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

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.15 mg/m³

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Overall assessment factor (AF):

225

Modified dose descriptor starting point:

LOAEC

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

5.9 mg/m³

Most sensitive endpoint:

acute toxicity

DNEL related information

Overall assessment factor (AF):

12.5

Modified dose descriptor starting point:

LOAEC

Local effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.9 mg/m³

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Overall assessment factor (AF):

37.5

Dose descriptor:

LOAEC

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

2 mg/m³

Most sensitive endpoint:

acute toxicity

DNEL related information

Overall assessment factor (AF):

37.5

Dose descriptor starting point:

NOAEC

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.08 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Overall assessment factor (AF):

30

Modified dose descriptor starting point:

NOAEL

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

40 mg/kg bw/day

Most sensitive endpoint:

acute toxicity

DNEL related information

Overall assessment factor (AF):

50

Modified dose descriptor starting point:

NOAEL

Local effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.01 mg/cm²

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Overall assessment factor (AF):

12.5

Dose descriptor:

other: NOAEL

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.4 mg/cm²

Most sensitive endpoint:

acute toxicity

DNEL related information

Overall assessment factor (AF):

37.5

Dose descriptor starting point:

other: LOAEL

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - workers

ACUTE:

 

Table:Available acute dose descriptors per endpoint for profenofos as a result of its hazard assessment

Endpoint		Quantitative dose descriptor (appropriate unit) or qualitative assessment		Associated relevant effect	Remarks on study
		Local	Systemic
Acute toxicity	oral	Not required	Not required	-	-
	dermal	LOAEC 13.2 mg/cm^2	NOAEL 2000 mg/kg	Local: Erythema and oedema Systemic: No observed effect	Acute rat dermal study
	inhalation	NOAEC 220 mg/m^3	NOAEC 220 mg/m^3	Local: signs of irritation post exposure Systemic: No observed effect	Acute rat inhalation study

 

Acute Dermal:

Local -

Dose descriptor selection: a NOAEC (local) value was not identified in the acute dermal toxicity study due to erythema and oedema observed at all levels. The lowest reliable dose descriptor available was LOAEC, with the value converted to mg/cm² value based on the quantity of test material applied to the test area of skin (for the acute dermal rat study a dose area of approximately 5 in², equivalent to 32.5 cm² was used, with a mean bodyweight of 214g).

Acute NOAEL = 2000 mg/kg bw * 214g / 1000g / 32.5 cm² =

Acute LOAEC = 13.2 mg/cm² (termed LOAEC as local effects of erythema and oedema were observed)

 

Dose response: as no NOAEC was identified, additional assessment factor (AF) was applied according to the guidance in Chapter R.8.

 

AF: default AFs were applied according to the guidance in Chapter R.8 (note allometric scaling not relevant for local effects).

AF = Interspecies * Intraspecies (worker) * Exposure duration * Dose-response * Quality of whole database

AF = 2.5 * 5 * 1 *3 *1 = 37.5

DNEL deviation: N(L)OAEC / AF

- Acute DNEL dermal local = 13.2 cm² / 37.5 = 0.4 mg/cm²

 

Systemic-

Dose descriptor selection: the lowest reliable dose descriptor was selected from the acute (rat) dermal study

 

Dose response: no systemic effects were observed, LD₅₀ value identified. As no clinical signs of toxicity were observed the LD₅₀ value was also deemed a NOAEL (systemic).

 

AF: default AFs were applied according to the guidance in Chapter R.8.

AF = Interspecies (including allometric scaling for rat to human) * Intraspecies (worker) * Exposure duration * Dose-response * Quality of whole database

AF = 2.5 *(4) * 5 * 1 *1 *1 = 50

DNEL derivation: NOAEL / AF

- Acute DNEL dermal systemic = 2000 mg/kg / 50 = 40 mg/kg

 

Acute inhalation:

Local -

Dose descriptor selection: a NOAEC (local) value was not identified in the acute inhalation toxicity study due to signs of respiratory irritation observed post dosing. In this limit study a single dose level where no deaths or systemic toxicological signs were observed was used as the dose descriptor. This value was corrected for duration of experimental exposure and human respiratory volumevs. worker respiration volume, according to the guidance in Chapter R.8 (Corrected NOAEC = NOAEC * experimental duration (x hrs) / human exposure duration (8 hrs) * human resting resp. volume (6.7 m³) / worker resp. volume (10 m³). Corrected NOAEC = 220 mg/m³ * 4/8 * 6.7/10 = 73.7 mg/m³)

 

Dose response: as no NOAEC was identified, additional assessment factor (AF) was applied according to the guidance in Chapter R.8.

