recorded at intervals throughout the study. All animals were subjected to a complete gross necropsy following their sacrifice or spontaneous death.

The following death rates were observed: 0 % at 3000 mg/kg bw, 0 % at 5000 mg/kg bw, 0 % at 8000 mg/kg bw and 20 % at 10000 mg/kg bw.

The acute oral LD50 of the test substance in rats of both sexes observed over a period of 14 days was estimated to be greater than 10000 mg/kg bw.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

discriminating dose

Value:

> 10 000 mg/kg bw

Quality of whole database:

GLP compliant OECD TG 401 study

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

Study period:

05 Dec 1991 to 19 Dec 1991

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

Version / remarks:

May 1981

GLP compliance:

yes

Test type:

traditional method

Limit test:

yes

Species:

rat

Strain:

other: Tif: RAI f (SPF) hybrids of RII/1 x RII/2

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Weight at study initiation: 193 to 218 g
- Housing: Group of 5 (by sex); Macrolon cages, Type 4 with standardised soft wood bedding
- Diet: Rat diet, ad libitum.
- Water: ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3
- Humidity (%): 55 ± 10
- Air changes (per hr): approximately 15
- Photoperiod (hrs dark / hrs light): 12 / 12

IN-LIFE DATES: From: 05 Dec 1991 To: 19 Dec 1991

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

nose only

Vehicle:

other: ethanol

Mass median aerodynamic diameter (MMAD):

>= 0.9 - <= 1.2 µm

Geometric standard deviation (GSD):

>= 2.6 - <= 3.4

Remark on MMAD/GSD:

In of the vicinity of the animals, 93 to 97% of the airborne particle mass had a diameter smaller than 7 µm.

Details on inhalation exposure:

INHALATION EXPOSURE
CHAMBER
All exposures were conducted in a nose—only exposure stem developed by a research centre and built from stainless steel by the testing facility. The chamber was designed to ensure a rapid equilibration (internal active volume less than one litre) and a uniform exposure of all animals in the system. In order to avoid rebreathing of the exhaled air, "fresh" test substance (in first—pass chamber air) was supplied to each animal via individual delivery and exhaust tubes. In addition to the necessary animal and sampling ports, identical "void" outlets were opened in proportion to the total air flow through the chamber. Thus the flow in any individual aerosol delivery tube was standardised to 2 L/min (velocity 1.25 m/s).

For the inhalation period, the rats were placed in Macrolon animal holders positioned radially around the exposure chamber, so that only the snouts and nostrils of the animals Were exposed to the aerosol. The chamber was maintained at an exactly balanced pressure to prevent leakage of the test atmosphere from the system, as well as dilution with outside air. The exhaust air was decontaminated by subsequent passage through a Pall HDC absolute filter.

AEROSOL
As a solid aerosol (dust) could not be generated from the test article with our equipment, CGA 114597 tech. had to be dissolved in a vehicle to help generate an appropriate concentration in the inhalation atmosphere. Preliminary experiments showed that a 10 % (w/w) solution of test substance tech. in ethanol was suitable for this purpose. For liquefaction the test substance has to be heated up to 60 °C. overnight in a drying kiln.
The aerosol was generated in two pneumatic nebulizers arranged in parallel with a small aspirating reservoir (1 - 2 mL) and an attached bulk fluid container (to keep solvent evaporation to a minimum). The nebulizers were operated at 10 and 10 L/min (input pressure 100 and 120 kPa), respectively, and the aerosol was diluted with filtered humidified air to yield a total flow of 32 L/min. Coarse particles were removed from the aerosol by means of a glass cyclone. The throughput of the test material solution was determined by weighing the nebulizers, reservoirs, and cyclone, before and after aerosol generation.
The control animals were exposed to an inhalation atmosphere of ethanol (61879 mg/m3) under the same conditions as described above, with a vehicle throughput similar to the value used in the generation of the test aerosol (air flow 32 L/min, input pressure 91 and 92 kPa).

