Lactofen

Endpoint summary

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

repeated dose toxicity: oral

Remarks:

other: Different studies summarized

Type of information:

other:

Adequacy of study:

supporting study

Reliability:

4 (not assignable)

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:

no further data avalable

Species:

other: rodents, dogs and monkeys

Strain:

not specified

Sex:

male/female

Route of administration:

oral: unspecified

Vehicle:

not specified

Duration of treatment / exposure:

Up to 104 weeks

Frequency of treatment:

daily

No. of animals per sex per dose:

no data; see summary

Dose descriptor:

NOAEL

Effect level:

0.79 mg/kg bw/day (nominal)

Based on:

not specified

Sex:

male/female

Basis for effect level:

other: one-year toxicity study, dogs

Critical effects observed:

not specified

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: Subchronic or Prechronic Exposure/

In a 90-day subchronic toxicity study, mice were fed diets containing 0, 40/2000, 200, 1000, 5000, or 10000 ppm lactofen (calculated doses: 0, 5.7, 29/286, 143, 714 or 1429 mg/kg/day). Further as a result of 100% mortality in 5000 and 10000 ppm males and females, the 40 ppm dose was increased to 2000 ppm at week 5. With the exception of one female, all of the 2000 ppm animals died between 5 and 10 weeks after the increase in the dose. Dose-related increases in serum cholesterol and total protein levels, as well as liver enzymes (ALP, ALT and AST) were observed in 200 and 1000 ppm males and females. Comparable increases in absolute and relative liver weights were seen at 200 ppm (males, 43 - 48%; females, 45 - 53%) and 1000 ppm (males, 198 - 221%; females, 189 - 190%). Gross examination revealed enlarged livers in 200, 1000 and 2000 ppm mice and enlarged spleens in 1000 and 2000 ppm mice. At 2000 and/or 1000 ppm, microscopic examination of the liver showed hepatocytic vacuolization, necrosis of individual hepatocytes, bile retention, coagulative necrosis, hyperplasia of biliary epithelium and increased extramedullary hematopoiesis; the kidney showed nephrosis and cortical fibrosis/scarring.

Reference: PPG Industries. 1983b. MRID No. 00132882. Available from EPA. Write to FOI, EPA, Washington, DC 20460.

•/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/

In a 4-week range-finding study, rats were fed diets at 0, 200, 1000, 5000 or 10000 ppm lactofen (76% a.i.). Animals in the high-dose group had 100% mortality by day 7. Increased liver and kidney weights were observed at doses of 1000 ppm and higher

• /LABORATORY ANIMALS: Subchronic or Prechronic Exposure/

In a 90-day subchronic toxicity study, rats were fed diets containing 0, 40, 200 or 1000 ppm lactofen (males: 0, 2.9, 14, 74 mg/kg/day; females: 0, 3.5, 17, or 85 mg/kg/day). At the high-dose level, increased relative (to body weight) liver weights in males (3.4%, control 2.8%) and females (3.1%, control 2.7%) and absolute liver weights in males (18.4 g, control 15.0 g) were observed. Gross findings were observed only in high-dose animals and included dark livers in high-dose males (15/19) and females 4/21); darkened renal cortex was also observed in high-dose males (15/19) and females (3/21). Histopathological evaluation of high-dose animals revealed brown pigmentation in hepatocytes and/or Kupffer cells (males, 17/19; females, 7/21; none in controls), and acidophilic hepatocellular degeneration in males (10/19, none in control) and females (1/21, none in controls) and hyperplasia of bile ducts in males (6/19; controls, 1/20). Other microscopic lesions included brown pigment in tubular epithelium in the kidneys of high-dose animals (males, 12/19; females, 3/21; none in controls).

