O-(4-bromo-2-chlorophenyl) O-ethyl S-propyl phosphorothioate

Endpoint summary

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Reference 1

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

26 October 2005 to 16 November 2005

Reliability:

1 (reliable without restriction)

Qualifier:

according to guideline

Guideline:

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

Deviations:

no

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1100 (Acute Oral Toxicity)

Deviations:

no

GLP compliance:

yes

Test type:

up-and-down procedure

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

female

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Doses:

350, 1100 mg/kg

No. of animals per sex per dose:

5/gp

Control animals:

no

Sex:

female

Dose descriptor:

LD50

Effect level:

ca. 620.5 mg/kg bw

Based on:

test mat.

95% CL:

ca. 350 - ca. 1 100

Individual bodyweights/weight gains and mortality are presented in Table 1, Individual cage-side observations and necropsy observations are presented in Tables 2 and 3, respectively.

 

350 mg/kg (3 animals)

All animals survived, appeared active and healthy and gained body weight over the 14-day observation period. There were no signs of gross toxicity, adverse pharmacologic effect or abnormal behavior. No gross abnormalities were noted for either animal when necropsied following the 14-day observation period.

 

1,100 mg/kg (3 animals)

All animals died within two days of test substance administration. Toxic signs noted prior to death included ocular discharge, hypoactivity, abnormal posture, piloerection, ano-genital staining and a reduced fecal volume. Gross necropsy of the decedents revealed discoloration of the intestines.

 

Table 7.2.1 -2: Individual body weights/weight gains doses and mortalities

Animal No.	Sex	Dose Level (mg/kg)	Body Weight (g)					Dose (mL)	Mortality
			Day 0 Weight	Day 7 Weight	Gain*	Day 14 Weight	Gain*		Day	Weight (g)
6099	F	350	200	218	18	247	47	0.048	E	-
6220	F		215	227	12	249	34	0.052	E	-
6372	F		223	234	11	282	59	0.054	E	-
6108	F	1,100	185	-	-	-	-	-	1	176
6261	F		219	-	-	-	-	0.16	2	201
6384	F		225	-	-	-	-	0.17	1	219

 

Table 7.2.1 -3: Individual cage side observations

Animal Number	Findings	Day of Occurrence
350 mg/kg
6099	Active and healthy	0-14
6220
6372
1100 mg/kg
6108	Active and healthy Hypoactive Ocular discharge (clear), hunched posture Dead	0 (1 hr) 0 (3-6 hrs) 0 (6 hrs) 1
6261	Active and healthy Hypoactive Ano-genital staining, reduced faecal volume Prone posture Dead	0 (1 hr) 0 (3 hrs)-1 1   1 2
6384	Active and healthy Hypoactive Hunched posture, piloerection) Dead	0 (1 hr) 0 (3-7 hrs) 0 (7 hrs) 1

 

Table 7.2.1 -4: Individual necropsy observations

Animal Number	Tissue	Findings
350 mg/kg
6099, 6220, 6372	All tissues and organs	No gross abnormalities
1100 mg/kg
6108, 6261, 6384	Intestines	Red

 

Conclusions:

Under the conditions of this study, the acute oral LD50 of Profenofos Technical is estimated to be 620.5 mg/kg of body weight in female rats with an approximate 95% Confidence Interval of 350 mg/kg (lower) to 1,100 mg/kg (upper).

Executive summary:

An acute oral toxicity test (Up and Down Procedure) was conducted with rats to determine the potential for Profenofos Technical to produce toxicity from a single dose via the oral route.

 

Based on an estimate of the LD50 supplied by the Sponsor (1,100 mg/kg), an initial dose of 350 mg/kg was administered to one healthy female rat by oral gavage. Following the Up and Down procedure, five additional females were tested at levels of 350 or 1,100 mg/kg. Females were selected for the test because they are frequently more sensitive to the toxicity of test compounds than males. All animals were observed for mortality, signs of gross toxicity, and behavioral changes at least once daily for 14 days after dosing or until death occurred. Body weights were recorded prior to administration and again on Days 7 and 14 (termination) following dosing or after death. Necropsies were performed on all animals.

 

Under the conditions of this study, the acute oral LD₅₀ of Profenofos Technical is estimated to be 620.5 mg/kg of body weight in female rats with an approximate 95% Confidence Interval of 350 mg/kg (lower) to 1,100 mg/kg (upper).

Reference 2

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

10 February 1993 to 25 February 1994

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Not stated in the study whether butyryl or acetyl cholinesterase activity was measured, with former have no biological relevance.

