Lactofen

Carcinogenicity

Key value for chemical safety assessment

Carcinogenicity: via oral route

Link to relevant study records

Reference

Endpoint:

carcinogenicity: oral

Type of information:

other:

Adequacy of study:

supporting study

Study period:

2012

Rationale for reliability incl. deficiencies:

other: Short description on comprehensive studies available via the internet by US EPA and pubchem.ncbi.nlm.nih.gov

Principles of method if other than guideline:

Different chronic studies are summarized.

Species:

other: mice, rats, dogs and monkeys

Strain:

not specified

Sex:

male/female

Route of administration:

oral: unspecified

Duration of treatment / exposure:

rat: 104 weeks; mice 78 weeks; dogs one-year; additional mechanistic studies with shorter exposure.

Frequency of treatment:

daily

Post exposure period:

no data

No. of animals per sex per dose:

see sumary

Conclusions:

Based on the weight-of-the-evidence of the toxicity database, there are sufficient data to classify lactofen as a non-genotoxic hepatocarcinogen in rodents with peroxisome proliferation being a plausible mode of action. Studies with transgenic mouse confirmed that essentially all of the of the effects of PPs in rodent liver are mediated by PPAR .

Executive summary:

Executive summary is derived from the following internet links on 2012 -11 -09.

http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=62276#x321

http://www.epa.gov/iris/subst/0280.htm

References of individual studies:

PPG Industries. 1982a. MRID No. 00128446, 00150367. Available from EPA. Write to FOI, EPA, Washington, DC 20460.

PPG Industries. 1982b. MRID No. 00117566. Available from EPA. Write to FOI, EPA, Washington, DC 20460.

PPG Industries. 1982c. MRID No. 00117564. Available from EPA. Write to FOI, EPA, Washington, DC 20460.

PPG Industries. 1982d. MRID No. 00133308. Available from EPA. Write to FOI, EPA, Washington, DC 20460.

PPG Industries. 1983a. MRID No. 00132885. Available from EPA. Write to FOI, EPA, Washington, DC 20460.

PPG Industries. 1985a. MRID No. 00150343, 00150366. Available from EPA. Write to FOI, EPA, Washington, DC 20460.

PPG Industries. 1985b. MRID No. 00132883, 00150329. Available from EPA. Write to FOI, EPA, Washington, DC 20460.

PPG Industries. 1985c. MRID No. 00150367, 00163307. Available from EPA. Write to FOI, EPA, Washington, DC 20460.

• /LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/

Ratswere fed diets containing 0, 50, 500, 1000, or 2000 ppm (0, 2, 19, 38, and 76 mg/kg/day, based on 20 ppm = 1 mg/kg) lactofen for104 weeks.Effects seen at 1000 ppm included increased incidence of mottled diffusely dark livers and kidneys, increased aspartate aminotransferase, alanine aminotransferase and alkaline phosphatase activities, decreased cholesterol, blood urea nitrogen, and total protein globulin levels, and increased incidence in the pigmentation of hepatocytes, Kupffer cells and renal cortical tubule cells. Effects seen at the 2000 ppm were similar to those seen at 1000 ppm, but more severe. Other effects at 2000 ppm included increased incidence in basophilic or eosinophilic foci of cellular alteration and increased incidence of neoplastic liver nodules.

• /LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/

Micewere fed diets containing lactofen at 0, 10, 50, or 250 ppm (0, 1.4, 7.1, or 36 mg/kg/day, based on 1 ppm = 0.143 mg/kg) for78 weeks. Effects seen at 50 ppm included increased liver weight, increased incidence of dark colored and/or enlarged livers, hepatocytomegaly (also observed in males at 10 ppm); increased incidences of focal cell alteration (females only), and hepatocellular adenomas; sinusoidal cell pigmentation in the liver was observed in all dose groups. At the highest-dose tested (250 ppm), the severity of these signs of toxicity was increased. Other effects noted at 250 ppm included increased incidence of non-neoplastic and neoplastic liver masses and increased kidney pigmentation.

• /LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/

In aone-year toxicity study, dogswere fed diets containing 0, 40, 200, or 1000/3000 (0, 0.79, 4.0, 20/59 mg/kg/day based on 1 mg/kg = 40 ppm) lactofen; because of lack of significant toxicity at 1000 ppm, the dose was increased to 3000 ppm after 4-months of treatment. Dogs fed the 1000/3000 ppm diet showed a slight increase in peroxisomal staining (based on the intensity of brown stippling of D.A.B. stained slides) in the livers. Relative liver weight was increased in high-dose females. There was no evidence of nuclear enlargement, increased mitotic activity, inflammation, or focal necrosis.

