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

Endpoint summary

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Reference 1

Endpoint:

chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Qualifier:

according to guideline

Guideline:

OECD Guideline 452 (Chronic Toxicity Studies)

Deviations:

no

GLP compliance:

yes

Limit test:

no

Species:

dog

Strain:

Beagle

Sex:

male/female

Route of administration:

oral: capsule

Vehicle:

other: lactose

Analytical verification of doses or concentrations:

yes

Duration of treatment / exposure:

12 months (once daily, 7 days/week)

Frequency of treatment:

Daily

Remarks:

Doses / Concentrations:0, 0.015, 0.05, 1, 12.5 mg/kg/dayBasis:other:

No. of animals per sex per dose:

4 animals/sex/dose

Control animals:

yes, concurrent vehicle

Dose descriptor:

NOEL

Effect level:

ca. 12.5 mg/kg bw/day (nominal)

Sex:

male/female

Basis for effect level:

other: The NOAEL for brain cholinesterase was deemed to be inexcess of 12.5 mg/kg, as no effect on enzyme activity or accompanying neutoroxic signs of toxicity were evident.

Critical effects observed:

not specified

OBSERVATIONS:

Clinical signs of toxicity:

No test material related clinical signs of toxicity were observed.

 

Mortality:

No mortality observed.

 

Auditory examination:

No auditory impairment

 

Bodyweight and bodyweight gain:

No test material related effects observed

 

Food consumption

No test material related effects observed

 

Eye examinations (+tonometry):

No test material related effects observed

 

Neurological examinations:

No test material related effects observed

 

Blood ands urinalysis:

Haematological findings:

Slightly decreased red blood cell parameters (erthrocyte count, haemoglobin concentration, haemocrit) were observed, however these were not thought to be of biological significance as they were either not dose related or only occured in one gender.

 

Clinical chemistry findings:

Throughout the study a dose related inhibition of plasma cholinesterase was recorded for males and females at all dose levels. As this was the butyryl form this was not considered biologically releant in light of the guidelines from JMPR (2007). Erythrocyte cholinesterase inhibition was seen for males and females at levels of 1 mg/kg and greater, however as brain cholinesterase activity was also measure, this was seen as the more relevant biomarker. No inhbition in this enzyme or neurotoxic estrase levels were affected by treatment. Therefore the NOAEL for brain cholinesterase was considered to be >12.5 mg/kg/day (refer to Table 7.5.1 -1).

 

Urinalysis:

There were no test material-related effects on urinalysis parameters.

 

SACRIFICE AND PATHOLOGY:

Organ weight:

No differences observed

 

Gross and histopathology:

No treatment related organ or tissue changes were noted at necropsy in any of the treated animals. An increased incidence of binucleated hepatocytes in the perilobular region was observed in 3/4 males and 4/4 females in the mid dose (1 mg/kg) group and all animals in the high dose group (12.5 mg/kg). The degree of change was minimal in the mid dose group and slight to moderate in the high dose group. In addition, 1/4 male dogs from the mid dose and 2/4 male dogs from the high dose group exhibited minimal to slight hyperplasia of the bile duct epithelium. As cell degeneration was not increased in these animals the toxicological significance of binucleated perilobular hepatocytes was not known.

 

Neurotoxicological evaluation

No difference between animals in the control group and compared to animals in the 500 ppm group were found following examination of the central and peripheral neural responses.

 

Table 7.5.1 -1: AChE %inhibition

Dose	Time	Plasma				RBC				Brain
(ppm)	(weeks)	Male	Sig	Female	Sig	Male	Sig	Female	Sig	Male	Sig	Female	Sig
0	-1	-	-	-	-	-	-	-	-	-	-	-	-
0	6	-	-	-	-	-	-	-	-	-	-	-	-
0	13	-	-	-	-	-	-	-	-	-	-	-	-
0	26	-	-	-	-	-	-	-	-	-	-	-	-
0	52	-	-	-	-	-	-	-	-	-	-	-	-
0.015	-1	13		-4	NS	-34		6	NS	-	-	-	-
0.015	6	55	*	42	*	-	-	-	-	-	-	-	-
0.015	13	55	*	41	*	-20	NS	6	NS	-	-	-	-
0.015	26	54	*	35	*	-24	NS	8	NS	-	-	-	-
0.015	52	26	NS	13	NS	-21	NS	10	NS	-15	NS	-9	NS
0.05	-1	-10	NS	0	NS	-24	NS	6	NS	-	-	-	-
0.05	6	62	*	68	*	-	-	-	-	-	-	-	-
0.05	13	63	*	68	*	-14	NS	20	NS	-	-	-	-
0.05	26	63	*	67	*	-11	NS	30	NS	-	-	-	-
0.05	52	35	*	47	*	-10	NS	20	NS	-10	NS	-18	NS
1	-1	16	NS	10	NS	-35	NS	-24	NS	-	-	-	-
1	6	89	*	82	*	-	-	-	-	-	-	-	-
1	13	88	*	80	*	58	*	57	*	-	-	-	-
1	26	91	*	83	*	63	*	50	*	-	-	-	-
1	52	82	*	74	*	57	*	56	*	-20	NS	-19	NS
12.5	-1	4	NS	9	NS	-27	NS	3	NS	-	-	-	-
12.5	6	93	*	92	*	-	-	-	-	-	-	-	-
12.5	13	92	*	92	*	81	*	88	*	-	-	-	-
12.5	26	92	*	94	*	82	*	85	*	-	-	-	-
12.5	52	88	*	87	*	83	*	86	*	11	NS	6	NS

 

Reference:

JMPR (2007). Pesticide residues in food. Joint FAO/WHO meeting on pesticide residues. Report of the Joint Meeting of the FAO Panel of Experts on Pesticide Residues in Food and the Environment and the WHO Core Assessment Group on Pesticide Residues. Geneva, Switzerland, 18 -27 September 2007.

Conclusions:

The NOAEL for brain cholinesterase was deemed to be inexcess of 12.5 mg/kg, as no effect on enzyme activity or accompanying neutoroxic signs of toxicity were evident. In terms of general toxicological NOAEL this was considered to be 0.05 mg/kg based on haematological and blood chemistry changes and histopathological findings in the liver.