Qualifier:

according to guideline

Guideline:

EPA OPP 81-1 (Acute Oral Toxicity)

Deviations:

no

GLP compliance:

yes

Test type:

standard acute method

Limit test:

no

Species:

rat

Strain:

other: Crl:CD BR/VAF/Plus

Sex:

male/female

Route of administration:

oral: gavage

Vehicle:

corn oil

Doses:

Phase 1: males: 100, 200, 400, 600, 800 mg/kg; females: 100, 200, 300, 800 mg/kg; Phase 2: 0, 0.1, 0.5, 25, 100, 400 mg/kg

No. of animals per sex per dose:

5 animals/sex

Control animals:

yes

Sex:

male/female

Dose descriptor:

other: NOEL

Effect level:

ca. 100 mg/kg bw

Based on:

other: clinical / behavioural signs and body weight changes

Sex:

male/female

Dose descriptor:

other: NOEL for brain cholinesterase inhibition

Effect level:

ca. 100 mg/kg bw

Based on:

other: based on inhibition in excess of 30% at 400 mg/kg

Table 7.2.1 -10: % inhibition

Dose (mg/kg)	Plasma				RBC				Brain
	Male	Sig	Female	Sig	Male	Sig	Female	Sig	Male	Sig	Female	Sig
0	0	NS	0	NS	0	NS	0	NS	0	NS	0	NS
0.1	7	NS	19	NS	3	NS	19	NS	-4	NS	-4	NS
0.5	5	NS	21	NS	-1	NS	15	*	-5	NS	8	NS
25	71	*	89	*	14	NS	31	*	3	NS	6	NS
100	86	*	94	*	21	NS	44	*	3	NS	14	NS
400	98	*	98	*	30	*	46	*	37	*	43	*

 

Following a single administration of Profenfos statistically significant levels of plasma and/or erythrocyte cholinesterase activity were observed at dose levels of 0.5 mg/kg and greater. Plasma cholinesterase activity was almost completely inhibited at 100 mg/kg and greater. Erythrocyte cholinesterase activity was more resilient, with levels of inhibition reaching 30% in males and 44% in females at 400 mg/kg. In accordance with the JMPR (2000) guidance, brain cholinesterase activity is the preferential endpoint of concern. In both males and females the level of inhibition exceed 20% (accompanied by statistical significance) at 400 mg/kg (highest dose tested). Even at almost levels of inhibition of plasma cholinesterase activity, erythrocyte cholinesterase acitivity ~30-46~% and brain cholinesterase activity ~37 – 43% in males and females dosed at 400 mg/kg, no clinical signs of toxicity were evident. Therefore, the NOAEL was considered to be 100 mg/kg, based on inhibition of brain cholinesterase activity observed at 400 mg/kg.

 

Reference:

JMPR (2000). Pesticide residues. Guidelines for the preparation of toxicological working papers for the WHO core assessment group of the Joint Meeting on Pesticide Residues. Geneva, Switzerland, December 2000. 

Conclusions:

The NOEL for brain cholinesterase inhibtion was 100 mg/kg for both males and females. The level of inhibition was deemed significant if the level of inhibition exceed 20%.

Executive summary:

The objective of this study was to determine the NOEL for clinical/behaviour/body weight effects in phase 1. For phase 2, the NOEL for erythrocyte, plasma and brain cholinesterase inhibition was determined

 

Five animals/sex were dose at levels of 100 to 800 mg/kg in order to determine the clinical toxiciological effects of profenofos (phase 1) and dosed of 0.1 to 400 mg/kg in order to determine the NOEL for cholinesterase inhibition (phase 2). Significant inhibiton (greater than 20%) in brain cholinesterase acitivty was observed in animals dosed at 400 mg/kg. Therefore the NOEL for brain cholinesterase inhibiton was deemed to be 100 mg/kg. The NOEL for clinical / behavioural signs was deemed to be 100 mg/kg.

 

Following a single administration of Profenfos statistically significant levels of plasma and/or erythrocyte cholinesterase activity were observed at dose levels of 0.5 mg/kg and greater. Plasma cholinesterase activity was almost completely inhibited at 100 mg/kg and greater. Erythrocyte cholinesterase activity was more resilient, with levels of inhibition reaching 30% in males and 44% in females at 400 mg/kg. In accordance with the JMPR (2000) guidance, brain cholinesterase activity is the preferential endpoint of concern. In both males and females the level of inhibition exceed 20% (accompanied by statistical significance) at 400 mg/kg (highest dose tested). Even at almost levels of inhibition of plasma cholinesterase activity, erythrocyte cholinesterase acitivity ~30-46~% and brain cholinesterase activity ~37 – 43% in males and females dosed at 400 mg/kg, no clinical signs of toxicity were evident. Therefore, the NOAEL was considered to be 100 mg/kg, based on inhibition of brain cholinesterase activity observed at 400 mg/kg.

