Fenamiphos

Endpoint summary

Description of key information

Endpoints for acute toxicity are covered by available animal studies.

The test substance is acutely toxic to rats following administration by the oral, dermal and inhalation route.

 

Oral

The oral LD50 in rats was 6.0 – 6.1 mg/kg bw in males and females.

 

Dermal

The dermal LD50 in rats was 72 – 92 mg/kg bw in males and females.

 

Inhalation

The LC50 inhalation of the test item in rats was 65 – 79 mg/m³ for 4 h (aerosol) exposure in males and females.

 

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:

May 1988

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 12, 1981

Deviations:

no

GLP compliance:

no

Test type:

standard acute method

Limit test:

no

Species:

rat

Strain:

Wistar

Remarks:

SPF-bred Wistar rats of the strain Bor: WISW (SPF-Cpb)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Winkelmann Experimental Animal Breeders in Borchen, Kreis Paderborn
- Females nulliparous and non-pregnant: yes
- Age at study initiation: 8 - 11 weeks (males, females)
- Weight at study initiation: males 173 (163 -184) grams, the females of 183 (174 -191) grams
- Fasting period before study: yes, 18 h
- Housing: groups of 5 in Type III Makrolon® cages with low-dust wood pellets
- Historical data: available
- Diet (ad libitum): Altromin 1324 Maintenance Diet for Rats and Mice made by Altromin GmbH in Lage
- Water (ad libitum): tap water (watering bottles)
- Acclimation period:
- Microbiological status when known: SPF
- Method of randomisation in assigning animals to test and control groups: on the basis of randomizing lists generated by a program on an HP 3000 computer system

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3
- Humidity (%): 50
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

oral: gavage

Vehicle:

polyethylene glycol

Remarks:

E 400

Details on oral exposure:

MAXIMUM DOSE VOLUME APPLIED: 5 mL/kg bw

Doses:

1.0, 4.0, 5.0, 5.6, 6.3, 10.0, 100.00 mg/kg bw (males)
1.0, 5.0, 6.3, 8.0 mg/kg bw (females)

No. of animals per sex per dose:

5 animals/sex

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: prior to treatment and on days four, eight and 15
- Necropsy of survivors performed: yes
- Clinical signs: yes, recorded several times on the day of treatment, and at least once daily thereafter

Statistics:

If calculation of the mean (median) lethal dose (LD50) is possible, this operation is
performed with computer assistance (HP 3000) using the method of A.P. Rosiello, J.M.
Essigmann and G.N. Wogan (1977) as modified by Pauluhn (1983). This procedure is based on the "maximum likelihood" method of C.I. Bliss (1938). If pairs of results with 0 % and 100 % mortality exist, the geometric mean of the pertinent doses is considered the "approximate LD50".

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

6.1 mg/kg bw

Based on:

test mat.

Key result

Sex:

male

Dose descriptor:

LD50

Effect level:

6 mg/kg bw

Based on:

test mat.

Mortality:

Mortality was observed at and above 5.6 mg/kg bw in males and 5.0 mg/kg bw in females (please refer to "Any other information on results incl. tables").

Clinical signs:

other: other: see "Remark"

Gross pathology:

Lung: dark, patchy, distended, fluid, gray stipples; liver: dark, spleen: patchy, pale or dark; kidney: patchy; renal pelvis: reddened; grandular stomach: reddened, covered with ulcer-like foci; small intestine: slightly reddened, well supplied with blood.

Dose [mg/kg bw]	Toxicological results*			Duration of signs	Time of death	Mortality [%]
male rats
1.0	0	0	5	--	--	0
4.0	0	5	5	20m – 1d	--	0
5.0	0	5	5	17m – 1d	--	0
5.6	3	5	5	14m – 3d	25m – 1h15 m	60
6.3	4	5	5	12m – 1d	20m – 1h15m	80
10.0	4	5	5	18m – 1d	37m – 1h30m	80
100.0	5	5	5	6m – 8m	7m – 8m	100
female rats
1.0	0	5	5	4h45m – 1d	--	0
5.0	1	5	5	21m – 1d	49m	20
6.3	3	5	5	14m – 1d	34m – 1h15m	60
8.0	4	5	5	8m – 1d	20m – 34m	80
LD50 males: 6.0 mg/kg bw / LD50 females: 6.1 mg/kg bw

* 1^st figure = number of dead animals / 2^nd figure = number of animals with cinical signs / 3^rd figure = number of animals in the group

Interpretation of results:

Category 2 based on GHS criteria

Conclusions:

The test substance is very toxic to rats following acute oral administration. The oral LD50 of the test substance in rats was 6.0 – 6.1 mg/kg bw in males and females, respectively.