Executive summary:

This study was conducted to assess the potential toxicity and to estimate the nOEL following exposure to CGA 15324 tech. administered in gelatin capsules to Beagle dogs. The test material was mixed with lactose and administered via capsule at daily doses of 0, 0.015, 0.05, 1 and 12.5 mg/kg/day to 4 animals/sex/gp for a period of at least 52 weeks.

 

No treatment related deaths wre observed in the study. In life observations and food consumption were not affected by treatment. Eye examination, intraocular pressure, neurological examination, urine analysis, organ weights and macroscopical examinations revealed no treatment realated changes. There was a slight treatment related depression in mean overal body weight gainin females in the high dose group, which was due to one female.

 

Erythrocyte count, haemoglobin concentration and haemocrit were reduced in males and females in the high dose group (12.5 mg/kg) and males treated at 1 mg/kg. A higher RBC volume was recorded for males at 12.5 mg/kg. In addition, at weeks 26 and 52 a slightly higher platelet count was recorded for males at >1mg/kg. Mean plasma protein and albumin levels were reduced in males and females dosed at 12.5 mg/kg and in males dosed at 1 mg/kg, mean globulin was lower in high dose females with the albumin:globulin ratio lower in males dosed at 1 and 12.5 mg/kg. This was considered to be the calcium binding properties of albumin. These effects were not considered biologically relevant as they were either not dose related or did not occur in the corresponding gender. Throughout the study a dose related inhibition of plasma cholinesterase was recorded for males and females at all dose levels tested, whereas a toxicological relevant inhibition of erythrocyte cholinesterase wa seen for males and females at >1mg/kg. Brain and cholinesterase and neurotoxic esterase levels were not affected.

 

On microsocpical examination, binucleated perilobular hepatocytes were increased in male and female groups (1 and 12.5 mg/kg) and were accompanied by hyperplasia of the bile duct epithelium in the male groups. In addition, bile pigments were increased in the convoluted renal tubules in high dose animals.

 

The NOAEL for brain cholinesterase was deemed to be inexcess of 12.5 mg/kg, as no effect on enzyme activity or accompanying neutoroxic signs of toxicity were evident. In terms of general toxicological NOAEL this was considered to be 0.05 mg/kg based on haematological and blood chemistry changes and histopathological findings in the liver.

Reference 2

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

10 September 1979 to 10 March 1980

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Non-GLP

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 409 (Repeated Dose 90-Day Oral Toxicity Study in Non-Rodents)

Deviations:

not applicable

GLP compliance:

no

Limit test:

no

Species:

dog

Strain:

Beagle

Sex:

male/female

Route of administration:

oral: feed

Vehicle:

unchanged (no vehicle)

Analytical verification of doses or concentrations:

yes

Duration of treatment / exposure:

continuous, 6 month duration

Frequency of treatment:

continuous

Remarks:

Doses / Concentrations:0, 0.2, 2, 100 and 500 ppmBasis:nominal in diet

Remarks:

Doses / Concentrations:0, 0.0072, 0.05, 2.9, 14.4 mg/kg/dayBasis:actual ingested

No. of animals per sex per dose:

7 animals/sex/group

Control animals:

yes, plain diet

Dose descriptor:

NOAEL

Effect level:

ca. 500 ppm

Sex:

male/female

Basis for effect level:

other: (equivalent to 14.4 mg/kg diet). No affect on brain cholinesterase activity

Critical effects observed:

not specified

OBSERVATIONS:

Clinical signs of toxicity:

No test material related clinical signs of toxicity were observed.

 

Mortality:

No mortality observed.

 

Auditory examination:

No auditory impairment

 

Bodyweight and bodyweight gain:

No test material related effects observed

 

Food consumption

High dose group males consumed less food during the first 3 weeks of the study.

 

Blood ands urinalysis:

Haematological findings:

Slightly decreased red blood cell parameters (erthrocyte count, haemoglobin concentration, haemocrit) were observed in the 500 ppm group.

 

Clinical chemistry findings:

In males plasma cholinesterase activity was depressed markedly from week 8 onwards in the low dose group, with the level of inhibition not exceeding 21%. Folloiwng 4 weeks of recovery activity levels recovered. At dose levels of 2, 100 and 500 ppm plasma cholinesterase %inhibition ranged from 27 -47%; 25 - 77% and 76 - 89% respectively. In females, plasma cholinesterase activity was unaffected at the low dose group, with %inhibition ranging from 45 - 64%; 70 -79% and 81 -90% for dose groups 2, 100 and 500ppm over the 6 month period.

 

Erythrocyte levels in males were not affected until week 26 in the low dose group where the level of inhibition reached 21%. At doses of 100 and 500ppm the levels of inhibition were marked from week 4 onwards, with level of inhibition ranging from 52 -74% and 68 - 91% respectively. For females, erythrocyte inhibtion at 0.2 and 2 ppm was not markedly reduced. At 100 and 500 ppm the level of inhibition ranged from 35 to 80% and 68 - 91% respectively. Brain cholinesterase activity appeared to be the most resistant to the effects of CGA15324. Both plasma and erythrocyte cholinesterase activity showed a tendency to recovery during the 4 week recovery period.

 

The status report after 17 weeks of treatment concluded that the NOEL for cholinesterase inhibition was 0.2 ppm for both genders. The data has been interpreted in light of the guidelines for the preparation of toxicological working papers for the WHO assessment group of the JMPR (Dec 2000).

