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

Toxicity to reproduction

Administrative data

Endpoint:

two-generation reproductive toxicity

Remarks:

based on test type (migrated information)

Type of information:

experimental study

Adequacy of study:

key study

Study period:

10 February 1992 to 13 November 1992

Reliability:

1 (reliable without restriction)

Data source

Reference

Reference 1

Reference Type:

study report

Title:

Unnamed

Year:

1994

Report date:

1994

Reference 2

Reference Type:

study report

Title:

Unnamed

Year:

1994

Report date:

1994

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 416 (Two-Generation Reproduction Toxicity Study)

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:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Administration / exposure

Route of administration:

oral: feed

Vehicle:

unchanged (no vehicle)

Details on mating procedure:

Stated below in 'Details on Study Schedule'

Analytical verification of doses or concentrations:

yes

Duration of treatment / exposure:

70 days of treatment prior to mating, then through to weaning

Frequency of treatment:

Continuous

Details on study schedule:

Following ~70 days of treatment, male and females within each dose group were randomly paired and cohabitated (1:1) for up to 3 weeks to yield F1 littes of the first generation (P0). On postpartum day 4, litters were culled to 8 pups leaving where possible equal number of male and female offspring. At 21 days of age pups were weaned. 30 male and 30 females within each dose level were randomly selected from among as many F1 litters as possible and continued on treatment as the P1 animals The P0 males were necropsied at 177-180 days of age after 134-137 days of dietary treatment. After weaning of F1 pups, the P0 females were necropsied at 183-186 days of age after 140-143 days of dietary treatment.After an additional 69 days of dietary treatment (at~109 days old), P1 animals were mated as described to yield the F2 litters. P1 males were necropsied at 171-177 days of age. After weaning of F2 pups, the P1 females were necropsied at 178-185 days of age.

Doses / concentrations

Doses / concentrations 1

Remarks:

Doses / Concentrations:0, 5, 100, 400 ppmBasis:nominal in diet

Doses / concentrations 2

Remarks:

Doses / Concentrations:P0 Males: 0, 0.22, 4.5, 18 mg/kg dietBasis:actual ingested

Doses / concentrations 3

Remarks:

Doses / Concentrations:P0 Females: 0, 0.31, 6.1, 25 mg/kg dietBasis:actual ingested

Doses / concentrations 4

Remarks:

Doses / Concentrations:P1 Females: 0, 0.28, 5.5, 22 mg/kg dietBasis:actual ingested

Doses / concentrations 5

Remarks:

Doses / Concentrations:P1 Males: 0, 0.21, 4.2, 17 mg/kg dietBasis:actual ingested

No. of animals per sex per dose:

30 animals/sex/group

Control animals:

yes, plain diet

Results and discussion

Results: P0 (first parental generation)

Effect levels (P0)

1

Dose descriptor:

NOEL

Remarks:

Toxicity

Effect level:

ca. 100 ppm (nominal)

Sex:

male/female

Basis for effect level:

other: (equivalent to ~7 mg/kg/day). Decreased bodyweight , bodyweight changes and food consumption at 400 ppm

Remarks on result:

other: Generation: Parental and pup (migrated information)

2

Dose descriptor:

NOAEL

Remarks:

Reproductive toxicity

Effect level:

ca. 400 ppm

Sex:

female

Basis for effect level:

other: (equivalent to ~35 mg/kg/day). No effects on reproductive parameters observed up to a maximum dose of 400 ppm

Results: F1 generation

Effect levels (F1)

Dose descriptor:

NOEL

Generation:

F1

Effect level:

7.38 mg/kg bw/day

Based on:

not specified

Sex:

not specified

Basis for effect level:

body weight and weight gain

Overall reproductive toxicity

Reproductive effects observed:

no

Lowest effective dose / conc.:

29.81 mg/kg bw/day

Treatment related:

not specified

Any other information on results incl. tables

PARENTAL ANIMALS:                                                       

Clinical signs and mortality:

No test material related clinical signs of toxicity were observed in males or females from either generation.

 

Bodyweight:

Significant reductions (p<0.05 or p<0.01) were observed at the 400 ppm males P₀ group throughout the study. A similar effect was observed in P₁ males at the same dose.

 

For P₀ females mean body weights were statistically lower over the gestational period. For P₁ females in the 400 ppm group interval body weight change was significantly lower on day 68 (end of mating phase) and there were no differences in cumulative weight changes.