• /LABORATORY ANIMALS: Subchronic or Prechronic Exposure/

Three male chimpanzees per dose group were orally dosed with lactofen at 5 and 75 mg/kg/day for three months, followed by a two-month recovery period. ... Compared to pre-treatment values, the activities of acetyl CoA oxidase, catalase and carnitine acetyl transferase in the liver were not affected by treatment. Histopathological evaluation of the liver biopsies did not show any evidence of nuclear enlargement, cytoplasmic eosinophilia, or hypertrophy; peroxisome content in the liver biopsies did not show any change in the pre- and post-treatment evaluations. Electron microscopic evaluation of liver did not reveal any evidence of peroxisome proliferation.

• /LABORATORY ANIMALS: Subchronic or Prechronic Exposure/

Male and female Crl:CD(S)Br rats and Crl:CD1 mice were fed diets containing ... technical lactofen at 0, 2, 10, 50, or 250 ppm, pure lactofen at 250 ppm, or nafenopin, at 500 ppm. After 7 weeks of treatment, male and female mice showed significant biochemical and pathological effects on the liver. Dose-dependent increases in relative liver weights, catalase and acyl CoA oxidase were observed in males and females; females also showed a significant increase in carnitine acetyl transferase. Liver histology revealed significant, dose-dependent increases in nuclear enlargement, cytoplasmic eosinphilia, hypertrophy and peroxisomal staining. Nafenopin-treated mice showed significant increases in all of the parameters measured. Similar findings were also observed in an 8-week study, in which rats were fed diets containing lactofen at 0 or 2000 ppm or nafenopin at 500 ppm. Lactofen-treated rats had significantly increased relative liver weights, carnitine acetyl transferase and acyl CoA oxidase. Histological examination revealed increased incidence of nuclear enlargement, cytoplasmic eosinophilia, hypertrophy and peroxisomal staining; catalase activity was not affected by treatment. The ratio of peroxisomes to mitochondria were determined. The ratios were 1/4.7 (21%) and 1/3.0 (33%) for control and treated (2000 ppm, 8 weeks) male rats, respectively, and 1/4.8 (21%) and 1/1.5 (66%) for control and treated (250 ppm, 7 weeks) mice, respectively.

• /LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/

Rats were 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 for 104 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 a one-year toxicity study, dogs were 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.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

0.79 mg/kg bw/day

Study duration:

chronic

Species:

dog

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Different studies (sub-acute - chronic) in different species (mice, rats, dogs and monkeys) are summarized by EPA. The short evaluations are available via the internet. The lowest NOAEL reported is 0.79 mg/kg in a one-year study in dogs. At higher doses increased incidence of proteinaceous casts in the kidney and statistically significant decreases in the absolute weight of thyroid and adrenal glands was reported in malesl.

summary data taken from the above mentioned EPA evaluation:

•/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/

In a90-day subchronic toxicity study, micewere fed diets containing 0, 40/2000, 200, 1000, 5000, or 10000 ppm lactofen (calculated doses: 0, 5.7, 29/286, 143, 714 or 1429 mg/kg/day). Further as a result of 100% mortality in 5000 and 10000 ppm males and females, the 40 ppm dose was increased to 2000 ppm at week 5. With the exception of one female, all of the 2000 ppm animals died between 5 and 10 weeks after the increase in the dose. Dose-related increases in serum cholesterol and total protein levels, as well as liver enzymes (ALP, ALT and AST) were observed in 200 and 1000 ppm males and females. Comparable increases in absolute and relative liver weights were seen at 200 ppm (males, 43 - 48%; females, 45 - 53%) and 1000 ppm (males, 198 - 221%; females, 189 - 190%). Gross examination revealed enlarged livers in 200, 1000 and 2000 ppm mice and enlarged spleens in 1000 and 2000 ppm mice. At 2000 and/or 1000 ppm, microscopic examination of the liver showed hepatocytic vacuolization, necrosis of individual hepatocytes, bile retention, coagulative necrosis, hyperplasia of biliary epithelium and increased extramedullary hematopoiesis; the kidney showed nephrosis and cortical fibrosis/scarring.

Reference: PPG Industries. 1983b. MRID No. 00132882. Available from EPA. Write to FOI, EPA, Washington, DC 20460.