 

Table 7.5.1 -2: AChE % Inhibition 

Dose	Time	Plasma				RBC				Brain
(ppm)	(weeks)	Male	Sig	Female	Sig	Male	Sig	Female	Sig	Male	Sig	Female	Sig
0.2	4	8	NS	-5	NS	-16	NS	-12	NS
0.2	8	20	NS	4	NS	-28	NS	-29	NS
0.2	13	17	NS	2	NS	-6	NS	-30	NS
0.2	17	21	NS	-26	NS	-10	NS	-6	NS
0.2	21	-	-	2	*	-	-	0	*
0.2	26	3	*	6	*	4	NS	-32		-8		8
0.2	R 30	-13		5		-40		-216
2	4	47	*	45	*	-12	*	-21	NS
2	8	45	*	52	*	-13	NS	-26	NS
2	13	60	*	64	*	2	*	-41	*
2	17	59	*	46	*	1	NS	-6	NS
2	21	-	-	47	*	-	-	1	*
2	26	27	*	50	*	21	NS	-13	NS	5		10
2	R 30	-36		-15		24		-16	NS
100	4	77	*	77	*	52	*	66	*
100	8	62	*	76	*	60	*	53	*
100	13	74	*	79	*	61	*	35	*
100	17	74	*	78	*	54	*	52	*
100	21	-	-	70	*	-	-	80	*
100	26	68	*	77	*	74	NS	66	*	-11		11
100	R 30	25	*	-18	NS	65		-3	NS
500	4	89	*	81	*	74	*	76	*
500	8	76	*	81	*	75	*	68	*
500	13	87	*	83	*	73	*	70	*
500	17	87	*	83	*	68	*	71	*
500	21	-	-	84	*	-	-	91	*
500	26	82	*	90	*	95	NS	91	*	-15		5
500	R 30	14		-21	NS	83		32	*

R - recovery

 

Urinalysis:

There were no test material-related effects on urinalysis parameters.

 

Opthalmoscopic examination:

A number of animals showed intercurrent changes of spontaneous and incidental nature. These effects were further evaluated. Histological examination of the eyes was unremarkable and some of the findings observed were confined to control dogs.

 

SACRIFICE AND PATHOLOGY:

Organ weight:

No differences observed

 

Gross and histopathology:

No treatment related organ or tissue changes were noted at necropsy in any of the treated animals.

 

Neurotoxicological evaluation

No difference between animals in the control group and compared to animals in the 500 ppm group were found following examination of the central and peripheral neural responses.

 

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:

In conclusion the NOEL for males and females is considere to be 500 ppm (14.4 mg/kg/day). This is based on no affect in brain acetylcholinesterase activity when assessed up to the maximum dose level tested.

Executive summary:

Groups of 7 beagle gods/sex were fed diets cotnaining 0, 0.2, 2, 100 and 500 ppm CGA 15324 for 6 months (equivalent to 0, 0.0072, 0.05, 2.9 and 14.4 mg/kg diet). One male and one female/gp were kept for a 4 week recovery period on control diet.

 

Animals in the high dose group were additionally subjected to a battery of tests to examine central and peripheral neural responses (e.g. muscle strength, tone, reflexes etc). At necropsy organs and tissue were examined for gross changes and subsequently histopathology.

 

Besides a transiently decreased diet intake in the males of the 500 ppm group, no effects with respect to mortality, clincial signs, including special neurologic examination, body weight, gross examination or histopathology. Both plasma and erythrocyte AChE inhibtion was evident, with levels of inhibtion ranging from 27 to 82% and 21 to 95% respectively for males at doses of 2 ppm and greater; and from 45 to 90% and 35 to 91% respectively for females at doses of 2ppm and greater and 100 ppm and greater, respectively.

 

The effects on the plasma and erythrocyte AChE activity showed a tendency to recover during the 4 week recovery period. Brain AChE activity remained unremarkable.

 

In light of the JMPR (2000) review, the NOAEL was based on brain cholinesterase inibition. As no affect on activity of this enzyme was observed up the maximum dose tested, the NOAEL was therefore considered to be 14.4 mg/kg for both male and females.

Reference 3

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

Not given

Reliability:

3 (not reliable)

Rationale for reliability incl. deficiencies:

other: IBTL study, non-GLP, non-guideline compliant. Study not validated by EPA, therefore data considered not reliable

Qualifier:

no guideline followed

GLP compliance:

no

Species:

dog

Strain:

Beagle

Sex:

male/female

Route of administration:

oral: feed

Vehicle:

unchanged (no vehicle)

Analytical verification of doses or concentrations:

no

Duration of treatment / exposure:

90 days

Frequency of treatment:

Once daily

Remarks:

Doses / Concentrations:0, 2, 20, 200 ppmBasis:nominal in diet

Remarks:

Doses / Concentrations:0, 0.05, 0.5, 5 mg/kg/dayBasis:other:

No. of animals per sex per dose:

5 animals/sex/gp for the control and high dose gp (with 1 animals/sex/gp kep on for a 4 week recovery post end of treatment)4 animals/sex/gp for the low and mid dose gps

Control animals:

yes, plain diet

Dose descriptor:

NOAEL

Effect level:

ca. 20 ppm

Sex:

male/female

Basis for effect level:

other: (equivalent to 0.5 mg/kg/day). Based on inhibition of brain cholinesterase activity of >20% at 200 ppm (~5 mg/kg diet)

Critical effects observed:

not specified

No test material related concerning clinical signs of toxicity, bodyweight, food consumption, mortaility, urinalysis, ophtahalmogic examinations, organ weights, gross pathology, histopathology, haemotology, clinical chemistry (with the exception of AChE inhbition discussed below) were observed.

 

Table 7.5.1 -3: AChE %inhibition

Dose	Time	Plasma				RBC				Brain
(ppm)	(weeks)	Male	Sig	Female	Sig	Male	Sig	Female	Sig	Male	Sig	Female	Sig
0	4	-	-	-	-	-	-	-	-	-	-	-	-
0	8	-	-	-	-	-	-	-	-	-	-	-	-
0	12	-	-	-	-	-	-	-	-	-	-	-	-
0	R-4	-	-	-	-	-	-	-	-	-	-	-	-
2	4	60		57		21		2		-		-
2	8	45		52		9		11		-		-
2	12	52		58		-42		-48		10		-1
20	4	50		66		13		30		-		-
20	8	32		63		18		50		-		-
20	12	40		69		10		31		9		-13
200	4	63		66		69		79		-		-
200	8	49		60		72		80		-		-
200	12	57		73		68		74		21		5
200	R-4	7		45		38		32		-3		-18

R-4 Recovery 4 weeks post end of treatment. 1 dog/sex used

 

The cholinesterase data has been interpreted in light of the guidelines for the preparation of toxicological working papers for the WHO assessment group of the JMPR (Dec 2000). Therefore, the most relevant endpoint was the brain cholinesterase activity. Whilst the author stated that activity of this enzyme remained normal throughout the experimental period, in light of the JMPR review, a level of inhibiton in excess of 20% is considered biologically relevant, with accompanying statistical analysis. In this case statistical analysis was not undertaken. However, due the evident dose response observed in males, the reduction observed is considered biologically relevant. The recovery period 4 week post the end of dosing in one male would suggest that the activity of brain cholinesterase recovered post treatment termination. The NOAEL therefore is considered to be 20 ppm (~0.5 mg/kg/day) based on brain cholinesterase inhibition at 200 ppm (~5 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 NOAEL is considered to be 20 ppm (~0.5 mg/kg/day) based on brain cholinesterase inhibition at 200 ppm (~5 mg/kg).