 

Food consumption:

For P₀ males food consumption was similar for the 5 and 100 ppm groups. Mean food consumption values for the 400 ppm group were consistently below the values for the 0 ppm group throughout the study with statistically significant reductions occurring for those intervals ending on days 3, 73 and 94. Similar observations were seen in the P₁ male generation

 

For P₀ females food consumption values for the control and the 5 and 100 ppm dose levels were generally similar throughout this generation. At 400 ppm food consumption values for the 400 ppm dose level were consistently slightly lower during the pre-mating phase, with statistically significant decreases observed only for study day 0 to 3 interval. Again, similar observations were seen in the P₁ female generation.

 

Overall mean test material consumption for both generations throughout the study was equivalent to 0.36, 7.38 and 29.81 mg/kg/day for dietary levels of 5, 100 and 400 ppm respectively.

 

Reproductive function and performance:

There were no treatment related effects on mating behaviour as the precoital interval was similar among all groups in both generations. For P₀ evidence of mating was observed in 70, 87, 87 and 87% of the females in the 0, 5, 100 and 400 ppm dose levels respectively within the first 4 days of cohabitation. For the P₁ generation evidence of mating was observed in 83, 80, 83 and 90% for females in the 0, 5, 100 and 400 ppm dose levels respectively.

 

Litters with liver born pups was similar across all dose groups, in both generations. Mean gestation length, mating index fertility and gestation indices were comparable among all groups, in both generations.

 

Parental post mortem results:

No gross necropsy observations suggestive of a relationship to treatment with CGA 15324 Technical. There were no histological lesions, either non-neoplastic or neoplastic considered to be related to dietary administration of the test material.

 

There were no treatment related effects on male reproductive organs.

 

OFFSPRING:

Bodyweight:

Mean body weight gain of F₁ and F₂ pups at 400 ppm were statistically reduced (p<0.05) on day 14 and 21, which coincided with the direct ingestion of diet containing test material. This onset was indicative of signs of toxicity from ingestion of test material and not a reproductive effect.

 

Pup survival indices

The % of total pups born alive and remaining alive on day 4 (total born viability), of live born pups on day 4 (live born viability) and of the pups after culling surviving to weaning were comparable among the control and treated groups for both F₁ and F₂ litters.

 

Offspring post mortem results:

F₁ and F₂ pups: There were no test material related effects on the number of preweaning losses calculated runts or external observations. No test material related macroscopic findings were observed in incidental (preweaning) deaths, day 4 culled pups or weanlings. There was no significant increase in the number of pups with malformations in the treated groups. All malformations were considered incidental.

Applicant's summary and conclusion

Conclusions:

In conclusion, the results of this study clearly demonstrate the absence of any adverse effects on reproductive parameters. The NOAEL for reproductive toxicity was at least 400 ppm (29.81 mg/kg/day). Based on reduced body weight gains and food consumption at 400 ppm, the NOEL for parental and pup toxicity was 100 ppm (7.38 mg/kg/day).

Executive summary:

CGA 15324 Technical was administered in the diet to rats at concentrations of 0, 5, 100 and 400 ppm (corresponding to 0, 0.4, 7 and 35 mg/kg/day) through two generations. Administrations started 10 weeks prior to the P₀ generation being paired and mated. Rats were randomly paired within dose groups to yield the F₁ generation. On lactation day 4 litters were culled to four male and for females where ever possible. Culled pups underwent a soft tissue examination with the focus on the brain and heart.

 

F₁ pups were weaned at 21 days of age. Within each dose level rats were randomly selected to continue on treatment as parent animals of the F₂ generation. They underwent the same study phases as P₀ animals. Adult animals were necropsied and reproductive tissues examined histologically.

 

At the 400 ppm dose level, reduced body weight gains and food consumption were noted in parental animals and pups of both sexes. There were no treatment related clinical signs, necropsy findings or histopathological observations at any dose level. Reproduction performance was not affected. There were no effects on mating, behaviour, gestation length, the number of litters with live born pups, the total number of pups/litter, preweaning losses, survival indices. No macroscopic findings were noted in pups.

 

In conclusion, the results of this study clearly demonstrate the absence of any adverse effects on reproductive parameters. The NOAEL for reproductive toxicity was at least 400 ppm (29.81 mg/kg/day). Based on reduced body weight gains and food consumption at 400 ppm, the NOEL for parental and pup toxicity was 100 ppm (7.38 mg/kg/day).