Nitrapyrin

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Peer reviewed literature. The study is regarded as reliable with restrictions because it was not conducted in compliance with GLP regulation but data are comprehensive and scientifically acceptable.

Data source

Reference

Reference Type:

publication

Title:

Teratologie Evaluation of Orally Administered Test Item in Rats and Rabbits

Author:

N. M. Berdasco, L. G. Lomax, M. A. Zimmer and T. R. Hanley JR.

Year:

1988

Bibliographic source:

Fundamental and applied toxicology 11, 464-471 (1988)

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Deviations:

not specified

GLP compliance:

not specified

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Nitrapyrin

EC Number:

217-682-2

EC Name:

Nitrapyrin

Cas Number:

1929-82-4

Molecular formula:

C6H3Cl4N

IUPAC Name:

2-chloro-6-(trichloromethyl)pyridine

Test animals

Species:

other: rats and rabbits

Strain:

other: Rats: Fischer 344; rabbits: NZ White rabbits

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Rats: Charles River Breeding Laboratories, I'nc Kingston, NY; rabbits: Hazelton-Dutchland Inc., Denver, PA.
- Weight at study initiation: Rats: 165-225 g; rabbits: 3.5 -4.5 kg
- Housing: Animals were housed singly in wire-bottom cages
- Diet: not specified, provided ad libitum
- Water: municipal driking water, provided ad libitum
- Acclimation period: 2 weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-22
- Humidity (%): 50
- Photoperiod (hrs dark / hrs light): 12

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on exposure:

- Dose volume: rats 4 mL; rabbits 1 mL
- Justification for use and choice of vehicle: solubilty of test item

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Solutions of test item were analyzed for stability.

Details on mating procedure:

- Impregnation procedure: Rats were mated in-house, rabbits were artificial inseminated.
- Proof of pregnancy: rats: presence of sperm in vaginal smear

Duration of treatment / exposure:

Rats were dosed from day 6 to day 15 of gestation.
Rabbits were dosed from day 6 to day 18 of gestation.

Frequency of treatment:

daily

Duration of test:

Rats: until c-section on day 21
Rabbits: until c-section on day 28

Doses / concentrations

Doses / concentrations 1

Remarks:

Doses / Concentrations:
Rabbits: 0, 3, 10, 30 mg/kw bw/day
Basis:
actual ingested

Doses / concentrations 2

Remarks:

Doses / Concentrations:
Rats: 0, 5, 15, 50 mg/kw bw/day
Basis:
actual ingested

No. of animals per sex per dose:

Rats: 29-30 animals per dose group
Rabbits: 25 animals per dose group

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: For the rats dose levels chosen were based on the results of a preliminary study with oral test item administration of 15, 50 and 100 mg/kg bw/day. For the rabits dose levels chosen were based on the results of a preliminary study with oral test item administration of 30, 100 and 200 mg/kg bw/day.

Examinations

Maternal examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily

BODY WEIGHT: Yes
- Time schedule: Rats: On day 0, 6-16 and 21 of gestation; rabbits: on day 6-19 and 28 of gestation

FOOD AND WATER CONSUMPTION: Yes, but for rats only in three day intervals.


POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 21 for rats and day 28 for rabbits
- Organs examined: Liver

Ovaries and uterine content:

The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes

Fetal examinations:

- External examinations: Yes
- Soft tissue examinations: Yes, half per litter
- Skeletal examinations: Yes, all per litter
- Head examinations: Yes, all per litter

Statistics:

Analyses of body weights and absolute and relative organ weights were performed using parametric or nonparametric ANOVA followed by either Dunnett's test or the Wilcoxon Rank-Sum test with Bonferroni's correction. Descriptive statistics (means and standard deviations) were calculated for food and water consumption. Evaluation of the frequency of preimplantation loss, resorptions among litters and the fetal population, and fetal alterations was performed by a censored Wilcoxon test with Bonferroni's correction, in which the litter was considered the experimental unit. Thee number of corpora lutea, implants, and litter size was analyzed using a nonparametric ANOV A followed by the Wilcoxon Rank-Sum lest with Bonferroni's correction. Pregnancy rate was analyzed
by the Fisher exact probability test. The fetal sex ratio was analyzed by a binomial distribution test. The nominal level used for statistical evaluation was 0.05.

Indices:

no data

Historical control data:

no data

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:

Maternal toxic effects:yes

Details on maternal toxic effects:
Rats: Administration of test item at 50 mg/kg bw/day to pregnant rats resulted in slight maternal toxicity which was characterized by slight histopathologic changes in the livers of pregnant rats. No adverse effects were noted in the lower treatment groups.
Rabbits: Administration of test item at 30 mg/kg bw/day to pregnant rabbits resulted in a decreased weight gain during the treatment period and increased absolute and relative liver weight. No adverse effects were noted in the lower treatment groups.

Effect levels (maternal animals)

1

Dose descriptor:

NOAEL

Remarks:

rats

Effect level:

15 mg/kg bw/day (nominal)

Based on:

test mat.

Basis for effect level:

other: maternal toxicity

2

Dose descriptor:

NOAEL

Remarks:

rabbits

Effect level:

10 mg/kg bw/day (nominal)

Based on:

test mat.

Basis for effect level:

other: maternal toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:yes

Details on embryotoxic / teratogenic effects:
For the rats, fetal examination revealed no evidence of fetotoxicity or teratogenicity among rats at dose levels up to 50 mg/kg/day.
For the rabbits, an increased incidence of crooked hyoid bone among fetal rabbits in the 30 mg/kg/day dose group was considered indicative of slight fetotoxicity but not teratogemcity.

Effect levels (fetuses)

1

Dose descriptor:

NOAEL

Remarks:

rats

Effect level:

50 mg/kg bw/day (nominal)

Based on:

test mat.

Basis for effect level:

other: teratogenicity

2

Dose descriptor:

NOAEL

Remarks:

rats

Effect level:

50 mg/kg bw/day (nominal)

Based on:

test mat.

Basis for effect level:

other: fetotoxicity

3

Dose descriptor:

NOAEL

Remarks:

rabbits

Effect level:

30 mg/kg bw/day (nominal)

Based on:

test mat.

Basis for effect level:

other: teratogenicity

4

Dose descriptor:

NOAEL

Remarks:

rabbits

Effect level:

10 mg/kg bw/day (nominal)

Based on:

test mat.

Basis for effect level:

other: fetotoxicity

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

not specified