 

AF: default AFs were applied, according to the guidance in Chapter R.8 (note allometric scaling not relevant for the inhalatory route of exposure).

AF = Interspecies * Intraspecies (worker) * Exposure duration * Dose-response * Quality of whole database

AF = 2.5 * 5 * 1 * 3 *1 = 37.5

DNEL deviation: Corrected NOAEC / AF

- Acute DNEL inhalation local & systemic = 73.7 mg/m³ / 37.5 = 2.0 mg/m³

 

Systemic –

Dose descriptor selection: the lowest reliable dose descriptor was NOAEL (systemic) value selected from the acute (rat) inhalation study. This value was corrected for duration of experimental exposure and human respiratory volume vs. worker respiration volume, according to the guidance in Chapter R.8 (Corrected NOAEC = NOAEC * experimental duration (x hrs) / human exposure duration (8 hrs) * human resting resp. volume (6.7 m³) / worker resp. volume (10 m³). Corrected NOAEC = 220 mg/m³ * 4/8 * 6.7/10 = 73.7 mg/m³).

Dose response: no systemic effects were observed, the LD₅₀ value was also deemed a NOAEL (systemic).

 

AF: default AFs were applied, according to the guidance in Chapter R.8 (note allometric scaling not relevant for the inhalatory route of exposure).

AF = Interspecies * Intraspecies (worker) * Exposure duration * Dose-response * Quality of whole database

AF = 2.5 * 5 * 1 * 1 *1 = 12.5

DNEL deviation: Corrected NOAEC / AF

- Acute DNEL inhalation local & systemic = 73.7 mg/m³ / 12.5 = 5.9 mg/m³

 

Table Acute DNELs for workers

Endpoint Specific DNELs for Workers
Endpoint		Corrected dose-descriptor		Overall AF	Endpoint Specific DNEL
		Local	Systemic		Local	Systemic
Acute toxicity	oral	Not required	Not required	-	-	-
	Derm	LOAEC 13.2  mg/cm^2	NOAEL 2000 mg/kg	Local 37.5 Systemic 50	0.4 mg/cm^2	40 mg/kg
	inhal	LOAEC 73.7  mg/m^3	NOAEC 73.7  mg/m^3	Local 37.5 Systemic 12.5	2.0 mg/m^3	5.9 mg/m^3

 

REPEAT

 

Table Available repeat dose descriptors per endpoint for profenofos as a result of its hazard assessment 

Endpoint		Quantitative dose descriptor (appropriate unit) or qualitative assessment		Associated relevant effect	Remarks on study
		Local	Systemic
Repeated dose toxicity sub-acute/ sub-chronic/ chronic	oral	Not required	Not required	-	-
	dermal (sub-acute)	NOAEC 0.13 mg/cm^2	NOAEL 2.5 mg/kg/day	Local: erythema Systemic: Significant inhibition in brain cholinesterase activity	21 day dermal, rabbit
	dermal (sub-chronic / chronic)	Not tested	-	-	-
	Inhalation (sub acute)	LOAEC 68 mg/m^3	LOAEC 68 mg/m^3	Local: Signs of irritation, increased secretion of the mucous membranes of the nose Systemic: Significant inhibition in brain cholinesterase activity, reduction in food intake and bodyweight	21-day inhalation, rat
	Inhalation (sub-chronic / chronic)	Not tested	-	-	-

 

Repeat (sub-acute) dermal:

Local -

Dose descriptor selection: although ancanthosis was observed at all doses in the absence of any skin irritation (resulting in the author not establishing a NOAEL), the severity did not increase in a dose related manner. Furthermore, no such effects were observed in the supporting study. Therefore the observation of ancanthosis was not considered to be toxicologically significant. Discounting this observation, no dermal effects were observed up to the maximum dose tested, the NOAEC was derived from the maximum dose applied (10 mg/kg/day) in the sub-acute (21 day) rabbit dermal study. The NOAEL value was converted to mg/cm² value based on the quantity of test material applied to the test area of skin (for the repeat dermal rabbit study animal weight ranged from 2420 to 3030g and the dose area of no less than 10% of the total body surface area (TBSA) was used. The 10% TBSA was calculated from Meek’s Formula (refer to 21 day dermal toxicity study report).