•/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/

In a 4-week range-finding study, ratswere fed diets at 0, 200, 1000, 5000 or 10000 ppm lactofen (76% a.i.). Animals in the high-dose group had 100% mortality by day 7. Increased liver and kidney weights were observed at doses of 1000 ppm and higher

• /LABORATORY ANIMALS: Subchronic or Prechronic Exposure/

In a 90-day subchronic toxicity study, ratswere fed diets containing 0, 40, 200 or 1000 ppm lactofen (males: 0, 2.9, 14, 74 mg/kg/day; females: 0, 3.5, 17, or 85 mg/kg/day). At the high-dose level, increased relative (to body weight) liver weights in males (3.4%, control 2.8%) and females (3.1%, control 2.7%) and absolute liver weights in males (18.4 g, control 15.0 g) were observed. Gross findings were observed only in high-dose animals and included dark livers in high-dose males (15/19) and females 4/21); darkened renal cortex was also observed in high-dose males (15/19) and females (3/21). Histopathological evaluation of high-dose animals revealed brown pigmentation in hepatocytes and/or Kupffer cells (males, 17/19; females, 7/21; none in controls), and acidophilic hepatocellular degeneration in males (10/19, none in control) and females (1/21, none in controls) and hyperplasia of bile ducts in males (6/19; controls, 1/20). Other microscopic lesions included brown pigment in tubular epithelium in the kidneys of high-dose animals (males, 12/19; females, 3/21; none in controls).

• /LABORATORY ANIMALS: Subchronic or Prechronic Exposure/

Three malechimpanzeesper dose group were orally dosed with lactofen at 5 and 75 mg/kg/day forthree months,followed by a two-month recovery period. ... Compared to pre-treatment values, the activities of acetyl CoA oxidase, catalase and carnitine acetyl transferase in the liver were not affected by treatment. Histopathological evaluation of the liver biopsies did not show any evidence of nuclear enlargement, cytoplasmic eosinophilia, or hypertrophy; peroxisome content in the liver biopsies did not show any change in the pre- and post-treatment evaluations. Electron microscopic evaluation of liver did not reveal any evidence of peroxisome proliferation.

• /LABORATORY ANIMALS: Subchronic or Prechronic Exposure/

Male and female Crl:CD(S)Br rats and Crl:CD1 micewere fed diets containing ... technical lactofen at 0, 2, 10, 50, or 250 ppm, pure lactofen at 250 ppm, or nafenopin, at 500 ppm. After7 weeksof treatment, male and female mice showed significant biochemical and pathological effects on the liver. Dose-dependent increases in relative liver weights, catalase and acyl CoA oxidase were observed in males and females; females also showed a significant increase in carnitine acetyl transferase. Liver histology revealed significant, dose-dependent increases in nuclear enlargement, cytoplasmic eosinphilia, hypertrophy and peroxisomal staining. Nafenopin-treated mice showed significant increases in all of the parameters measured. Similar findings were also observed in an 8-week study, in which rats were fed diets containing lactofen at 0 or 2000 ppm or nafenopin at 500 ppm. Lactofen-treated rats had significantly increased relative liver weights, carnitine acetyl transferase and acyl CoA oxidase. Histological examination revealed increased incidence of nuclear enlargement, cytoplasmic eosinophilia, hypertrophy and peroxisomal staining; catalase activity was not affected by treatment. The ratio of peroxisomes to mitochondria were determined. The ratios were 1/4.7 (21%) and 1/3.0 (33%) for control and treated (2000 ppm, 8 weeks) male rats, respectively, and 1/4.8 (21%) and 1/1.5 (66%) for control and treated (250 ppm, 7 weeks) mice, respectively.

• /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 for 104 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.

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
Short description on comprehensive studies available via the internet by US EPA and pubchem.ncbi.nlm.nih.gov

Repeated dose toxicity: via oral route - systemic effects (target organ) glandular: adrenal gland; glandular: thyroids; urogenital: kidneys

Justification for classification or non-classification

There are no significant or severe effects at or below the guidance values given in EU classification criteria 67/548/EWG or regulation no. 1272/2008 (GHS).