Executive summary:

CGA 15324 Technical was feed to male and female dogs at dose level of 0, 2, 20, 200 ppm (equialent to 0, 0.05, 0.5, 5 mg/kk/day) for 90 days. Each group consisted of 4 animals/sex, with the control and high dose groups including an additional animal/sex which were used to assess any potential reverisble effects of the test material 4 weeks post treatment cessation.

 

No significant abnormalities in the following parameters were observed: body weight, food consumption, clinical signs of toxicity, mortality, haematology and blood chemistry parameters, urinalysis, opthalmologic examinations, organ weights, gross pathology or histopathology.

 

Whilst reductions in erythrocyte and plasma cholinesterase activities were observed, the cholinesterase data has been interpreted in light of the guidelines for the preparation of toxicological working papers for the WHO assessment group of the JMPR (Dec 2000). Therefore, the most relevant endpoint was the brain cholinesterase activity. Whilst the author stated that activity of this enzyme remained normal throughout the experimental period, in light of the JMPR review, a level of inhibiton in excess of 20% is considered biologically relevant, with accompanying statistical analysis. In this case statistical analysis was not undertaken. However, due the evident dose response observed in males, the reduction observed is considered biologically relevant. The recovery period 4 week post the end of dosing in one male would suggest that the activity of brain cholinesterase recovered post treatment termination. The NOAEL therefore is considered to be 20 ppm (~0.5 mg/kg/day) based on brain cholinesterase inhibition at 200 ppm (~5 mg/kg).

Reference 4

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Non-GLP. No justification for max dose tested, no organ weights taken, no histopathology taken

Qualifier:

no guideline followed

Principles of method if other than guideline:

Does not conform to any particular guideline

GLP compliance:

no

Limit test:

no

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Route of administration:

oral: feed

Vehicle:

unchanged (no vehicle)

Analytical verification of doses or concentrations:

yes

Duration of treatment / exposure:

13 weeks / dietary

Frequency of treatment:

Continuous.

Remarks:

Doses / Concentrations:0, 0.01, 0.03, 0.1, 0.3, 1.0, 3.0, 10, 30, 100, 300, 1000ppmBasis:nominal in diet

Remarks:

Doses / Concentrations:Males: 0, 0.001, 0.003, 0.009, 0.022, 0.0848, 0.212, 0.872, 2.139, 8.399, 21.115, 85.923 mg/kg/dayBasis:actual ingested

Remarks:

Doses / Concentrations:Females: 0, 0.001, 0.003, 0.010, 0.026, 0.094, 0.254, 0.962, 2.590, 9.191, 24.836, 96.812 mg/kg/dayBasis:actual ingested

No. of animals per sex per dose:

25 animals/sex/group

Control animals:

yes, plain diet

Dose descriptor:

NOAEL

Effect level:

ca. 300 ppm

Based on:

other:

Sex:

male/female

Basis for effect level:

other: (equivalent to ~21.15 or 24.8 mg/kg for males and females respectively). Based on ~30% inhibition of brain cholinesterase activity at 1000 ppm.

Critical effects observed:

not specified

Clinical signs of toxicity:

No test material related clinical signs of toxicity were observed.

 

Mortality:

No mortality observed.

 

Functional examination:

Not undertaken

 

Bodyweight and bodyweight gain:

Test material related changes in body weight gains consisted of slightly lower body weights for animals treated at 100 ppm and markedly lower for animals treated at 1000 ppm compared to the control group. This data however was only reported for the first 4 weeks and not the entire treatment period.

 

Food consumption:

Moderately lower food consumption (compared to controls) was observed in both male and females.

 

Blood and urinalysis:

Haematological findings:

There were no test material-related effects on haematology parameters.

 

Clinical chemistry findings:

Cholinesterase activity was depressed in both genders at levels of 10 ppm and greater. Brain cholinesterase activity appeared to be the most resistant to the effects of CGA15324.

 

Table 7.5.1 -4: AChE % Inhibition   

Dose	Time	Plasma				RBC				Brain
(ppm)	(weeks)	Male	Sig	Female	Sig	Male	Sig	Female	Sig	Male	Sig	Female	Sig
0.01	4	-3	-	2	-	0	-	2	-	2	-	-4	-
0.03	4	-5	-	-3	-	1	-	-2	-	-2	-	-1	-
0.1	4	-2	-	4	-	7	-	0	-	-6	-	-2	-
0.3	13	-5	NS	-2	NS	4		1	NS	-5	NS	-5	NS
1	4	-2	-	-7	-	4	-	3	-	-1	-	3	-
3	13	-4	NS	3	NS	9	NS	6	NS	5	NS	1	NS
10	4	6	-	26	-	33	-	30	-	-2	-	1	-
30	13	22	*	45	*	50	NS	47	NS	6	NS	1	NS
100	4	22	-	65	-	78	-	74	-	-2	-	2	-
300	13	39	*	72	*	62	NS	57		14	NS	11	*
1000	4	43	-	78	-	78	-	60	-	30	-	29	-

Urinalysis:

There were no test material-related effects on urinalysis parameters.

 

SACRIFICE AND PATHOLOGY:

Organ weight:

Not undertaken.

 

Gross and histopathology:

No treatment related organ or tissue changes were noted at necropsy in any of the treated animals. No histopathology was undertaken.

Conclusions:

In conclusion the NOEL was deemed to be 300 ppm (~23 mg/kg/day), based on inhibition of brain cholinesterase activity at 30% or greater in both genders.

