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

Repeated dose toxicity: oral

Administrative data

Endpoint:

chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1999

Report date:

1999

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 452 (Chronic Toxicity Studies)

Deviations:

no

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

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

EC Number:

255-255-2

EC Name:

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

Cas Number:

41198-08-7

Molecular formula:

C11H15BrClO3PS

IUPAC Name:

4-bromo-2-chlorophenyl ethyl (propylsulfanyl)phosphonate

Test material form:

liquid

Test animals

Species:

dog

Strain:

Beagle

Sex:

male/female

Administration / exposure

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

Doses / concentrations

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

Results and discussion

Effect levels

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.

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

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.

Applicant's summary and conclusion

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.