 

Reference:

JMPR (2000). Pesticide residues. Guidelines for the preparation of toxicological working papers for the WHO core assessment group of the Joint Meeting on Pesticide Residues. Geneva, Switzerland, December 2000. 

Reference 3

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

Study period not stated

Reliability:

1 (reliable without restriction)

Qualifier:

according to guideline

Guideline:

EPA OPP 81-1 (Acute Oral Toxicity)

Deviations:

no

GLP compliance:

yes

Test type:

standard acute method

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Doses:

200, 400, 100, 1500 mg/kg

No. of animals per sex per dose:

5 males and 5 females/gp

Control animals:

no

Sex:

male/female

Dose descriptor:

LD50

Effect level:

ca. 630 mg/kg bw

Based on:

test mat.

Sex:

male

Dose descriptor:

LD50

Effect level:

ca. 492 mg/kg bw

Based on:

test mat.

95% CL:

ca. 363 - 666

Sex:

female

Dose descriptor:

LD50

Effect level:

ca. 809 mg/kg bw

Based on:

test mat.

95% CL:

ca. 600 - 1 090

Table 7.2.1 -9: Number of animals treated and died/dose level

Dose (mg/kg)	Number dead / Number treated
	Males	Females	Combined
200	0/5	0/5	0/10
400	1/5	0/5	1/10
1000	5/5	4/5	9/10
1500	-	5/5	5/5

 

Prominent clinical signs included decreased activity, aggression, ataxia, tremors, diaorrhoea, exophthalmos, gasping, lacrimation, nasal discharge, piloerection, polyuria, prolapsed penis and salivation.

Conclusions:

The acute oral LD50 (with 95% confidence limits) for male and females was 492 (363 - 666) and 809 (600 - 1090) mg/kg respectively. A combined LD50 was determined at 630 mg/kg.

Executive summary:

An acute oral toxicity test (standard acute method) was conducted with rats to determine the potential for Profenofos Technical to produce toxicity from a single dose via the oral route.

 

Five animals/sex were dose at levels of 200, 400, 100 and 1500 mg/kg. All animal were observed for mortality, signs of gross toxicity, and behavioral changes at least once daily for 14 days after dosing or until death occurred. Prominent clinical signs of toxicity included (but were not limited to) decreased activity, agreesion, ataxia, body tremors and diarrhoea. Necropsy findings included (but not limited to) distended GI tract (due to gas), testes drawn into the abdomen.

 

The acute oral LD₅₀ (with 95% confidence limits) for male and females was 492 (363 - 666) and 809 (600 - 1090) mg/kg respectively. A combined LD₅₀ was determined at 630 mg/kg.

Reference 4

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

8 September 2004 to 5 October 2004

Reliability:

1 (reliable without restriction)

Qualifier:

according to guideline

Guideline:

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

Deviations:

no

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1100 (Acute Oral Toxicity)

Deviations:

no

GLP compliance:

yes

Test type:

up-and-down procedure

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

female

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Doses:

199, 630, 2000 mg/kg

No. of animals per sex per dose:

up to 3/gp

Control animals:

no

Sex:

female

Dose descriptor:

LD50

Effect level:

ca. 1 178 mg/kg bw

Based on:

test mat.

95% CL:

ca. 630 - ca. 2 000

Individual body weights/weight gains, doses and mortalities in Table 1. Individual cage-side and necropsy observations are presented in Tables 2 and 3, respectively.

 

199 mg/kg (1 animal)

This animal survived, gained body weight, and appeared active and healthy over the 14-day observation period. There were no signs of gross toxicity, adverse pharmacologic effects, or abnormal behaviour. No gross abnormalities were noted for the animal when necropsied following the 14-day observation period.

 

630 mg/kg (3 animals)

All animals survived administration of the test substance. Following test substance administration, all three rats exhibited clinical signs including ocular discharge, facial staining, hypoactivity, hunched posture, ano-genital staining and a reduced fecal volume. All animals recovered from the above clinical signs by Day 10 and appeared active and healthy for the remainder of the study. Although one animal lost body weight from Day 0 through Day 7, all animals gained weight over the entire 14-day observation period. No gross abnormalities were noted for any of the animals when necropsied following the 14-day observation period.

 

2,000 mg/kg (3 animals)

All three animals died within one day of test substance administration. Toxic signs noted prior to death included ocular discharge, hypoactivity, abnormal posture and a reduced faecal volume. Gross necropsy of the decedents revealed discoloration of the intestines.