Executive summary:

Thirteen groups (25 anmals/sex) were fed Profenofos in the diet at levels of 0, 0.01, 0.03, 0.1, 0.3, 1.0, 3.0, 10, 30, 100, 300 and 1000 ppm equivalent to compound intakes of 0, 0.001, 0.0025, 0.009, 0.25, 0.09, 0.24, 0.87, 2.4, 8.4, 22 and 85 mg/kg/day respectively. Five rats of each sex in each test group and both controls were sacrificed after 2 and 4 weeks. The remaining animals in one control group and n the 0.3, 3.0, 30 and 300 ppm test groups were killed after 13 weeks. Cholinesterase activity was determined in plasma, erythrocyte and brain and differences were analysed statistically only for those animals treated for 13 weeks. Histopathological examination was not undertaken as part of this study.

 

The treatment produced neither mortalities nor clinicl signs in any of the test groups. Reduced food consumption and a dose related growth depression occurred at the 100 to 1000 ppm levels. Results of haematology, clinical chemistry (with the exception of the cholinesterase measurements) and urinalysis were unremarkable and did not indicate any relationship to treatment. At doses of 10ppm and greater, plasma and erythrocyte cholinesterase activities were inhibited, being more pronounced in females and generally reaching a plateau after 4 weeks. Plasma cholinesterase was inhibited by 6 -43% in males and 26 - 78% in females in the 10 to 1000ppm dose range. The corresponding figures for erythrocyte cholinesterase inhibition were 33 - 78% for males and 30 - 60% for females. Slightly lower brain cholinesterase activities were present at 300 ppm in males (14%) and females (11%), and were not statisitcally significant nor biologically relevant. At 1000ppm brain cholinesterase was inhibited by 30% in males and 29% in females.

 

Necropsies performed during or at the end of the study did not reveal any treatment related changes that were grossly observable.

 

In conclusion the NOEL was deemed to be 300 ppm (~23 mg/kg/day), based on inhibition of brain cholinesterase activity at 30% or greater in both genders.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

12.5 mg/kg bw/day

Study duration:

subchronic

Species:

dog

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

Not stated

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Non GLP, no guideline compliant, but broadly similar to the requirements of OECD 412.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 412 (Subacute Inhalation Toxicity: 28-Day Study)

Deviations:

not applicable

GLP compliance:

no

Limit test:

no

Species:

rat

Strain:

other: RAI

Sex:

male/female

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

nose only

Vehicle:

air

Analytical verification of doses or concentrations:

yes

Duration of treatment / exposure:

6 hrs/day

Frequency of treatment:

once daily, 5 days/week for a total of 21 days

Remarks:

Doses / Concentrations:0, 68, 219, 449 mg/m3Basis:analytical conc.

No. of animals per sex per dose:

9 animals/sex/gp

Control animals:

yes, concurrent vehicle

Dose descriptor:

LOAEC

Effect level:

ca. 68 mg/m³ air (analytical)

Sex:

male/female

Basis for effect level:

other: Based on the reduced feed intake, reduced body weight gains and a signficant reduction in brain cholinesterase activity in erythrocyte in all treated groups

Critical effects observed:

not specified

Mortality:

All animals from the high dose group died within 5 days of the start of dosing. One female from the intermediate dose group died on the fifth experimental day and one control female died on day 16 due to blood collection.

 

Clinical observations:

Clinical observations were limited to the high dose group, with signs including exophthalmos, dyspnoea, tremor, unkempt fur, partially lateral position and irritation and secretion of the mucous membranes of the eyes and nose. These signs appeared 2 days post initiation of dosing.

 

Bodyweight:

Bodyweight gain of the males of dosed at 68 and 219 mg/m³ was reduced during the entire exposure period when compared with the control group, whereas that of the females was reduced during the first 10 days only. After that time, the bodyweight of the females was comparable to that of the controls. Animals dosed at 449 mg/m³ all lost weight until they died.

 

At the end of the recovery period, bodyweight gain was comparable to that of the vehicle control.

 

Food consumption:

Food consumption of the male rats dosed at 219 mg/m³ was decreased during the entire exposure period, where as that of the females of this group as well as all rats dosed at 68 mg/m³ was decreased during the first week of exposure only.

 

At the end of the recovery period, food consumption was comparable to that of the vehicle control.

 

Aerodynamic particle size distribution:

Data was only presented graphically as a distribution for each dose level.

 

Blood and urinalysis:

Haematological findings:

Haematological parameters tested were comparable for treated and respective control groups for both sexes.

 

Clinical chemistry findings:

Dose related inhibition of serum, RBC and brain cholinesterase activities were evident in treated rabbits of both sexes. Due to the biological relevance of both RBC and brain cholinesterase activities, only these have been discussed.

 

High dose: as all animals did prior to the scheduled necropsy, no data was available.

 

Mid dose: significant inhibition (p<0.01) of both erythrocyte and brain cholinesterase was observed in males (72% and 80% respectively) and females (64% and 80% respectively). The effects on erythrocyte cholinesterase was reversible, however brain cholinesterase activity remained 18 – 30% lower compared to the vehicle controls.

 

Low dose: significant inhibition (p<0.01) of both erythrocyte and brain cholinesterase was observed in males (64% and 65% respectively) and females (53% and 61% respectively).

 

Table 7.5.3-1:AChE %inhibition

Dose		Plasma				RBC				Brain
(mg/m^3)		Male	Sig	Female	Sig	Male	Sig	Female	Sig	Male	Sig	Female	Sig
0	Day 21	0		0		0		0		0		0
0	Day 42	0		0		0		0		0		0
68	Day 21	35	*	46	*	64	*	53	*	61	*	61	*
219	Day 21	43	*	59	*	72	*	64	*	80	*	80	*
219	Day 42	24	*	24	*	-17	*	7	*	18	*	30	*

* p<0.01

 

Sacrifice and pathology:

Organ weight:

Due to bodyweight loss in both the low and mid dose groups organ/body weight ratios were increased, however organ to brain weights were comparable to the controls.

 

Gross and histopathology:

Gross pathology: Animals in the high dose group showed acute congestion of all organs. All animals in the mid dose group were slightly emaciated. Animals from the low dose group showed no macroscopic changes which could be attributed to the administration of the test material.

 

Histopathology: Animals from the high dose group which died in the first week, acute congestion of the parenchymatous organs and also marked congestion of the nasal mucous membranes and in the majority of animals severe interstitial or purulent keratitis were observed. Rats in the low dose group showed only incidental findings which were not attributed to administration of the test material.

 

Ophthalmic examinations:

Only animals in the high dose group showed signs of irritation of the conjunctivae, all other animals were normal.