ANALYSIS OF INHALATION ATMOSPHERES
The air flow through the chamber was measured with flow meters. Adjustments to maintain a total flow of 32 L/min could be made with needle valves. However, no deviations were observed in any of the exposures, once the equilibrium was reached (within the first 10 minutes after beginning of exposure).
The aerosol concentration in the chamber was determined gravimetrically 5 times during the exposure period. Samples of the test atmosphere (1 L) were passed through a GF 92 filter. The air flow rate for the sample collection was kept constant (2 L/min) by means of a constant flow air sampler, regardless of filter loading. After sampling, an equal amount of clean air was aspirated through the filter to remove possible remnants of the volatile solvent. In a separate set of control experiments, the remaining contribution of adsorbed solvent was found.to be negligible. The mean and standard deviation of the resulting aerosol concentrations for the exposure was calculated.
Particle size analysis was conducted four times during the exposure, using an eight—stage cascade impactor, equipped with collection substates punched from regenerated cellulose filters. The air flow rate for the measurements was adjusted to 2 L/min by means of a constant flow air sampler. The amount of particles in the eight size classes was determined gravimetrically.

The following environmental parameters inside the inhalation chamber were monitored at approximately the same intervals as the concentration determinations:
- Temperature
- Relative humidity
- Oxygen content

Analytical verification of test atmosphere concentrations:

yes

Duration of exposure:

4 h

Concentrations:

4434 mg/m3 (actual concentration)

No. of animals per sex per dose:

5

Control animals:

yes

Details on study design:

OBSERVATIONS
MORBIDITY/MORTALITY
The animals were examined for clinical symptoms and mortalities during and after the exposure, as well as daily thereafter for 14 days.

BODY WEIGHTS
Body weights were recorded immediately prior to exposure and on days 7 and 14 of the observation period.

GROSS PATHOLOGY
Examinations were performed on all animals, which were killed after 14 days by ether anaesthesia. Particular attention was given to the respiratory tract.

Statistics:

The body weights of the treated animals and the controls were compared by analysis of variance.

Key result

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 4 434 mg/m³ air (analytical)

Based on:

test mat.

Exp. duration:

4 h

Mortality:

No mortality was observed.

Clinical signs:

other: All test substance treated animals showed symptoms of piloerection, hunched posture, dyspnoea and reduced locomotor activity. These findings disappeared within 4 days

Body weight:

In the test substance exposed animals, mean body weight gain was reduced significantly in males and females on day 7, and was normal again on day 14.

Gross pathology:

No treatment-related macroscopic observations were seen. No exposure-related deviations from normal morphology could be detected.

Table 1 Exposure atmospheres

Exposure group	1	2
Exposure day	06Dec 1991	05Dec 1991
Mean exposure concentration(mg/m3)	61879 *	6321
Mean exposure concentration ± SD**		4434 162
Mass median aerodynamicdiameter (MMAD) (µm) Geometric standard dev.(GSD) Particles < 7 µm (% w/w) Particles<3 µm (% w/w)		0.9-1.2 2.6-3.4 93-97 77-86
Air flow (L/min) through generator 19 20 — through chamber	19 32	20 32
Mean chamber temperature (°C)  ± SD Mean relative humidity (%) ± SD Mean oxygen content (%) ± SD	21.6 0.2 55 1 21.0 0.0	22.5 0.2 50 1 21.0 0.0

*Vehicle control: ethanol

**After sampling, an equal amount of clean air was aspirated through the filter to remove possible remnants of the volatile solvent.

Table 2 In-life observations

Observations

Exp day

de

ae

1

2

3

4

5

6

7

8

9

>9

Control males

++

+

piloerection

+

hunched post.

+

dyspnea

+

red.loc.act

+

Test substanceexposed males

piloerection

++

+

+

hunched post.

++

+

+

dyspnea

+

++

+

+

+

red.loc.act

+

Control females

piloerection

++

+

hunched post.

+

dyspnea

+

red.loc.act

+

Test substanceexposedfemales

piloerection

++

+

+

+

hunched post.

++

+

+

dyspnea

+

++

+

+

red.loc.act

+

Exp day = exposure day

de = during exposure; ae = after exposure

+- slight; ++ = moderate +++ = marked;

hunched post.= hunched posture; red.loc.act. = reduced locomotor activity

Interpretation of results:

GHS criteria not met

Conclusions:

The acute inhalation LC50 of the test substance in rats was found to be greater than 4434 mg/m3 for both males and females.

Executive summary:

The acute inhalation toxicity of the test substance was evaluated in groups of 5 male and 5 female Tif:RAI rats in accordance with OECD TG 403 following GLP principles. The animals were examined for clinical symptoms and mortalities during and after the exposure, as well as daily thereafter for 14 days. Body weights were recorded immediately prior to exposure and on days 7 and 14 of the observation period. Examinations were performed on all animals, which were killed after 14 days by ether anaesthesia. Particular attention was given to the respiratory tract.  