 

The 10% TBSA over the duration of the study ranged from 194.7 to 226.1 cm². For the purposes of this CSR mean values for both weight and 10% TBSA have been calculated: 2725g and 210.4 cm² respectively.

 

NOAEL = dose (mg/kg bw) * bw (g) / 1000g / skin area (cm²).

Sub-acute NOAEL = 2.5 mg/kg bw * 2725g / 1000g / 210.4 cm²

Sub-acute NOAEC = 0.03 mg/cm²

 

Dose response: no local effects, which were considered dose related were observed.

AF: default AFs were applied, according to the guidance in Chapter R.8 (note allometric scaling not relevant for local effects).

AF = Interspecies * Intraspecies (worker) * Exposure duration * Dose-response * Quality of whole database

AF = 2.5 * 5 * 1 * 1 *1 = 12.5

DNEL derivation: NOAEC / AF

- Repeat (sub-acute) DNEL dermal local = 0.13 mg/cm² / 12.5 = 0.01 mg/cm²

 

Systemic -

Dose descriptor selection: the lowest reliable dose descriptor was selected from the sub-acute (21 day) dermal study.

Dose response: no systemic effects or clinical signs of toxicity were observed; therefore an NOAEL value was determined.

AF: default AFs were applied, according to the guidance in Chapter R.8.

AF = Interspecies (including allometric scaling for rabbit to human) * Intraspecies (worker) * Exposure duration * Dose-response * Quality of whole database

AF = 2.5 *(2.4) * 5 * 1 *1 *1 = 30

DNEL derivation: NOAEL / AF

- Repeat (sub-acute) DNEL dermal systemic = 2.5 mg/kg / 30 = 0.08 mg/kg

 

From the available toxicological data on brain acetylcholinesterase inhibition, the duration of the study does not markedly increase the level of inhibition of this enzyme (refer to Section 7.5, Table 7.5-1). Therefore, the sub acute DNELs for local and systemic effects are considered applicable for the both a sub-chronic and chronic exposure scenario without the need to apply further AF for duration extrapolation.

 

Repeat (sub-acute) inhalation:

Local / systemic -

Dose descriptor selection: a NOAEC was not identified in the sub-acute (21 day) rat inhalation study due to signs of irritation to mucous membranes of the eyes and nose (local effects) and inhibition of brain cholinesterase activity (systemic effects). The lowest reliable dose descriptor available was LOAEC. This value was corrected for duration of experimental exposure and human respiratory volumevs. worker respiration volume, according to the guidance in Chapter R.8. (Corrected LOAEC = LOAEC * experimental duration (x hrs) / human exposure duration (8 hrs) * human resting resp. volume (6.7 m³) / worker resp. volume (10 m³). Corrected NOAEC = 68 mg/m³ * 6/8 * 6.7/10 = 34.2 mg/m³).

 

Dose response: as no NOAEC was identified, additional AF was applied according to the guidance in Chapter R.8.

 

AF: Default AFs were applied, according to the guidance in Chapter R.8 (note allometric scaling not relevant for the inhalatory route of exposure).

AF = Interspecies * Intraspecies (worker) * Exposure duration * Dose-response * Quality of whole database

AF = 2.5 * 5 * 1 * 3 *1 = 37.5

DNEL deviation: Corrected LOAEC / AF

- Repeat (sub-acute) DNEL inhalation local & systemic = 34.2 mg/m³ / 37.5 = 0.9 mg/m³

 

Extrapolation from a sub acute to sub-chronic / chronic exposure for local effects was not deemed relevant as the local effects would be expected to occur at the same dose irrespective of whether a sub-chronic or chronic scenario was utilised compared to a sub-acute dosing phase. The Repeat (sub-acute) DNEL inhalation for local effects would therefore provide protection in a sub-chronic / chronic scenario.