Executive summary:

A study for acute oral toxicity in rats was conducted with the test substance according to OECD 401 (adopted May 12, 1981). The test item was formulated with polyethylene glycol E 400. Groups of 5 male and 5 female rats were each administered by gavage a single dose of the test substance. The application volume was 5 mL/kg bw. The recovery period was 14 days. The animals were subjected to gross pathological examination after the recovery period.

Mortality was observed at and above 5.6 mg/kg bw in males and 5.0 mg/kg bw in females. Clinical signs (palmospasms, labored breathing, apathy, diarrhea, clonic craps, piloerection, issolated cases of spastic gait and bloody eyes) were recorded in all dose groups and animals, except for 1 mg/g bw in males. No adverse effects were observed in regard to the bodyweight. The gross necropsy revealed cahnges in the lung, liver, spleen, kidney, renal pelvis and small intestine.

It was concluded that the test substance is very toxic to rats following acute oral administration. The oral LD50 of the test subtance in rats was 6.0 – 6.1 mg/kg bw in males and females, respectively.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

6 - 6.1 mg/kg bw

Quality of whole database:

Klimisch 1

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:

2000-05-25 to 2000-09-15

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:

adopted May 12 1981

Deviations:

no

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1300 (Acute inhalation toxicity)

Version / remarks:

August 1998

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

traditional method

Limit test:

no

Species:

rat

Strain:

Wistar

Remarks:

SPF bred Wistar rats, strain Hsd Cpb:WU

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Harlan-Winkelmann GmbH, Borchen (Germany)
- Females nulliparous and non-pregnant: yes
- Age at study initiation: approx. 8 weeks
- Weight at study initiation: females: 163.0 - 175.4 g, males: 171.6 - 204.6 g
- Housing: housed singly in conventional Makrolon® Type II cages, with type BK 15 low-dust wood granulate
- Historical data: available
- Diet (ad libitum): standard fixed-formula diet (Altromin® 1324 pellets maintenance diet for rats and mice, Altromin GmbH, Lage)
- Water (ad libitum): tap water
- Acclimation period: at least 5 days
- Microbiological status when known: SPF
- Method of randomisation in assigning animals to test and control groups: A computerized list of random numbers served the purpose to assign animals at random to the treatment groups.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 2
- Humidity (%): approx. 50
- Air changes (per hr): approx. 10
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

nose only

Vehicle:

other: a mixture consisting of polyethylene glycol 400 (PEG) and ethanol (1:1; w/v)

Mass median aerodynamic diameter (MMAD):

1.31 - 1.44

Geometric standard deviation (GSD):

2.12 - 2.28

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Plexiglas exposure tubes applying a directed-flow nose-only exposure principle

- Exposure chamber volume:
The aluminum inhalation chamber has the following dimensions: inner diameter = 14 cm, outer diameter = 35 cm (two-chamber system), height = 25 cm (internal volume = about 3.8 L).

- Method of holding animals in test chamber:
Tubes were chosen that accommodated the animals size. These tubes were designed so that the rat's tail remained outside the tube, thus restrained-induced hyperthermia can be avoided.

- Source and rate of air (airflow):
During the exposure period air flows were monitored continuously and, if necessary, readjusted to the conditions required. Air flows were measured with calibrated flow-meters and/or soap bubble meter (Gilibrator, Strb'hlein Instruments, Kaarst) and were checked for correct performance at regular intervals.

- Method of conditioning air:
Compressed air was supplied by Boge compressors and was conditioned (i.e. freed from water, dust, and oil) automatically by a VIA compressed air dryer. Adequate control devices were employed to control supply pressure.

- System of generating aerosols:
Under dynamic conditions the test substance was nebulized into a baffle (pre-separator) from which the substance was conveyed into the intake of the cylindrical inhalation chamber. The test substance was nebulized using a binary nozzle with conditioned compressed air (15L/min; dispersion pressure approximately 600 kPa; for details see Table 1, result section). The solution was fed into the nozzle by a digitally controlled Hamilton Microlab pump.