  

Table 7.2.1 -6: Individual body weights/weight gains doses and mortalities

Animal No.	Sex	Dose Level (mg/kg)	Body Weight (g)					Dose (mL)	Mortality
			Day 0 Weight	Day 7 Weight	Gain*	Day 14 Weight	Gain*		Day	Weight (g)
6909	F	199	223	237	14	268	45	0.031	14	-
6937	F	630	210	186	-24	218	8	0.092	14	-
7082	F		181	197	16	241	60	0.080	14	-
7198	F		202	216	14	253	51	0.089	14	-
7000	F	2000	219	-	-	-	-	0.30	1	197
7121	F		226	-	-	-	-	0.40	1	214
7224	F		212	-	-	-	-	0.29	1	198

 

Table 7.2.1 -7: Individual cage side observations

Animal Number	Findings	Day of Occurrence
199 mg/kg
6909	Active and healthy	0-14
630 mg/kg
6937	Active and healthy Hypoactive Hunched posture Ocular discharge (red) Reduced faecal volume Facial staining Ano-genital staining	0 (1 hr), 10-14 0 (3 hrs)-4 0 (6 hrs)-2 1-3 1-8 4-7 4-9
7082	Active and healthy Hypoactive Ano-genital staining	0 (1 hr), 4-14 0 (3 hrs)-1 1-3
7198	Active and healthy Hypoactive Reduced faecal volume	0 (0.5 hr), 2-14 0 (3-5 hrs) 1
2000 mg/kg
7000	Active and healthy Hypoactive Hunched posture Ocular discharge (clear or red) Prone, reduced fecal volume Dead	0 (1 hr) 0 (3 hrs)-1 (am) 0 (4 hrs) 0 (4 hrs) –1 (am) 1 (am) 1 (pm)
7124	Active and healthy Ocular discharge (clear), hypoactive Prone Dead	0 (1 hr) 0 (3-9 hrs) 0 (9 hrs) 1
7224	Active and healthy Hypoactive Hunched posture, red ocular discharge Dead	0 (1 hr) 0 (3-6 hrs) 0 (6 hrs) 1

 

Table 7.2.1 -8: Individual necropsy observations

Animal Number	Tissue	Findings
199 mg/kg
6909	All tissues and organs	No gross abnormalities
630 mg/kg
6937, 7082, 7198	All tissues and organs	No gross abnormalities
2000 mg/kg
7000, 7124, 7224	Intestines	Red

 

Conclusions:

Under the conditions of this study, the acute oral LD50 of Profenofos Technical (CGA15324) is estimated to be 1178 mg/kg of body weight in female rats with a 95% Confidence Interval of 630 (lower) to 2000 (upper).

Executive summary:

An acute oral toxicity test (Up and Down Procedure) was conducted with rats to determine the potential for Profenofos Technical to produce toxicity from a single dose via the oral route.

 

Based on an estimate of the LD₅₀ supplied by the Sponsor, (630 mg/kg), an initial dose of 199 mg/kg was administered to one healthy female rat by oral gavage. Following the Up and Down procedure, six additional females were tested at levels of 630 or 2,000 mg/kg. Females were selected for the test because they are frequently more sensitive to the toxicity of test compounds than males. All animal were observed for mortality, signs of gross toxicity, and behavioral changes at least once daily for 14 days after dosing or until death occurred. Body weights were recorded prior to administration and again on Days 7 and 14 (termination) following dosing or after death. Necropsies were performed on all animals.  

 

Under the conditions of this study, the acute oral LD₅₀ of the test substance is estimated to be 1178 mg/kg of body weight in female rats with a 95% Confidence Interval of 630 (lower) to 2000 (upper).

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

620.5 mg/kg bw

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Reference 1

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

11 October 2004 to 2 November 2004

Reliability:

1 (reliable without restriction)

Qualifier:

according to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1300 (Acute inhalation toxicity)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.2 (Acute Toxicity (Inhalation))

Deviations:

no

GLP compliance:

yes

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

nose only

Vehicle:

other: none

Analytical verification of test atmosphere concentrations:

yes

Remarks:

2.2 mg/L

Duration of exposure:

ca. 4 h

Concentrations:

2 mg/L

No. of animals per sex per dose:

5 animals/sex/gp

Control animals:

no

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 2.2 mg/L air (analytical)

Based on:

other: no deaths observed

Exp. duration:

4 h

Mortality:

No deaths were observed.

 

Clinical observations:

During exposure clinical observations were associated with restraint, including wet fur and salivation. In addition all animals had increased breathing rate.

 

Post exposure hunched posture and piloerection were observed in one female.

 

Changes indicative of irritation of the respiratory tract (increased breathing rate and abnormal respiratory noise in some animals) were observed post exposure.

 

By day 3, post exposure, the clinical condition of the animals had greatly improved, with all animals fully recovered by day 7 of the study.