Upon a four hour acute inhalation exposure and a 14 days post-treatment observation period, no mortalities were elicited by the test substance at a concentration of 4434 mg/m3. Due to the properties of the test material, it was not possible to generate higher concentrations of test substance. The exposure to the maximum attainable concentration was thus considered a limit test as stated in the OECD TG 403. The mass median aerodynamic diameter (MMAD) of the particles was between 0.9 and 1.2 µm, with a geometric standard deviation (GSD) of 2.6 to 3.4. In the vicinity of the animals, 93 to 97 % of the airborne particle mass had a diameter smaller than 7 µm. The animals of both sexes exposed to the test substance experienced the symptoms piloerection, hunched posture, dyspnoea, and reduced locomotor activity to a similar extent. They recovered within 4 days. From the absence of mortalities, it can be assumed that the LC50 for male and female rats is greater than 4434 mg/m3 air.  

In conclusion, the acute inhalation LC50 of the test substance in rats was found to be greater than 4434 mg/m3 for both males and females

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

discriminating conc.

Value:

> 4 434 mg/m³ air

Physical form:

inhalation: aerosol

Quality of whole database:

GLP compliant OECD TG 403 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:

Jun/Jul 1980 to Sep/Oct 1980

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

comparable to guideline study

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

GLP compliance:

yes

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

Sprague-Dawley

Remarks:

CD

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Females nulliparous and non-pregnant: yes
- Age at study initiation: Young adult : 7 – 9 weeks
- Weight at study initiation: 195 – 263 g
- Housing: singly in metal cages with wire mesh floors.
- Diet: standard laboratory rodent diet, ad libitum.
- Water: provided, ad libitum.
- Acclimation period: at least 3 days.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 24 - 25
- Humidity (%): 51 (mean)
- Air changes (per hr): approximately 15
- Photoperiod (hrs dark / hrs light): 12 / 12

IN-LIFE DATES: From: Jun/Jul 1980 To: Sep/Oct 1980

Type of coverage:

occlusive

Vehicle:

corn oil

Details on dermal exposure:

TEST SITE
- Area of exposure: dorso-lumbar region
- % coverage: 10 % of the total body surface
- Type of wrap if used: The treated area was covered with aluminium foil held in place with an impermeable dressing encircled firmly round the trunk.

REMOVAL OF TEST SUBSTANCE
- Washing: After 24 hours, the dressings were removed and treated area was washed with warm (40 – 50 °C) water and finally blotting dry with absorbent paper.

TEST MATERIAL
- Amount applied: not exceeding 5 mL/kg
- Concentration: 40 % w/v test substance suspended in corn oil
- Constant volume or concentration used: yes

Duration of exposure:

24 hours

Doses:

2000 mg/kg bw (Study 1 and 2)

No. of animals per sex per dose:

5 (Study 1 and 2)

Control animals:

yes, concurrent vehicle

Remarks:

Only study 1

Details on study design:

TEST PROCEDURE/ DESIGN:
- Study 1: A group of 5 male and 5 female rats was treated at 2000 mg/kg which was considered to be the maximum practical dose. A vehicle control group of 5 male and 5 female rats was treated with corn oil at the same dose volume as the test group.
- Study 2: A further 5 male (numbered 1 to 5 inclusive) and 5 female (numbered 6 to 10 inclusive) rats were treated at 2000 mg/kg in order to provide tissues for histopathological examination.

- Duration of observation period following administration: 14 days.
- Frequency of weighing: Individual body weights of the animals were recorded on Days 1, 8 and 15.
- Frequency of observations: Animals were observed immediately after dosing and at approximately intervals for the remainder of Day 1. On Day 2 the animals were observed once in the morning and once at the end of the experimental day. On subsequent days the animals were observed once in the morning and once at the end of the experimental day (Study 2) or once daily (Study 1).
- Necropsy of survivors performed: yes, on Day 15 and were subjected to a macroscopic post mortem examination. The macroscopic appearance of abnormal organs was recorded.
- Clinical signs: Clinical signs were recorded at each observation time. The nature, severity, approximate time of onset and duration of each toxic sign. Local dermal reactions were recorded 24 hours after application of the test material and daily thereafter. The dermal reactions were assessed on a numerical basis according to the arbitrary scoring system as mentioned in Table 1 of' Any other information on materials and methods incl. tables'.

