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

Repeated dose toxicity: dermal

Administrative data

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)

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1998

Report date:

1998

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

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

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:

rabbit

Strain:

New Zealand White

Sex:

male/female

Administration / exposure

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)

Doses / concentrations

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

Results and discussion

Effect levels

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

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

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.

 

Applicant's summary and conclusion

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.