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

Repeated dose toxicity: inhalation

Administrative data

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.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1977

Report date:

1977

Materials and methods

Test guideline

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

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:

rat

Strain:

other: RAI

Sex:

male/female

Administration / exposure

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

Doses / concentrations

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

Results and discussion

Effect levels

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

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

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.

Applicant's summary and conclusion

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.