Conclusions:

Based on the reduced feed intake, reduced body weight gains and a signficant reduction of cholinesterase activity in erythrocyte and brain in all treated groups a NOAEC could not be established for this study.

Executive summary:

CGA15324 was administered to rats for 6hours/day, 5 days/week in a 21 -day toxicity (nose only) inhalation study at concentrations of 0, 68, 219 and 449 mg/m³. Nine animals/sex/group; were used, with 4 animals/sex/group kept for a 21 day recovery period following exposure.

 

All rats from the high dose group and 1 female from the intermediate group died during the 1^st week of exposure. Food intake of the males from the intermediate dose group was decreased during the entire exposure period, whereas that of the females of this group as well as all of the rats from the low dose group was decreased during the first week of exposure only.

 

Bodyweight gain of the male rats of the low and intermediate dose groups was reduced during the entire exposure period when compared with the control group, where as that of the females was reduced during the first 10 days only. At the end of the recovery period the food intake and body weight gain to the males from the intermediate dose group was comparable with that of the controls.

 

Results of the haematological and blood chemistry analysis were generally unremarkable for both treated rats and controls. Cholinesterase activity of plasma, erythrocyte and brain was significantly depressed in all the groups treated with CGA15324 in a dose-dependent manner. In all cases the approximate level of inhibition was assessed to 40% to 70% of the control values.

 

Based on the reduced feed intake, reduced body weight gains and a significant reduction of cholinesterase activity in erythrocyte and brain in all treated groups a NOAEC could not be established for this study.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LOAEC

68 mg/m³

Study duration:

subacute

Species:

rat

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records

Reference

Reference 1

Endpoint:

short-term repeated dose toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Study period:

29 December 1997 to 22 January 1998

Reliability:

1 (reliable without restriction)

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.3200 (Repeated Dose Dermal Toxicity -21/28 Days)

Deviations:

no

GLP compliance:

yes

Limit test:

no

Species:

rabbit

Strain:

New Zealand White

Sex:

male/female

Type of coverage:

semiocclusive

Vehicle:

other: 0.5% Tween 80 in distilled water

Analytical verification of doses or concentrations:

yes

Duration of treatment / exposure:

6 hrs/day

Frequency of treatment:

In total 21 days (5 days/week for the first 14 days and daily thereafter)

Remarks:

Doses / Concentrations:0, 2.5, 5, 10 mg/kgBasis:nominal per unit body weight

No. of animals per sex per dose:

10 animals per sex for 0, 2.5 and 5 mg/kg gps11 males and 9 females for 10 mg/kg gp

Control animals:

yes, concurrent vehicle

Dose descriptor:

NOAEL

Effect level:

ca. 2.5 mg/kg bw/day

Sex:

male/female

Basis for effect level:

other: Inhibition of brain cholinesterase activity by more than 20% at 5 mg/kg/day and higher

Critical effects observed:

not specified

No treatment related mortality occurred. No signs of irritation were detected at the skin application site.

 

Bodyweight and food consumption was unaffected. No ocular changes were seen and no effects were recorded on haematological parameters. The evaluation or organ weights did not reveal any treatment-related changes. Upon microscopic examination, all treated groups were observed to have an increased incidence of acanthosis at the skin application site.

 

Table 7.5.2 -2: AChE % inhibition

Dose (mg/kg/day)

Plasma

RBC

Brain

Male

Sig

Female

Sig

Male

Sig

Female

Sig

Male

Sig

Female

Sig

2.5

86

*

81

*

47

*

58

*

14

*

16

NS

5

97

*

95

*

72

*

79

*

33

*

33

*

10

97

*

98

*

84

*

90

*

47

*

47

*

* p<0.05; ** P<0.01

 

The dermal application of CGA 1324 tech, at >2.5 mg/kg resulted in dose related inhibition of the cholinesterase activities in erythrocyte and brain of male and female rabbits. Whilst almost complete inhibition of plasma cholinesterase was observed, erythrocyte and brain cholinesterase activities are considered more relevant markers of activity.The degree of acetyl cholinesterase in erythrocytes and brain was less severe.

 

Conclusions:

Under the conditions of this test, dermal treatment with CGA 15324 tech. was well tolerated. There was no irritating effect on the skin, but an increased incidence of acanthosis at the application site was observed in all treated groups. However the severity of ancanthosis did not increase in a dose related manner, therefore this was not considered toxicologically relevant. The NOAEL was deemed to be 2.5 mg/kg/day, based on significant inhibition of this enzyme at doses of 5 mg/kg/day and greater.

Executive summary:

Profenofos was administered via the dermal route tp New Zealand White rabbits subjected to repeated dermal application under sem-occulsive conditions for 22 days on a 5 day/week basis during weeks 1 and 2 and daily from day 15 to 22. The exposure period was 6 hours/day. Test material doses of 0, 2.5, 5 and 10 mg/kg/day were applied to 10 rabbits/sex/group.

 

The treatment produced no significant clinical signs, no effect on mean body weights or food consumption. No signs of irritation occured at the application site. No ocular changes were seen and no effect on haematological parameters. Organ weights did not reveal any treatment related effects. Macroscopic post mortem examination did not indicate any treatment related changes. Upon microscopic examination all treated groups were observed to have an increased incidence of acanthosis at the skin application site.

 

A treatment related inhibition of cholinesterase activities in plasma (butyl form), erythrocyte and brain (the acetyl form in both cases) was seen at all doses tested. At the end of the study there was a statisically significant decrease in plasma activity, with almost complete inhibition observed in both genders at all doses tested. Erythrocyte activity ranged from 47 to 90% in male and females, with statistically significant brain cholinesterase inhibition inexcess of 20% observed at doses of 5 mg/kg/day and greater.