• A technical grade of lactofen (1'[carboethoxy]ethyl 5-[2-chloro-4-[trifluoro-methyl] phenoxy]-2-nitrobenzoate) has been shown to induce liver tumors in mice. To determine a possible mechanism of action, the effect of exposure for 7 weeks to dietary concentrations of 2, 10, 50, and 250 ppm technical grade lactofen and 250 ppm of pure lactofen was studied for various liver parameters in groups of male and female CD-1 mice. Liver-weight to body-weight ratio, liver catalase, liver acyl-CoA oxidase, liver cell cytoplasmic eosinophilia, nuclear and cellular size, and peroxisomal staining were increased by the tumorigenic dose of lactofen, i.e., 250 ppm, in a fashion similar to the comparison chemical nafenopin (500 ppm), which is a peroxisome proliferator. Lower doses of lactofen that were reported as nontumorigenic had little or no effect on these parameters.[Butler EG et al; Toxicol Appl Pharmacol 93 (1): 72-80 (1988)] PubMed Abstract

Overall conclusion by EPA:

• Based on the weight-of-the-evidence of the toxicity database, there are sufficient data to classify lactofen as a non-genotoxic hepatocarcinogen in rodents with peroxisome proliferation being a plausible mode of action. Studies with transgenic mouse confirmed that essentially all of the of the effects of PPs in rodent liver are mediated by PPAR .

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LOAEL

36 mg/kg bw/day

Species:

mouse

Quality of whole database:

Based on the mechanistic studies of the toxicity database, there are sufficient data to classify lactofen as a non-genotoxic hepatocarcinogen in rodents with peroxisome proliferation being a plausible mode of action. This has significant implication for assessment of human hazard, since this mechanism is not relevant for humans.

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

Based on the mechanistic studies of the toxicity database, there are sufficient data to classify lactofen as a non-genotoxic hepatocarcinogen in rodents with peroxisome proliferation being a plausible mode of action. This has significant implication for assessment of human hazard, since this mechanism is not relevant for humans.

Additional information

Based on the mechanistic studies of the toxicity database, there are sufficient data to classify lactofen as a non-genotoxic hepatocarcinogen in rodents with peroxisome proliferation being a plausible mode of action. This has significant implication for assessment of human hazard, since this mechanism is not relevant for humans.

summary on indicudual studies is taken from the EPA evaluation:

• /LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/

Ratswere fed diets containing 0, 50, 500, 1000, or 2000 ppm (0, 2, 19, 38, and 76 mg/kg/day, based on 20 ppm = 1 mg/kg) lactofen for104 weeks.Effects seen at 1000 ppm included increased incidence of mottled diffusely dark livers and kidneys, increased aspartate aminotransferase, alanine aminotransferase and alkaline phosphatase activities, decreased cholesterol, blood urea nitrogen, and total protein globulin levels, and increased incidence in the pigmentation of hepatocytes, Kupffer cells and renal cortical tubule cells. Effects seen at the 2000 ppm were similar to those seen at 1000 ppm, but more severe. Other effects at 2000 ppm included increased incidence in basophilic or eosinophilic foci of cellular alteration and increased incidence of neoplastic liver nodules.

• /LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/

Mice were fed diets containing lactofen at 0, 10, 50, or 250 ppm (0, 1.4, 7.1, or 36 mg/kg/day, based on 1 ppm = 0.143 mg/kg) for 78 weeks. Effects seen at 50 ppm included increased liver weight, increased incidence of dark colored and/or enlarged livers, hepatocytomegaly (also observed in males at 10 ppm); increased incidences of focal cell alteration (females only), and hepatocellular adenomas; sinusoidal cell pigmentation in the liver was observed in all dose groups. At the highest-dose tested (250 ppm), the severity of these signs of toxicity was increased. Other effects noted at 250 ppm included increased incidence of non-neoplastic and neoplastic liver masses and increased kidney pigmentation.

• /LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/

In aone-year toxicity study, dogswere fed diets containing 0, 40, 200, or 1000/3000 (0, 0.79, 4.0, 20/59 mg/kg/day based on 1 mg/kg = 40 ppm) lactofen; because of lack of significant toxicity at 1000 ppm, the dose was increased to 3000 ppm after 4-months of treatment. Dogs fed the 1000/3000 ppm diet showed a slight increase in peroxisomal staining (based on the intensity of brown stippling of D.A.B. stained slides) in the livers. Relative liver weight was increased in high-dose females. There was no evidence of nuclear enlargement, increased mitotic activity, inflammation, or focal necrosis.

• A technical grade of lactofen (1'[carboethoxy]ethyl 5-[2-chloro-4-[trifluoro-methyl] phenoxy]-2-nitrobenzoate) has been shown to induce liver tumors in mice. To determine a possible mechanism of action, the effect of exposure for 7 weeks to dietary concentrations of 2, 10, 50, and 250 ppm technical grade lactofen and 250 ppm of pure lactofen was studied for various liver parameters in groups of male and female CD-1 mice. Liver-weight to body-weight ratio, liver catalase, liver acyl-CoA oxidase, liver cell cytoplasmic eosinophilia, nuclear and cellular size, and peroxisomal staining were increased by the tumorigenic dose of lactofen, i.e., 250 ppm, in a fashion similar to the comparison chemical nafenopin (500 ppm), which is a peroxisome proliferator. Lower doses of lactofen that were reported as nontumorigenic had little or no effect on these parameters.[Butler EG et al; Toxicol Appl Pharmacol 93 (1): 72-80 (1988)] PubMed Abstract

Overall conclusion by EPA:

• Based on the weight-of-the-evidence of the toxicity database, there are sufficient data to classify lactofen as a non-genotoxic hepatocarcinogen in rodents with peroxisome proliferation being a plausible mode of action. Studies with transgenic mouse confirmed that essentially all of the of the effects of PPs in rodent liver are mediated by PPAR .

Carcinogenicity: via oral route (target organ): digestive: liver