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No mortality was observed in either study.

Clinical signs:

other: In Study 1, there was no observable dermal irritation at the site of application in either the treated or control animals. In Study 2, 5/10 test substance exposed rats showed lethargy, and 1/10 showed decreased respiratory rate. There was no dermal irrita

Gross pathology:

Histopathology on study 2 animals showed small focal areas of epidermal ulceration with an associated acute inflammatory cell infiltration into the superficial dermis in the treated skin area of 2 females.
All animals showed minimal mononuclear cell aggregations and/or occasional foci of extramedullary haemopoiesis in the liver. 4/10 rats showed minor lesions in the kidneys.
Terminal autopsy findings were considered to be within normal limits.

Table 2 Mortality ratio, and group mean body weights (g) of rats dosed percutaneously with test substance

(Study 1)

Sex	Dosage (g/kg)	Body Weight (g) at			Mortality ratio (No of deaths)/No dosed)
		Dosing	1 week	2 weeks
males	0	250 253	291 281	340 325	0/5
		241	279	334
		238	285	334
		251	286	332
	Mean	247	284	333
	2.0	234	263	299	0/5
		240	285	331
		253	302	361
		228	277	322
		245	275	305
	Mean	240	280	324
females	0	222 241	239 257	279 284	0/5
		244	262	281
		248	265	300
		227	240	261
	Mean	236	253	281
	2.0	230	244	271	0/5
		221	234	258
		242	259	272
		232	246	271
		223	247	272
	Mean	230	246	269

Table 3 Mortality ratio, and group mean body weights (g) of rats dosed percutaneously with test substance

(Study 2)

Sex	Dosage (g/kg)	Body weight at			Mortality ratio (no of deaths / no dosed)
		Dosing	1  week	2 weeks
males	2.0	240	270	299	0/5
		263	309	360
		251	300	344
		248	290	326
		246	296	341
	Mean	250	293	334
females	2.0	212	218	241	0/5
		205	219	229
		216	231	250
		200	208	209
		214	228	236
	Mean	209	221	233

 

 

Table 4 Signs of reaction to treatment ratio of rats percutaneously with test substance

(Study 2)

Signs	Signs of reaction ratio (No showing signs/ No. dosed)
	Dose (g/kg)
	2.0
Lethargy Decreased respiratory rate	5/10 1/10

Interpretation of results:

GHS criteria not met

Conclusions:

The acute median lethal percutaneous dose (LD50) to rats of test substance was found to be greater than 2000 mg/kg bw which was considered to be the maximum practical dosage under the conditions of this test.

Executive summary:

An acute dermal study was performed in accordance with OECD TG 402 following GLP principles. The test was conducted with Sprague-Dawley derived rats to determine the potential for the test substance to produce toxicity from a single topical application. Two studies were performed; the first (Study 1) include a group of 5 male and 5 female rats was treated at 2000 mg/kg which was considered to be the maximum practical dose. A vehicle control group of 5 male and 5 female rats was treated with corn oil at the same dose volume as the test group. In a second study (Study 2) a further 5 male and 5 female rats were treated at 2000 mg/kg in order to provide tissues for histopathological examination. Animals were observed immediately after dosing and at approximately intervals for the remainder of Day 1. On Day 2 the animals were observed once in the morning and once at the end of the experimental day. On subsequent days the animals were observed once in the morning and once at the end of the experimental day (Study 2) or once daily (Study 1). 

No mortality was observed. From Study 2, 5/10 rats showed lethargy, and 1/10 showed decreased respiratory rate. In Study 1, no effects on body weight gain were observed. In Study 2, 2/5 females showed a decreased body weight gain during the first week, and 3/5 females during the second week, compared to the controls of Study 1. Histopathology on Study 2 animals showed small focal areas of epidermal ulceration with an associated acute inflammatory cell infiltration into the superficial dermis in the treated skin area of 2 females. All animals showed minimal mononuclear cell aggregations and/or occasional foci of extramedullary haemopoiesis in the liver. 4/10 rats showed minor lesions in the kidneys. 