 

The author of the study concluded that no NOAEL could be established, due to acanthosis observed at all doses levels. However, as the severity of ancanthosis was not considered dose related and the severity never increased, this was not considered toxicologically relevant. Whilst statistically significant inhibition of erythrocyte cholinesterase activity was observed at the lowest dose of 2.5 mg/kg/day and greater, guidance set out in the JMPR review (2000) states that ‘inhibition of brain acetylcholinesterase activity and clinical signs to be the primary endpoint of concern in toxicological studies’, whilst ‘inhibition of erythrocyte acetylcholinesterase activity is also considered to be an adverse effect, insofar as it is used as a surrogate for brain and peripheral nerve acetylcholinesterase inhibition, when data on the brain enzyme are not available’. In this study, brain cholinesterase activity was also measured, with significant inhibition in (excess of 20%) was observed at levels of 5 mg/kg/day and greater. Therefore the NOAEL for brain cholinesterase activity was 2.5 mg/kg/day, with no clinical signs of toxicity associated with cholinesterase inhibition.

 

References:

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 2

Endpoint:

short-term repeated dose toxicity: dermal

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

12 March 1984 to 3 April 1984

Reliability:

1 (reliable without restriction)

Qualifier:

according to guideline

Guideline:

OECD Guideline 410 (Repeated Dose Dermal Toxicity: 21/28-Day Study)

Version / remarks:

(1981)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EPA OPP 82-2 (Repeated Dose Dermal Toxicity -21/28 Days)

Version / remarks:

(1982)

Deviations:

no

GLP compliance:

yes

Limit test:

no

Species:

rabbit

Strain:

New Zealand White

Sex:

male/female

Type of coverage:

semiocclusive

Vehicle:

other: 0.5% Tween 80 in purified water

Analytical verification of doses or concentrations:

yes

Duration of treatment / exposure:

21 days (dosed for 5 consecutive days/week)

Frequency of treatment:

once daily

Remarks:

Doses / Concentrations:0.05, 1, 10 mg/kgBasis:nominal per unit body weight

No. of animals per sex per dose:

5 animals/sex/gp

Control animals:

yes, concurrent vehicle

Dose descriptor:

NOAEL

Effect level:

ca. 1 mg/kg bw/day

Based on:

other:

Sex:

male/female

Basis for effect level:

other: Based on significant reduction in brain cholinesterase activity and hyperactivity at 10 mg/kg/day

Critical effects observed:

not specified

OBSERVATIONS:                                

Clinical signs of toxicity:                    

Two high dose male rabbits exhibited hyperactivity on study day 11. Gross overt effects manifested among high dose females included a few incidences of diarrhoea, soft faeces, hyperactivity and a single incident of hypotonia. Low and mid dose animals of both sexes showed no test material induced signs of toxicity.

 

Dermal findings were noted as well defined erythema in the mid-dose groups of both sexes and in high dose females during the third week of treatment. No oedema was observed at any point during the study in any animal, regardless of treatment or sex.

 

Mortality:

All animals survived to the scheduled necropsy

 

Bodyweight and bodyweight gain:

No statistically significant differences in mean weekly body weights were seen between treated groups and their respective controls during the experimental period.

 

Food consumption:

There were no statistically significant differences in mean weekly food consumption between treated groups and their respective controls.

 

Blood:

Haematological findings:

Haematological parameters tested were comparable for treated and respective control groups for both sexes.

 

Clinical chemistry findings:

Dose related inhibition of serum, RBC and brain cholinesterase activities were evident in treated rabbits of both sexes. Due to the biological relevance of both RBC and brain cholinesterase activities, only these have been discussed.

 

High dose: statistically significant (p<0.01) reduction in RBC cholinesterase activities in both sexes (12 and 28% inhibition observed in male and females respectively).

A statistically significant (p<0.05) reduction in brain cholinesterase activity was only observed in males, with a 30% inhibition observed. A 15% inhibition was observed in females

 

Both the mid and low dose groups no statistically significant reductions in cholinesterase activity were observed.

 

Table 7.5.2 -1: AChE %inhibition

Dose (ppm)

Plasma

RBC

Brain

Male

Sig

Female

Sig

Male

Sig

Female

Sig

Male

Sig

Female

Sig

0.05

-11

NS

-15

NS

-8

NS

-11

NS

-1

NS

-1

NS

1

-4

NS

1

NS

2

*

7

NS

15

NS

-14

NS

10

27

*

41

**

12

**

28

**

30

*

15

NS

* p<0.05; **p<0.05

 

Sacrifice and pathology:

Organ weight:

Slight, but statistically significant (p<0.05) reductions in mean adrenal and ovary weights and organ/body weight ratios were seen in high dose female; however the absolute values were considered to be within acceptable limits. All other mean organ weights and organ/body weight ratios among treated groups of both sexes were statistically comparable to those of their appropriate controls.

 

Gross and histopathology:

Gross pathology: There were no other remarkable macroscopic findings noted at the scheduled necropsy.However 2 high dose animals (1/sex) had dark or red lesions on the lungs.

Histopathology: no test material-related microscopic changes were noted at the scheduled necropsy in the skin. Vaculoation of renal epithelial cells was seen in all treated groups and control females. This change however was not considered biologically relevant.

 

Ophthalmic examinations:

There were no ophthalmic lesions attributed to test material exposure.

Conclusions:

The dermal application of Profenofos Technical to rabbits for 3 weeks (5 days/week) induced significnat reductions in brain cholinesterase activity at dose of 10 mg/kg/day. The NOAEL was therefore deemed to be 1 mg/kg/day.

Executive summary:

The dermal application of Profenofos Technical to rabbits was associated with inhibition of serum (not biologically relevant), erythrocyte and brain cholinesterase activities, typical of organophosphate poisoning. Except for brain cholinesterase activity in high dose females, the reductions were statistically significant in both male and female high dose groups. A minimal, but statistically significant decrease in erythrocyte cholinesterase activity also occurred in ,mid dose males, however the reduction was considered to be biologically non-significant because the mean enzyme level was only depressed by 1.9% as compared to the predose baseline values.

 

Dermal application of Profenofos Technical was physically well tolerated by all animals, without sighs of intoxication other than dermal erythema. Except for depressed cholinesterase activities, there was no evidence of systemic intoxication based upon post mortem evaluations.