 

Bodyweight:

Three males and 1 female had gained weight by day 8 of the study. All males and 2 females had gained weight by the end of the study. The remaining females showed some evidence of weight gain during the study.

 

Necropsy:

There were no test material related changes observed.

 

Table 7.2.2-1: Particulate concentration

Target particulate concentration (mg/L)	Measured particulate concentration (mg/L) Mean ± SD
2	2.20±0.25

 

Table 7.2.2-2: Aerodynamic particle size distribution

Time into exposure (minutes)	Median size (MMAD) (um)	GSD
62	3.51	1.65
180	3.01	1.59

Conclusions:

Nose only exposure to a particulate concentration of 2.2 mg Profenofos Technical (CGA15324)/L resulted in no deaths and no adverse effects. It is concluded that the LD50 of Profenofos Technical (CGA15324) exceeds 2.2 mg/L.

Executive summary:

A group of 5 male and 5 female SD rats were exposed nose only for a single 4 hour period to Profenofos Technical (CGA15324) at a target particulate concentration of 2 mg/L. Test atmospheres were analysed for particulate concentration and Profenofos Technical (CGA15324). The particle size distribution of the test atmosphere was analysed twice during the exposure period. Following exposure, the animals were retained without treatment for 14 days. Clinical observations and bodyweights were recorded throughout the study and at the end of the scheduled period, the animals were killed and subjected to a gross examination post mortem.

 

The achieved test atmospheres had the following characteristics: Achieved concentration: 2.2 mg/L, MMAD 3.51 and 3.01 um, GSD 1.675 and 1.59.

 

There were no deaths. Transient signs of respiratory irritation were seen in all animals. There were no test material related macroscopic findings observed at necropsy.

 

Nose only exposure to a particulate concentration of 2.2 mg Profenofos Technical (CGA15324)/L resulted in no deaths and no adverse effects. It is concluded that the LD₅₀ of Profenofos Technical (CGA15324) exceeds 2.2 mg/L.

Reference 2

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

28 October 2005 to 11 November 2005

Reliability:

1 (reliable without restriction)

Qualifier:

according to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1300 (Acute inhalation toxicity)

Deviations:

no

Qualifier:

according to guideline

Guideline:

other: JMAFF 12 Nouan-8147 (2000)

Deviations:

no

GLP compliance:

yes

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

nose only

Vehicle:

air

Remarks:

none

Analytical verification of test atmosphere concentrations:

yes

Remarks:

2.03 mg/L

Duration of exposure:

ca. 4 h

Concentrations:

2 mg/L

No. of animals per sex per dose:

5 animals/sex/gp

Control animals:

no

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 2.03 mg/L air (analytical)

Based on:

other: no deaths observed

Exp. duration:

4 h

Mortality:

No deaths were observed.

 

Clinical observations:

No adverse clinical signs of toxicity were observed during or post exposure.

 

Bodyweight:

All animals gained weight.

 

Necropsy:

There were no test material related changes observed.

 

Table 7.2.2 -3: Particulate concentration

Target particulate concentration (mg/L)	Measured particulate concentration (mg/L) Mean ± SD
2	2.03±0.20

 

Table 7.2.2 -4: Aerodynamic particle size distribution

Time into exposure (minutes)	Median size (MMAD) (um)	GSD
60	2.5	1.77
180	2.5	1.59

Conclusions:

Under the conditions of this study, the single exposure acute inhalation LC50 of Profenofos Technical is greater than 2.03 mg/L in male and female rats.

Executive summary:

A group of 5 male and 5 female SD rats were exposed nose only for a single 4 hour period to Profenofos Technical (purity 89%) at a target particulate concentration of 2 mg/L. Test atmospheres were analysed for particulate concentration and Profenofos Technical. The particle size distribution of the test atmosphere was analysed twice during the exposure period. Following exposure, the animals were retained without treatment for 14 days. Clinical observations and bodyweights were recorded throughout the study and at the end of the scheduled period, the animals were killed and subjected to a gross examination post mortem.

 

The achieved test atmospheres had the following characteristics: Achieved concentration: 2.03 mg/L, MMAD 2.5 um, GSD 1.77 and 1.59.

 

There were no deaths or clinical signs observed. There were no test material related macroscopic findings observed at necropsy.

 

Nose only exposure to a particulate concentration of 2.03 mg Profenofos Technical/L resulted in no deaths and no adverse effects. It is concluded that the LD₅₀ of Profenofos Technical exceeds 2.03 mg/L.