The LD50 of the test substance after single dermal administration to rats of both sexes, observed over a period of 14 days is greater than 2000 mg/kg bw which was considered to be the maximum practical dosage under the conditions of this test.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

discriminating dose

Value:

> 2 000 mg/kg bw

Quality of whole database:

GLP compliant OECD TG 402 like study

Additional information

Acute oral toxicity study in rats, Ullmann 1982

Groups of 5 male and 5 female Wistar KFM-HAN rats received a single oral dose of 3000, 5000, 8000 and 10000 mg/kg bw of the test substance in a study performed according to OECD TG 401 following GLP principles. The animals were assessed daily for the following 14 days for any signs of systemic toxicity and their body weights were recorded at intervals throughout the study. All animals were subjected to a complete gross necropsy following their sacrifice or spontaneous death.

The following death rates were observed: 0 % at 3000 mg/kg bw, 0 % at 5000 mg/kg bw, 0 % at 8000 mg/kg bw and 20 % at 10000 mg/kg bw.

The acute oral LD50 of the test substance in rats of both sexes observed over a period of 14 days was estimated to be greater than 10000 mg/kg bw.

Acute inhalation toxicity study in rats, Hartmann 1992

The acute inhalation toxicity of the test substance was evaluated in groups of 5 male and 5 female Tif:RAI rats in accordance with OECD TG 403 following GLP principles. The animals were examined for clinical symptoms and mortalities during and after the exposure, as well as daily thereafter for 14 days. Body weights were recorded immediately prior to exposure and on days 7 and 14 of the observation period. Examinations were performed on all animals, which were killed after 14 days by ether anaesthesia. Particular attention was given to the respiratory tract.  

Upon a four hour acute inhalation exposure and a 14 days post-treatment observation period, no mortalities were elicited by the test substance at a concentration of 4434 mg/m3. Due to the properties of the test material, it was not possible to generate higher concentrations of test substance. The exposure to the maximum attainable concentration was thus considered a limit test as stated in the OECD TG 403. The mass median aerodynamic diameter (MMAD) of the particles was between 0.9 and 1.2 µm, with a geometric standard deviation (GSD) of 2.6 to 3.4. In the vicinity of the animals, 93 to 97 % of the airborne particle mass had a diameter smaller than 7 µm. The animals of both sexes exposed to the test substance experienced the symptoms piloerection, hunched posture, dyspnoea, and reduced locomotor activity to a similar extent. They recovered within 4 days. From the absence of mortalities, it can be assumed that the LC50 for male and female rats is greater than 4434 mg/m3 air.  

In conclusion, the acute inhalation LC50 of the test substance in rats was found to be greater than 4434 mg/m3 for both males and females

Acute dermal toxicity in rats, Kynoch 1981

An acute dermal study was performed in accordance with OECD TG 402 following GLP principles. The test was conducted with Sprague-Dawley derived rats to determine the potential for the test substance to produce toxicity from a single topical application. Two studies were performed; the first (Study 1) include a group of 5 male and 5 female rats was treated at 2000 mg/kg which was considered to be the maximum practical dose. A vehicle control group of 5 male and 5 female rats was treated with corn oil at the same dose volume as the test group. In a second study (Study 2) a further 5 male and 5 female rats were treated at 2000 mg/kg in order to provide tissues for histopathological examination. Animals were observed immediately after dosing and at approximately intervals for the remainder of Day 1. On Day 2 the animals were observed once in the morning and once at the end of the experimental day. On subsequent days the animals were observed once in the morning and once at the end of the experimental day (Study 2) or once daily (Study 1). 

No mortality was observed. From Study 2, 5/10 rats showed lethargy, and 1/10 showed decreased respiratory rate. In Study 1, no effects on body weight gain were observed. In Study 2, 2/5 females showed a decreased body weight gain during the first week, and 3/5 females during the second week, compared to the controls of Study 1. Histopathology on Study 2 animals showed small focal areas of epidermal ulceration with an associated acute inflammatory cell infiltration into the superficial dermis in the treated skin area of 2 females. All animals showed minimal mononuclear cell aggregations and/or occasional foci of extramedullary haemopoiesis in the liver. 4/10 rats showed minor lesions in the kidneys. 

The LD50 of the test substance after single dermal administration to rats of both sexes, observed over a period of 14 days is greater than 2000 mg/kg bw which was considered to be the maximum practical dosage under the conditions of this test.

Justification for classification or non-classification

Based on the result of the acute oral, acute dermal and acute Inhalation toxicity study classification for acute toxicity is not warranted in accordance with EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation No. (EC) 1272/2008.