 

The dermal application of Profenofos Technical to rabbits for 3 weeks (5 days/week) induced significant reductions in brain cholinesterase activity at dose of 10 mg/kg/day. The NOAEL was therefore deemed to be 1 mg/kg/day.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

2.5 mg/kg bw/day

Study duration:

subacute

Species:

rabbit

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Repeat oral toxicity

In the key study (Altmann, 1999) and supporting study (Gfeller, 1981) dogs were dosed for 1 year (gelatine capsules) or 6 months (diet) respectively. No clinical signs of toxicity or adverse neurological signs were observed in either study. Both plasma and erythrocyte cholinesterase activities were much more sensitive to the effects of Profenofos than brain cholinesterase activity. Guidance set out in the JMPR review (2000) states that ‘inhibition of brain acetylcholinesterase activity and clinical signs to be the primary endpoint of concern in toxicological studies’, whilst ‘inhibition of erythrocyte acetylcholinesterase activity is also considered to be an adverse effect, insofar as it is used as a surrogate for brain and peripheral nerve acetylcholinesterase inhibition, when data on the brain enzyme are not available’. Therefore in these studies, as no affect on brain cholinesterase activity was observed up to the highest dose tested, the NOAELs were set at 12.5 and 14.4 mg/kg/day for the 1 year and 6 month studies, respectively.

 

Finally, in the third dog study, whilst considered unreliable (due to the data being generated by IBTL and not independently reviewed by the US EPA etc), the NOAEL was determine as 0.5 mg/kg/day based on inhibition of brain cholinesterase at 5 mg/kg/day. This data would appear to support the key 1 year dog study, with the true NOAEL in this study appearing to be more closer to 1 mg/kg/day than 0.05 mg/kg/day.

 

In the other supporting study (Piccirillo, 1978) rats were administered Profenofos in the diet for 90 days. The only effects observed were inhibition of cholinesterase activities in plasma, erythrocyte and brain. Whilst significant inhibition in both plasma and erythrocyte cholinesterase activities were observed ranging from 22 -78% and 30 -78% respectively, brain cholinesterase activities were only significantly inhibited in excess of 20% at a level of 1000 ppm. Even with high levels of brain cholinesterase inhibition, no clinical signs of toxicity were present. Furthermore no adverse effects were observed during gross pathological examination. Therefore as specified in the guidance (detailed above), the NOAEL was determined based on brain cholinesterase inhibition, with a NOAEL of ~21.1 mg/kg/day established.

Hence for brain cholinesterase inhibition the overall lowest (most sensitive) relevant NOAEL was 12.5 mg/kg/day.

 

Repeat dermal toxicity

In the key study (Cantoreggi, 1998) acanthosis was observed in all treatment groups, however this occurred in a non-dose related manner and the severity did not increase with dose, thus giving an indication that this was not a treatment related association. Furthermore, ancanthosis was observed in the absence of any skin irritation. To further support the lack of toxicological relevance, ancanthosis was not observed in the supporting study up to the same maximum dose of 10 mg/kg/day. Whist statistically significant inhibition of erythrocyte cholinesterase activity was observed at the lowest dose of 2.5 mg/kg/day and greater, in accordance with the guidance (as stated above), brain cholinesterase activity was deemed the most relevant endpoint of concern, with statistically significant inhibition in (excess of 20%) at levels of 5 mg/kg/day and greater. Therefore the systemic NOAEL was based on brain cholinesterase activity, 2.5 mg/kg/day, with no clinical signs of toxicity associated with cholinesterase inhibition at any treatment level.

 

The supporting study (Tai, 1984) exhibited little or no clinical signs of toxicity. The NOAEL was therefore based on significant inhibition of brain cholinesterase activity at a level of 20% and greater. This was observed at a dose level of 10 mg/kg/day. The NOAEL was therefore considered to be 1 mg/kg/day.

 

Repeat inhalation toxicity

The key study (Sachsse, 1977) failed to establish a NOAEC due to reduced food intake, reduced body weight gains and a significant reduction in cholinesterase activity in erythrocyte and brain in all treated groups. Therefore the LOAEC was deemed to be 68 mg/m³.

 

Summary

Erythrocyte acetylcholinesterase activity was found to be significantly more sensitive to Profenofos than brain acetylcholinesterase activity in rats, mice, rabbits and dogs, irrespective of the duration of the study. Furthermore, in no species were any signs of toxicity (including toxicological signs associated with cholinergic poisoning) seen at doses that did not also produce statistically significant inhibition of brain acetylcholinesterase. Therefore in accordance with recommendations from Carlock et al., (1999) and the JMPR review on Profenofos, brain acetylcholinesterase activity was considered the more appropriate end-point for risk assessment.

 

Irrespective of the duration of the study (single dose, through to a 2 year dietary study) the data indicate that the extent of brain acetylcholinesterase inhibition does not markedly increase. The data is suggestive of an adaptive effect observed on the activity of brain acetylcholinesterase in response to Profenofos; with the enzyme becoming more resilient to the potential effects of Profenofos over time. This can be demonstrated in several instances where either comparable / increasing doses over time in the same species have little effect on brain cholinesterase inhibition.

 

Table Comparision of brain cholinesterase activity over time

Species / Duration	Route	Dose (mg/kg bw)	%Brain AChE inhibition
Dog / 90 day	Dietary	0.05	10
		0.5	9
		5 (maximum dose)	21
Dog / 6 month	Dietary	0.0072	8
		0.05	10
		2.9	11
		14.4 (maximum dose)	5
Dog / 1 year	Dietary	0.015	-
		0.05	-
		1	-
		12.5	11
Rat / single dose	Oral	0.1	-
		0.5	6
		25	8
Rat / 90 day	Dietary	0.9	-
		2.1	6
		8.4	-
		21.1	14
Rat / 2 year	Dietary	6 (maximum dose)	-

- no inhibition

                                               

References:

Carlock, L.L., Chen, W.L., Gordon, E.B., Killeen, J.C., Manley, A., Meyer, L.S., Mullin, L.S., Pendino, K.J., Percy, A., Sargent, D.E., Seaman, L.R., Svanborg, N.K., Stanton, R.H., Tellone, C.I. and van Goethem, D.L. (1999). Regulating and assessing risks of cholinesterase-inhibiting pesticides: divergent approaches and interpretations. J. Toxicol. Environ. Health B. Crit. Rev. 2(2); 105 -160.

 

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. 

Repeated dose toxicity: inhalation - systemic effects (target organ) neurologic: central nervous system

Repeated dose toxicity: dermal - systemic effects (target organ) neurologic: central nervous system

Justification for classification or non-classification

According to Regulation (EC) No 1272/2008 Profenofos is not classified for repeat dose toxicity.