- Method of particle size determination: Gravimetric analyses

- Treatment of exhaust air:
The exhaust air was purified via cotton-wool/HEPA filters. These filters were disposed of by Bayer AG.

- Temperature, humidity, pressure in air chamber:
Temperature and humidity measurements were made using a computerized system
(Hydra, Fluke-Philips). The values were recorded at intervals of 5 min (computerized
recording). The test atmosphere temperature and humidity were measured at the exposure location. Humidity and temperature were measured using a FTF-sensor (Elka-Elektronik, Liidenscheid). The sensor was calibrated using saturated salt solutions according in a two-point calibration at 33% (MgCI2) and at 75% (NaCI) relative humidity. The calibration of the temperature sensor is also checked at two temperatures using a reference thermometer. The measured values were evaluated using a spread-sheet software.

TEST ATMOSPHERE
- Brief description of analytical method and equipment used: BERNER-TYPE AERAS lowpressure critical orifice cascade impactor (Hauke, Gmunden, Austria).
- Samples taken from breathing zone: yes
- Time needed for equilibrium of exposure concentration before animal exposure: not specified

VEHICLE
- Composition of vehicle: a mixture consisting of polyethylene glycol 400 (PEG) and ethanol (1:1; w/v)
- Justification of choice of vehicle: The solvent in this vehicle promotes the formation of smaller particles due to its evaporation.


TEST ATMOSPHERE
- Particle size distribution: in the respirable range
- MMAD (Mass median aerodynamic diameter) / GSD (Geometric st. dev.): 1.4 / 2.2

Analytical verification of test atmosphere concentrations:

yes

Duration of exposure:

4 h

Concentrations:

0, 63.6, 64.7, 92.1, 243.1, 510.8 mg/m3 (males and females);

No. of animals per sex per dose:

5 animals/ sex

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Body weights were measured before exposure, on days 3 and 7, and weekly thereafter. Individual weights are also recorded at death, if applicable. The period of observation was for 2 weeks.
The appearance and behavior of each rat were examined carefully several times on the day of exposure and at least once daily thereafter. Weekend assessments were made once a day (morning). Assessments from restraining tubes were made only if unequivocal signs occurred.
- Necropsy of survivors performed: yes
- Other observations: The rectal temperatures were measured directly after cessation of exposure (approximately within 14hour after the end of exposure) using a Digimed digital thermometer with a rectal probe for rats.

Statistics:

yes

Key result

Sex:

male/female

Dose descriptor:

LC50

Effect level:

74 mg/m³ air

Based on:

act. ingr. (total fraction)

95% CL:

67 - 85

Exp. duration:

4 h

Mortality:

Mortalitiy was observed in males at and above 63.6 mg/m3 air, in females at and above 64.7 mg/m3.

Clinical signs:

other: Please refer to "Any other information on results incl. tables"

Body weight:

Decreased body weights were observed in both sexes.

Gross pathology:

Lung less collapsed, dark-red discolorations, intestine bloated, parenchymatous organs pale, corneal opacity.

Other findings:

RECTAL TEMPERATURE
The rats exposed to the test substance experienced a statistically significant decrease in body temperature.

CLINICAL SIGNS

Piloerection, hair-coat ungroomed, bradypnea, labored breathing pattern, dyspnea, irregular breathing pattern, motility reduced, limp, tremor, fasciculations, giddiness, high-legged gait, prostration (lying on belly), exophthalmos, miosis, corneal opacity, chromodacryorrhea, nostrils: red encrustations, salivation, pallor, emaciation, periorbicular red stains.

 

Table 1: Results summary

Atmosphere concentration [mg/m³ air]	Toxicological result #	Duration of signs	Time of death	Mortality [%]
male rats
0	0/0/5	--	--	--
63.6	1/4/5	0 d – 9 d	0 d	20
64.7	2/3/5	0 d – 7 d	0 d	40
92.1	5/-‘/5	--	< 4 h	100
243.1	5/-/5	--	< 4 h	100
510.8	5/-/5	--	< 4 h	100
female rats
0	0/0/5	--	--	--
63.6	0/5/5	0 d – 6 d	--	--
64.7	1/4/5	0 d – 7 d	0 d	20
92.1	4/2/5	0 d – 6 d	0 d, 1 d	80
243.1	5/-/5	--	< 4 h	100
510.8	5/-/5	--	< 4 h	100
LC50 males & females: 74 mg/m³ air

# 1^st number = number of dead animals

2^nd number  = number of animals with clinical signs

3^rd number   = number of animals used rats died during the exposure period

 

Interpretation of results:

Category 2 based on GHS criteria

Conclusions:

The aerosolized test substance (liquid aerosol) proved to have a high acute inhalation toxicity. The LC50 inhalation of the test item in rats was 65 – 79 mg/m3 for 4 h (aerosol) exposure in males and females, respectively.

