Nitrapyrin

Carcinogenicity

Description of key information

Yano et al. (2008) reported the results of a two-year dietary oncogenicity study in B6C3F1 Mice. Here, the NOEL for carcinogenicity was cited to be 75 mg/kg bw/day with no increase in the incidence of neoplasms for treated animals. Furthermore, Yano et al. (2008) reported the results of a second two-year dietary oncogenicity study in B6C3F1 mice which was conducted using higher dose levels. This study identified liver, stomach, epididymal and Harderian gland tumors. In order to assess the relevance of these findings for human risk assessment, a Scientific Advisory Group (SAG) examined relevant microscopic changes in these tissues and also evaluated genotoxicity and mechanistic data. The consensus of the SAG was that  the test item acted via a nongenotoxic-cytotoxic mode of action in the forestomach and liver. Thus, exposure conditions do not produce similar target organ toxicity in exposed individuals and thus would not be expected to increase the risk of cancer.
The US-EPA RED (2005) document reports the results of a two year chronic toxicity and oncogenicity study in Fischer 344 rats. The NOAEL and the LOAEL for toxicity were determined to be 5 and 20 mg/kg bw/day, respectively. At 20 mg/kg bw/day an increase in kidney tumors related to the alpha-2µ-globulin model were observed which are regarded as not relevant to humans.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Link to relevant study records

Reference

Endpoint:

carcinogenicity: oral

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.

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.4300 (Combined Chronic Toxicity / Carcinogenicity)

Deviations:

not specified

GLP compliance:

not specified

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Route of administration:

oral: feed

Vehicle:

not specified

Analytical verification of doses or concentrations:

not specified

Dose descriptor:

NOAEL

Effect level:

5 mg/kg bw/day

Based on:

test mat.

Sex:

not specified

Remarks on result:

other: Effect type: toxicity (migrated information)

Dose descriptor:

LOAEL

Effect level:

20 mg/kg bw/day

Based on:

test mat.

Sex:

not specified

Basis for effect level:

other: Based on decreased body weight gain in males. Increase in kidney tumors related to the alpha 2µ globulin model (not relevant to humans).

Remarks on result:

other: Effect type: toxicity (migrated information)

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

125 mg/kg bw/day

Study duration:

chronic

Species:

mouse

Quality of whole database:

Authorative secondary source with dose decriptor provided only. Original study report was not available.

Carcinogenicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Carcinogenicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

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 carcinogenicity 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 carcinogenicity under Regulation (EC) No 1272/2008, as amended for the sixth time in Regulation (EC) No 605/2014.  

Additional information

Repeated dose toxicity oral:

The results of three oncogenicity studies using the oral route of administration were cited in peer reviewed and authorative secondary sources with no or very limited information on methodology provided.

Yano et al. (2008) reported the results of a two-year dietary oncogenicity study in B6C3F1 mice using the following dose levels: 0, 5, 25 or 75 mg/kg/day. The NOEL for carcinogenicity was cited to be 75 mg/kg bw/day with no increase in the incidence of neoplasms for treated animals.

Furthermore, Yano et al. (2008) reported the results of a second two-year dietary oncogenicity study in B6C3F1 mice which was conducted using higher dose levels: 0, 125 or 250 mg/kg/day. This study identified liver, stomach, epididymal and Harderian gland tumors.

In order to assess the relevance of these findings for human risk assessment, a Scientific Advisory Group (SAG) examined relevant microscopic changes in these tissues and also evaluated genotoxicity and mechanistic data. The consensus of the SAG was that the test item acted via a nongenotoxic-cytotoxic mode of action in the forestomach and liver. Thus, exposure conditions do not produce similar target organ toxicity in exposed individuals and thus would not be expected to increase the risk of cancer.

The US-EPA RED (2005) document reports the results of a two year chronic toxicity and oncogenicity study in Fischer 344 rats. The NOAEL and the LOAEL for toxicity were determined to be 5 and 20 mg/kg bw/day, respectively. At 20 mg/kg bw/day an increase in kidney tumors related to the alpha 2µ globulin model were observed (not relevant to humans).

In conclusion, nitrapyrin was considered not to have mutagenic or genetic toxicity concern.

Justification for selection of carcinogenicity via oral route endpoint:
Most recent study using highest testing doses.