 

Repeat (sub-chronic) inhalation:

Local -

Refer toRepeat (sub-acute) DNEL inhalation local value.

 

Systemic –

Dose descriptor selection: a NOAEC was not identified in the sub-acute (21 day) rat inhalation study due to signs of irritation to mucous membranes of the eyes and nose (local effects) and inhibition of brain cholinesterase activity (systemic effects). The lowest reliable dose descriptor available was LOAEC. This value was corrected for duration of experimental exposure and human respiratory volumevs. worker respiration volume, according to the guidance in Chapter R.8. (refer above to Repeat (sub acute) inhalation). As the value was extrapolated from a sub-acute to a chronic scenario, additional AF was applied according to the guidance in Chapter R.8.

 

Dose response: as no NOAEC was identified, additional AF was applied according to the guidance in Chapter R.8.

 

AF: default AFs were applied, according to the guidance in Chapter R.8 (note allometric scaling not relevant for the inhalatory route of exposure).

AF = Interspecies * Intraspecies (worker) * Exposure duration * Dose-response * Quality of whole database (note, no additional AF for exposure duration was used as human data confirm no adverse effects following use of Profenofos)

AF = 2.5 * 5 * 3 * 3 *1 = 225

DNEL deviation: Corrected LOAEC / AF

- Repeat (chronic) DNEL inhalation systemic = 34.2 mg/m³ / 112.5 = 0.3 mg/m³

 

Repeat (chronic) inhalation:

Local -

Refer toRepeat (sub-acute) DNEL inhalation local value.

 

Systemic –

Dose descriptor selection: a NOAEC was not identified in the sub-acute (21 day) rat inhalation study due to signs of irritation to mucous membranes of the eyes and nose (local effects) and inhibition of brain cholinesterase activity (systemic effects). The lowest reliable dose descriptor available was LOAEC. This value was corrected for duration of experimental exposure and human respiratory volumevs. worker respiration volume, according to the guidance in Chapter R.8. (refer to Section1.2.1). As the value was extrapolated from a sub-acute to a chronic scenario, additional AF was applied according to the guidance in Chapter R.8.

 

Dose response: as no NOAEC was identified, additional AF was applied according to the guidance in Chapter R.8.

 

AF: default AFs were applied, according to the guidance in Chapter R.8 (note allometric scaling not relevant for the inhalatory route of exposure).

AF = Interspecies * Intraspecies (worker) * Exposure duration * Dose-response * Quality of whole database (note, no additional AF for exposure duration was used as human data confirm no adverse effects following use of Profenofos)

AF = 2.5 * 5 * 6 * 3 *1 = 225

DNEL deviation: Corrected LOAEC / AF

- Repeat (chronic) DNEL inhalation systemic = 34.2 mg/m³ / 225 = 0.15 mg/m³

 

Table 7-4:Chronic DNELs for workers

Endpoint Specific DNELs for Workers
Endpoint		Corrected dose-descriptor		Overall AF	Endpoint Specific DNEL
		Local	Systemic		Local	Systemic
Repeated dose toxicity sub-acute/ sub-chronic/ chronic	oral	Not required	Not required	-	-	-
	dermal (sub-acute / sub-chronic / chronic)	NOAEC 0.13  mg/cm^2	Starting dose not corrected (NOAEL 2.5 mg/kg/day)	Local 12.5 Systemic 30	0.01 mg/cm^2	0.08 mg/kg
	Inhalation (sub-acute)	LOAEC 34.2mg/cm^2	LOAEC 34.2  mg/cm^2	37.5	0.9 mg/m^3	0.9 mg/m^3
	Inhalation (sub chronic)			Local 37.5 Systemic 112.5	0.9 mg/m^3	0.3 mg/m^3
	Inhalation (chronic)			Local 37.5 Systemic 225	0.9 mg/m^3	0.15  mg/m^3

 

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Additional information - General Population

The substance is formulated into plant protection products that are not used within the EU, therefore, exposure to the general public is not expected.