Reference 3

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

Not stated

Reliability:

3 (not reliable)

Rationale for reliability incl. deficiencies:

other: Details of test material lacking from report. Type of inhalation exposure not reported

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

Deviations:

no

GLP compliance:

yes

Test type:

standard acute method

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

whole body

Remarks:

assumed to be whole body based on chamber size

Vehicle:

air

Analytical verification of test atmosphere concentrations:

yes

Remarks:

2.23, 2.77, 4.57, 6.30 mg/L

Duration of exposure:

ca. 4 h

Concentrations:

Intended doses not stated

No. of animals per sex per dose:

5 animals/sex/gp

Control animals:

no

Sex:

male/female

Dose descriptor:

LC50

Effect level:

ca. 3.36 mg/L air (analytical)

95% CL:

2.53 - 4.47

Exp. duration:

4 h

Conclusions:

The combined sex LC50 was calculated to be 3.36 mg/L (95% confidence limits 2.53 - 4.47 mg/L)

Executive summary:

A group of 5 male and 5 female SD rats were exposed for a single 4 hour period to CGA15324 at a target particulate concentrations of 2.23, 2.77, 4.57 and 6.30 mg/L. The type of exposure was assumed to be whole body (based on the size of the exposure chamber [500 L]).

 

There were no deaths or clinical signs observed. There were no test material related macroscopic findings observed at necropsy.

 

Nose only exposure to a particulate concentration of 3.36 mg CGA15324/L resulted in no deaths and no adverse effects. It is concluded that the LD₅₀of Profenofos Technical exceeds 3.36 mg/L (95% confidence limites 2.53 - 4.47 mg/L).

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LC50

Value:

220 mg/m³

Acute toxicity: via dermal route

Link to relevant study records

Reference

Reference 1

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Study period:

27 October 2005 to 10 November 2005

Reliability:

1 (reliable without restriction)

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1200 (Acute Dermal Toxicity)

Deviations:

no

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Deviations:

no

Qualifier:

according to guideline

Guideline:

other: JMAFF 12 Nouan 8147 (2000)

Deviations:

no

GLP compliance:

yes

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Type of coverage:

occlusive

Vehicle:

unchanged (no vehicle)

Duration of exposure:

24 hour exposure

Doses:

2000 mg/kg

No. of animals per sex per dose:

5 animals/sex/gp

Control animals:

no

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

other: no deaths observed

Individual body weights and doses are presented in Table 1. Individual cage-side and necropsy observations are presented in Tables 2 and 3, respectively.

 

All animals survived, gained body weight, and appeared active and healthy during the study. Apart from dermal irritation (erythema and edema) noted at the dose site of four females between Days 1 and 2, there were no other signs of gross toxicity, adverse pharmacologic effects or abnormal behavior. No gross abnormalities were noted for any of the animals when necropsied at the conclusion of the 14-day observation period.

 

Table 7.2.3-1: Individual bodyweights/weight gains and doses

Animal No.	Sex	Body Weight (g)					Dose# ml
		Day 0 Weight	Day 7 Weight	Gain*	Day 14 Weight	Gain*
6089	M	220	253	33	316	96	0.29
6090	M	241	261	20	338	97	0.32
6091	M	247	269	22	322	75	0.33
6092	M	243	273	30	356	113	0.33
6093	M	246	277	31	347	101	0.33
6094	F	190	211	21	236	46	0.25
6095	F	178	190	12	233	55	0.24
6096	F	191	204	13	241	50	0.26
6097	F	196	210	14	247	51	0.26
6098	F	189	207	18	242	53	0.25

* - Body weight gain from Day 0.

# -The test substance was administered as received. Specific Gravity – 1.487 g/ml. 

 

Table 7.2.3-2: Individual cage-side observations

Animal Number	Findings	Day of Occurrence
MALES 6089 – 6093	Active and healthy	0-14
FEMALES 6094, 6096, 6097	Active and healthy Erythema / oedema present at dose site	0-14 1-2
6095	Active and healthy	0-14
6098	Active and healthy Erythema / oedema present at dose site	10-14 1

 

Table 7.2.3-3: Individual necropsy observations

Animal Number	Tissue	Findings
MALES 6089 – 6093	All tissues and organs	No gross abnormalities
FEMALES 6094 - 6098	All tissues and organs	No gross abnormalities

Conclusions:

Under the conditions of this study, the single dose acute dermal LD50 of Profenofos Technical is greater than 2000 mg/kg of body weight in male and female rats.

Executive summary:

An acute dermal toxicity test was conducted with rats to determine the potential for Profenofos Technical to produce toxicity from a single topical application.

 

Two thousand milligrams of the test substance per kilogram of body weight was applied to the skin of ten healthy rats for 24 hours. The animals were observed for mortality, signs of gross toxicity, and behavioral changes at least once daily for 14 days. Body weights were recorded prior to application and again on Days 7 and 14 (termination). Necropsies were performed on all animals at terminal sacrifice.