Executive summary:

A study on the acute inhalation toxicity of the test substance on rats has been conducted in accordance with OECD Guideline No. 403, Directive 92/69/EEC and OPPTS 870.1300. Groups of rats were nose-only exposed to mean liquid aerosol concentrations of 64, 65, 92, 243, and 511 mg/m³ air. This concentration was chosen to meet the limit concentration defined by the OPPTS 870.1300 testing guideline. Attempts were made so that aerosol generated was respirable to rats. In all groups of rats exposed to the test substance a concentration-dependent mortality occurred on the day of exposure.
The following clinical signs were observed: piloerection, hair-coat ungroomed, bradypnea, labored breathing pattern, dyspnea, irregular breathing pattern, motility reduced, limp, tremor, fasciculations, giddiness, high-legged gait, prostration (lying on belly), exophthalmos, miosis, corneal opacity, chromodacryorrhea, nostrils: red encrustations, salivation, pallor, emaciation, periorbicular red stains, hypothermia, decreased reflexes, decreased body weights. Signs occurred in a concentrationdependent manner and subsided almost entirely up to the end of the first postexposure week. Necropsy findings were suggestive of increased bronchial secretions. All findings are consistent with the pathomechanism of a cholinesterase inhibitor. With respect to the respirability of the aerosol generated internationally recognized recommendations such as of SOT (1992) were fulfilled i.e. the average MMAD was «1.4 urn (GSD «2.2).
In summary, the aerosolized test substance (liquid aerosol) proved to have a high acute inhalation toxicity. The LC₅₀ inhalation of the test item in rats was 65 – 79 mg/m³ for 4 h (aerosol) exposure in males and females, respectively. 

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LC50

Value:

65 - 79 mg/m³ air

Physical form:

inhalation: aerosol

Quality of whole database:

Klimisch 1

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:

July 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)

Deviations:

no

GLP compliance:

no

Test type:

standard acute method

Limit test:

no

Species:

rat

Strain:

not specified

Sex:

male/female

Type of coverage:

occlusive

Vehicle:

other: lutrol, warm

Details on dermal exposure:

TEST MATERIAL
- Amount applied: 0.05 - 2 mL

Duration of exposure:

24 h

Doses:

- 25, 35, 40, 45, 50, 65, 75, 100, 125, 1000 mg/kg bw (males)
- 25, 50, 75, 100, 125, 1000 mg/kg bw (females)

No. of animals per sex per dose:

males: 5 animals/group at dose levels: 25 and 1000 mg/kg bw; 10 animals/group at dose levels 35, 40, 45, 50, 65, 100, 125 mg/kg bw; 20 animals at 75 mg/kg bw;
females: 5 animals/group at dose levels: 25 and 1000 mg/kg bw; 10 animals/group at dose levels 50, 75, 100, and 125 mg/kg bw

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days

Key result

Sex:

male

Dose descriptor:

LD50

Effect level:

72 mg/kg bw

Based on:

test mat.

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

92 mg/kg bw

Based on:

test mat.

Mortality:

Mortalitiy occured in male animals at and above doses of 45 mg/kg bw and at and above 75 mg/kg bw in females (please refer to Table 1 "Any other information on results incl. tables").

