Nitrapyrin

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Link to relevant study records

Reference

Endpoint:

one-generation reproductive toxicity

Remarks:

based on generations indicated in Effect levels (migrated information)

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Authorative secondary source with limited information provided. Original study report was not available.

Principles of method if other than guideline:

Secondary literature source no data about the method was available.

GLP compliance:

not specified

Species:

rat

Sex:

male/female

Route of administration:

oral: unspecified

Dose descriptor:

NOAEL

Effect level:

5 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Dose descriptor:

LOAEL

Effect level:

20 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Dose descriptor:

NOAEL

Remarks:

Reproduction

Effect level:

75

Based on:

test mat.

Sex:

male/female

Dose descriptor:

LOAEL

Remarks:

Reproduction

Effect level:

> 75 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

20 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Dose descriptor:

LOAEL

Generation:

F1

Effect level:

75 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Reproductive effects observed:

not specified

Effect on fertility: via oral route

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

75 mg/kg bw/day

Study duration:

chronic

Species:

rat

Quality of whole database:

Authorative secondary source with limited information on methodology provided only. Original study report was not available.

Additional information

Justification for selection of Effect on fertility via oral route:
Sole reference available.

Effects on developmental toxicity

Description of key information

In a teratogenicity study on rats and rabbits using the oral route of administration (Berdasco et al., 1998) the following dose decriptors were derived: for rats the NOAEL for maternal toxicity was determined to be 15 mg/kg bw/day, while the NOAEL for teratogenicity and fetotoxicity were determined to be 50 mg/kg bw/day. For rabbits the NOAEL for maternal toxicity was determined to be 10 mg/kg bw/day, the NOAEL for teratogenicity was determined to be 30 mg/kg bw/day and the NOAEL for fetotoxicity was determined to be 10 mg/kg/bw/day.
Supporting studies: 
The US-EPA RED (2005) document cites the results of the results of a two-generation reproduction study in fischer 344 Rats. Here the NOAEL for parental toxicity was cited to be 5 mg/kg bw/day. The NOAEL for reproduction toxicity was cited to be 75 mg/kg bw/day. The NOAEL for the offspring was cited to be 20 mg/kg bw/day.
The US-EPA RED (2005) document cites the results of a further developmental toxicity study in rats with test item. Here the NOAEL was cited to be 50 mg/kg bw/day.

Link to relevant study records

Reference

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.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Deviations:

not specified

GLP compliance:

not specified

Limit test:

no

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

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

Remarks:

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

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.

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

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.

Dose descriptor:

NOAEL

Remarks:

rats

Effect level:

15 mg/kg bw/day (nominal)

Based on:

test mat.

Basis for effect level:

other: maternal toxicity

Dose descriptor:

NOAEL

Remarks:

rabbits

Effect level:

10 mg/kg bw/day (nominal)

Based on:

test mat.

Basis for effect level:

other: maternal toxicity

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.

Dose descriptor:

NOAEL

Remarks:

rats

Effect level:

50 mg/kg bw/day (nominal)

Based on:

test mat.

Basis for effect level:

other: teratogenicity

Dose descriptor:

NOAEL

Remarks:

rats

Effect level:

50 mg/kg bw/day (nominal)

Based on:

test mat.

Basis for effect level:

other: fetotoxicity

Dose descriptor:

NOAEL

Remarks:

rabbits

Effect level:

30 mg/kg bw/day (nominal)

Based on:

test mat.

Basis for effect level:

other: teratogenicity

Dose descriptor:

NOAEL

Remarks:

rabbits

Effect level:

10 mg/kg bw/day (nominal)

Based on:

test mat.

Basis for effect level:

other: fetotoxicity

Abnormalities:

not specified

Developmental effects observed:

not specified

Effect on developmental toxicity: via oral route

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

30 mg/kg bw/day

Study duration:

subacute

Species:

rabbit

Quality of whole database:

Peer reviewed literature. The study was not conducted in compliance with GLP regulation but data are comprehensive and scientifically acceptable.

Additional information

Key study:

Berdasco et al. (1988) evaluated the teratogenicity of the test item using pregnant Fischer 344 rats and New Zealand White rabbits. The study was conducted in a similar manner to OECD guideline 414. In this study the test item was orally administered (gavage) at 0, 5, 15, or 50 mg/kg bw/day on gestation days 6 through 15 for rats and at 0, 3, 10, or 30 mg/kg bw/day on gestation days 6 through 18 for rabbits. In rats, 50 mg/kg bw/day produced slight histopathologic changes in the livers of pregnant females. Fetal examination revealed no evidence of fetotoxicity or teratogenicity among rats at dose levels up to 50 mg/kg/day. Among rabbits a significant depression in maternal weight gain and increased absolute and relative liver weights were observed at 30 mg/kg/day. An increased incidence of crooked hyoid bone among fetal rabbits in the 30 mg/kg/day dose group was considered indicative of fetotoxicity but not teratogenicity. Accordingly, for rats the NOAEL for maternal toxicity was determined to be 15 mg/kg bw/day, while the NOAEL for teratogenicity and fetotoxicity were determined to be 50 mg/kg bw/day. For rabbits the NOAEL for maternal toxicity was determined to be 10 mg/kg bw/day, the NOAEL for teratogenicity was determined to be 30 mg/kg bw/day and the NOAEL for fetotoxicity was determined to be 10 mg/kg/bw/day.

Supporting studies:

The US-EPA RED (2005) document cites the results of the results of a two-generation reproduction study in fischer 344 Rats. Here the NOAEL for parental toxicity was cited to be 5 mg/kg bw/day.

The NOAEL for reproduction toxicity was cited to be 75 mg/kg bw/day. The NOAEL for the offspring was cited to be 20 mg/kg bw/day. The US-EPA RED (2005) document cites the results of a further developmental toxicity study in rats with test item. Here the NOAEL was cited to be 50 mg/kg bw/day.

Justification for selection of Effect on developmental toxicity: via oral route:
Study with highest information content.

Justification for classification or non-classification

Dangerous Substance Directive (67/548/EEC)
The available information are considered reliable and suitable for classification purposes under Directive 67/548/EEC. As a result and according to the harmonised Annex I classification the substance is not considered to be classified for toxicity to reproduction under Directive 67/548/EEC, as amended for the 31st time in Directive 2009/2/EG.

 

Classification, Labelling, and Packaging Regulation (EC) No 1272/2008

The available information are considered reliable and suitable for classification purposes under Regulation (EC) No 1272/2008. As a result and according to the harmonised Annex VI classification the substance is not considered to be classified for toxicity to reproduction under Regulation (EC) No 1272/2008, as amended for the sixth time in Regulation (EC) No 605/2014.