 

All animals survived, gained body weight and appeared active and healthy during the study. Apart from dermal irritation (erythema and edema) noted at the dose site of four females between Days 1 and 2, there were no other signs of gross toxicity, adverse pharmacologic effects or abnormal behavior. No gross abnormalities were noted for any of the animals when necropsied at the conclusion of the 14-day observation period.

 

Under the conditions of this study, the single dose acute dermal LD₅₀ of Profenofos Technical is greater than 2000 mg/kg of body weight in male and female rats.

Reference 2

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

9 September 2004 to 23 September 2004

Reliability:

1 (reliable without restriction)

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1200 (Acute Dermal Toxicity)

Deviations:

no

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Deviations:

no

Qualifier:

according to guideline

Guideline:

other: JMAFF 59 NohSan 4200 (1985)

Deviations:

no

GLP compliance:

yes

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Type of coverage:

occlusive

Vehicle:

unchanged (no vehicle)

Duration of exposure:

24 hour exposure

Doses:

2000 mg/kg

No. of animals per sex per dose:

5 animals/sex/gp

Control animals:

no

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

other: no deaths observed

Individual body weights and doses are presented in Table 1. Individual cage-side and necropsy observations are presented in Tables 2 and 3, respectively.

 

All animals survived, gained body weight, and appeared active and healthy during the study. There were no signs of gross toxicity, dermal irritation, adverse pharmacological effects or abnormal behaviour. No gross abnormalities were noted for any of the animals when necropsied at the end of the 14 day observation period.

 

Table 7.2.3-4: Individual bodyweights/weight gains and doses

Animal No.	Sex	Body Weight (g)					Dose# ml
		Day 0 Weight	Day 7 Weight	Gain*	Day 14 Weight	Gain*
6926	M	267	301	34	377	110	0.37
6927	M	265	287	22	384	119	0.37
6928	M	280	313	33	397	117	0.39
6929	M	280	321	41	370	90	0.39
6930	M	286	307	21	369	83	0.39
6931	F	195	212	17	230	35	0.27
6932	F	200	222	22	244	44	0.28
6933	F	178	199	21	240	62	0.25
6934	F	192	216	24	250	58	0.26
6935	F	200	212	21	249	49	0.28

* - Body weight gain from Day 0.

# - The test substance was administered as received. Specific Gravity – 1.446 g/ml

 

Table 7.2.3-5: Individual cage-side observations

Animal Number	Findings	Day of Occurrence
MALES 6926 - 6930	Active and healthy	0-14
FEMALES 6931 - 6935	Active and healthy	0-14

 

Table 7.2.3 -6: Individual necropsy observations

Animal Number	Tissue	Findings
MALES 6926 - 6930	All tissues and organs	No gross abnormalities
FEMALES 6931 - 6935	All tissues and organs	No gross abnormalities

 

Conclusions:

Under the conditions of this study, the single dose acute dermal LD50 of Profenofos Technical (CGA15324) is greater than 2000 mg/kg of body weight in male and female rats.

Executive summary:

An acute dermal toxicity test was conducted with rats to determine the potential for Profenofos Technical to produce toxicity from a single topical application.

 

Two thousand milligrams per kilogram of body weight of the test substance was applied to the skin of ten healthy rats for 24 hours. The animals were observed for mortality, signs of gross toxicity, and behavioural changes at least once daily for 14 days. Body weights were recorded prior to application and again on Days 7 and 14 (termination). Necropsies were performed on all animals at terminal sacrifice.

 

All animals survived, gained body weight and appeared active and healthy during the study. There were no signs of gross toxicity, dermal irritation, adverse pharmacologic effects or abnormal behaviour. No gross abnormalities were noted for any of the animals when necropsied at the conclusion of the 14-day observation period.

 

Under the conditions of this study, the single dose acute dermal LD₅₀ of Profenofos Technical (CGA15324) is greater than 2000 mg/kg of body weight in male and female rats.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 000 mg/kg bw

Additional information

Acute oral toxicity

Of the two studies conducted using the Up and Down procedure, the key study returned an LD₅₀ value of 621 mg/kg (purity 89%, with <2% chlorobenzene), with the supporting study returning an LD₅₀ value of 1178 mg/kg (purity 92.1%). In the key study, 3 female rats were given each 350 or 1000 mg/kg. At 350 mg/kg no clinical signs were observed, with 2/3 rats administered 1100 mg/kg dying. Ocular discharge, hypoactivity, abnormal posture, piloerection, ano-genital staining and reduced faecal volume were noted prior to death. Necropsy revealed discolouration of the intestines.