Clinical signs:

other: other: The following clinical symptoms were seen in male and female rats: apathy, laboured breathing, tremor, abdominal position, salivation, red lacrimation and soft faeces. Symptoms appeared in males after 66 min and in females after 41 min of exposure;

Gross pathology:

not specified

Other findings:

not specified

Table 1: Results summary

Dose [mg/kg bw]	Toxicological results*
	male rats	female rats
25	0/5/5	0/5/5
35	0/10/10	-
40	0/10/10	-
45	1/10/10	-
50	3/10/10	0/10/10
65	4/10/10	-
75	11/20/20	2/10/10
100	8/10/10	6/10/10
125	9/10/10	9/10/10
1000	5/5/5	5/5/5
	LD50: 72 mg/kg bw	LD50: 92 mg/kg bw

* 1^st figure = number of dead animals / 2^nd figure = number of animals with clinical signs / 3^rd figure = number of animals in the group

Interpretation of results:

Category 2 based on GHS criteria

Conclusions:

The test item is toxic to rats following dermal administration in a lipophilic vehicle. The dermal LD50 of the test item in rats was 72 – 92 mg/kg bw in males and females, respectively.

Executive summary:

In a acute dermal toxiciy study equivalent to OECD 402, the test item was dissolved, emulsified, suspended in Lutrol (warm) and applied under occlusive conditions to groups of non-fasted male and female rats for an exposure duration of 24 hours at dose levels of 25, 35, 40, 45, 50, 65, 75, 100, 125 and 1000 mg/kg bw. The treatment volume was 0.05 - 2 mL/kg bw. The recovery period was 14 days.

Mortalitiy occured in male animals at and above doses of 45 mg/kg bw and at and above 75 mg/kg bw in females. Clinical signs were observed in all animals and all dose levels (apathy, laboured breathing, tremor, abdominal position, salivation, red lacrimation and soft faeces).

It was concluded that the test item is toxic to rats following dermal administration in a lipophilic vehicle. The dermal LD50 of the test item in rats was 72 – 92 mg/kg bw in males and females, respectively.

 

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

72 - 92 mg/kg bw

Quality of whole database:

Klimisch 1

Additional information

The information provided below was taken from the original plant protection dossier on the active substance submitted in 2017 for inclusion of the test substance to Annex I of Directive 91/414/EEC and has been previously evaluated in the Draft Renewal Assessment Report (DAR) according to the Commission Regulation (EU) No 1107/2009 (2003) (revisioned in the Renewal Assesment Report (December 2018)) and subject to peer review by EFSA and Member States (2006). The summaries as published in the RAC opinion (2011) are given below.

 

Oral toxicity: Two acute oral studies were available.

Kroetlinger (1988): In the first study, performed according to OECD 401, doses of 1, 4, 5, 5.6, 6.3, 10 and 100 mg/kg bw in males and 1, 5, 6.3 and 8 mg/kg bw in females were used. Clinical signs were observed at doses ≥ 1 and 4 mg/kg bw in females and males, respectively, and included palmospasms, laboured breathing, apathy, diarrhoea, clonic cramps, piloerection, isolated cases of spastic gait and bloody eyes. These symptoms, which were mainly moderate in intensity, subsided within a few hours.
Apathy persisted up to the third day. Mortality occurred at doses ≥ 5 and 5.6 mg/kg bw in females and males, respectively. Pathology revealed dark, patchy, distended lungs with fluid and grey stipples; dark livers; patchy, pale or dark spleens; patchy kidneys; reddened renal pelvis; reddened glandular stomach, covered with ulcer like foci; and slightly reddened small intestines, well supplied with blood. The oral LD50 of the test substance in rats was 6.0 – 6.1 mg/kg bw in males and females, respectively.

 

Kroetliger (2000): The second study was a limit study with a dose of 25 mg/kg bw, performed according to OECD 423. All animals died within 10 minutes. Palmospasm, dyspnea, and swollen buccal regions were observed. Additionally, in one animal each, chromodacryorrhea and increased salivation occurred. The liver had dark-red discoloration and the lungs were slightly collapsed. The oral LD50 of the test substance in rats was < 25 mg/kg bw for females.

 

 

Dermal toxicity:

Flucke (1980): One acceptable dermal study was available, with applied doses of 25, 35, 40, 45, 50, 65, 75, 100, 125, 1000 mg/kg bw in males and 25, 50, 75, 100, 125, 1000 mg/kg bw in females. The test subtance was dissolved, emulsified, and suspended in Lutrol (warm) and applied under occlusive conditions bto non-fasted male and female rats for an exposure duration of 24 hours. The treatment volume was 0.05 – 2 mL/kg bw, but no information on the application surface is provided. The recovery period was 14 days. All treated animals showed symptoms of toxicity (not specified). Mortality was observed at doses ≥ 75 and 45 mg/kg bw in females and males, respectively.