 

In the supporting study, rats administered 199 mg/kg displayed no clinical signs of toxicity. Rats given 630 mg/kg exhibited clinical signs of toxicity which were similar to those previously reported. No mortality or clinical signs were observed 10 days after treatment. All rats dosed at 2000 mg/kg died within one day of dosing. Clinical signs were similar to those already reported.

 

The second supporting study, Kuhn (1990), undiluted Profenofos was administered at doses of 200, 400 and 1000 mg/kg to 5 male and 5 female rats. An additional 5 females received 1500 mg/kg. Most animals at the 100 and 1500 mg/kg dose group died within the first few days after treatment. Prominent clinical signs included decreased activity, aggression, ataxia, tremors, diarrhoea, exophthalmos, gasping, lacrimation, nasal discharge, piloerection, polyuria, prolapsed penis and salivation. The oral LD₅₀ was calculated to be 630 mg/kg.

 

The third supporting study, (Glaza, 1994) was not designed to determine an LD₅₀ value, but rather to establish NOEL for both systemic toxicity and also inhibition of cholinesterase activity. Whilst this study is included as supporting data, no information is included in the study to confirm whether butyryl or acetyl cholinesterase activity was measured (the former having no biological relevance). The following NOEL were established:

NOEL systemic males/females: 100 mg/kg

NOEL erythrocyte cholinesterase inhibition males: 25 mg/kg (based on 21% inhibition at 100 mg/kg)

NOEL erythrocyte cholinesterase inhibition females: 0.5 mg/kg (based on 31% inhibition at 25 mg/kg)

NOEL brain cholinesterase inhibition males/females: 100 mg/kg (based on inhibition in excess of 30% at 400 mg/kg)

  

Acute dermal toxicity

Both the key (Durando, 2005) and supporting study (Merkel, 2004) tested Profenfos (purity 89% and 92.1% respectively) using a limit dose protocol study design. Clinical signs of dermal irritation (erythema and oedema) were reported in the key study, with no signs of toxicity or dermal irritation reported in the supporting study. In both cases no treatment related gross abnormalities were observed at necropsy. The LD₅₀ value for both studies was in excess of 2000 mg/kg.

 

Acute inhalation toxicity

The key (Rattray, 2004) and the supporting study (Durando, 2005) were limit dose studies, where rats were administered Profenofos (purity 92.1% and 89% respectively) nose only for a single 4 hr exposure. In both cases the LD₅₀ values were in excess of 2 mg/L (>2.2 and >2.03 mg/L respectively), equivalent to 200 mg/m³. Changes indicative of irritation of the respiratory tract (increased breathing rate and abnormal respiratory noise in some animals) were observed post exposure in the Rattray (2004) only.

 

The second supporting study (Horath, 1982) also utilised a single 4 hour expose. However the route of inhalatory exposure was not stated. Based on the size of the inhalatory chamber, it was assumed that a whole body exposure was used. Again this study displayed clinical signs of respiratory irritation, with an LC₅₀ value of 3.36 mg/L determined (equivalent to 336 mg/m³).

 

Summary

The clinical signs of toxicity following acute exposure were typical of cholinergic poisoning, which appeared at doses greater than 100 mg/kg. Profenofos was of low toxicity when administered via the dermal route to rats (LD₅₀ >2000 mg/kg) or via the inhalation route (LC₅₀ >2 mg/L). Where the NOEL was determined this was based on inhibition of brain cholinesterase activity, clinical signs of toxicity did not accompany the inhibition observed.

Justification for classification or non-classification

Acute toxicity oral:

The test material is classified as ‘Acute Tox 4’ and the hazard statement ‘H302: Harmful if swallowed’ should be applied according to the harmonised classification in Regulation 1272/2008, and the LD50 620.5 mg/kg bw result.

 

Acute toxicity dermal:

The test material is classified as ‘Acute Tox 4’ and the hazard statement ‘H312: Harmful in contact with skin’ should be applied according to the harmonised classification in Regulation 1272/2008, although the LD50 is greater than 2000 mg/kg bw, which would indicate no classification. It was decided that the classification should reflect the harmonised value in Regulation 1272/2008.

 

Acute toxicity inhalation:

The test material is classified as ‘Acute Tox 4’ and the hazard statement ‘H332: Harmful if inhaled' should be applied according to the harmonised classification in Regulation 1272/2008, and the LC50 220 mg/m3 result.

 

Under 67/548/EEC Profenofos was classified as R20/21/22 ‘Harmful by inhalation, in contact with skin and if swallowed. This classification was harmonised to Regulation 1272/2008 (Index Number 015-135-00-0) Acute Tox. 4 H302, H312 and H332.