The dermal LD50 of the test item in rats was 72 – 92 mg/kg bw in males and females, respectively.

 

 

Inhalation toxicity: Two acute inhalation studies were available.

Thyssen (1979): In the first study (not according to OECD) the test subtance was dissolved and the solution (57, 62, 100 and 155 mg/m³ for males, 57, 62, 100, 155 and 191 mg/m3 for females) was aerosolised into dynamic flow inhalation chambers. Rats were exposed for a period of 4 hours (nose-only). The animals were kept under observation for 14 days. Clinical signs were observed in all animals and included muscle twitching, cramps (at lethal concentrations), inactivity, stiff gait, dirty hair coat, drowsiness, breathing disorders. Mortality occurred at doses ≥ 62 and 100 mg/m³ in females and males, respectively. Since no data on particle size and distribution were available, the study is acceptable as supportive study only. The LC₅₀ (air) of 100 mg/m³ was both established for both male and female rats (4 h).

Pauluhn (2001): In the second study (in accordance with OECD 403) actual concentrations of 63.6, 64.7, 92.1, 243.1 and 510. 8 mg/m³ were applied to rats (nose only). The MMAD of the aerosol particles in the atmosphere ranged from 1.31-1.44 μm at different concentrations (geometric standard deviation ranged from 2.12-2.41). Clinical signs were observed in all dosed animals and included piloerection, hair-coat ungroomed, bradypnea, laboured breathing pattern, dyspnea, irregular breathing pattern, reduced motility, limp, tremor, fasciculations, giddiness, high-legged gait, prostration, exophthalmos, miosis, corneal opacity, chromodacryorrhea, red encrustations of the nostrils, salivation, pallor, emaciation and periorbicular red stains. Mortality occurred at doses ≥ 64.7 and 63.6 mg/m³ in females and males, respectively. Pathology revealed less collapsed lungs with dark-red discolorations, bloated intestines, pale parenchymatous organs and corneal opacity.

The LC50 inhalation of the test item in rats was 65 – 79 mg/m³ for 4 h (aerosol) exposure in males and females.

 

A summary of the results of acute toxicity studies is presented in Table 1.

 

Table 1: Summary of acute toxicity studies

Test / Reference	Key data	CLP
Acute oral / Kroetlinger (1988)	LD50 of 6 mg/kg, rat, oral	Acute Tox. 2 (H300)* (5-50 mg/kg)
Acute oral / Kroetlinger (2000)	LD50 rat < 25 mg/kg bw for females	Acute Tox. 2 (H300)* (5-50 mg/kg)
Acute dermal / Flucke (1980)	LD50 of 72 mg/kg, rat, dermal	Acute Tox. 2 (H310)* (50-200 mg/kg)
Acute inhalation / Pauluhn (2001)	LC50 (aerosol) 65 – 79 mg/m3 for 4 h (aerosol)	Acute Tox. 2 (H330)* (0.05-0.5 mg/L)
Acute inhalation / Thyssen (1979)	LC50 (air) of 100 mg/m^3 for both male and female rats (4 h)	Acute Tox. 2 (H330)* (0.05-0.5 mg/L)
*In line with the harmonized classification and labelling approved by the European Union  (Adaptation to Technical Progress (ATP) 2 to Regulation (EC) No 1272/2008).

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.

 

Oral toxicity

Based on available data on acute toxicity, the test item is classified for acute oral toxicity as Acute Tox. 2 (H300) according to Regulation (EC) No 1272/2008 (CLP), as amended for the eighteenth time in Regulation (EU) 2022/692.

 

Dermal toxicity

Based on available data on acute toxicity, the test item is classified for acute dermal toxicity as Acute Tox. 2 (H310) according to Regulation (EC) No 1272/2008 (CLP), as amended for the eighteenth time in Regulation (EU) 2022/692.

 

Inhalation toxicity

Based on available data on acute toxicity, the test item is classified for acute inhalation toxicity as Acute Tox. 2 (H330) according to Regulation (EC) No 1272/2008 (CLP), as amended for the eighteenth time in Regulation (EU) 2022/692.

 

This classification is line with the harmonized classification and labelling approved by the European Union (Adaptation to Technical Progress (ATP) 2 to Regulation (EC) No 1272/2008).