Methanesulfonamide, N-[2-[(4,6-dimethoxy-1,3,5-triazin-2-yl)carbonyl]-6-fluorophenyl]-1,1-difluoro-N-methyl-

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.28 mg/m³

Most sensitive endpoint:

carcinogenicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

12.5

Modified dose descriptor starting point:

NOAEC

Value:

3.49 mg/m³

Explanation for the modification of the dose descriptor starting point:

NOAECcorr = NOAELoral*(1/0.38 m³/kg bw/day)*(ABSoral-rat/ABSinh-human)*(6.7 m³ (8h)/10 m³ (8h)) = 1.98 mg/kg bw/day*(1/0.38 m³/kg bw/day)*0.67 = 3.49 mg/m³

AF for dose response relationship:

1

Justification:

The dose descriptor starting point is based on a NOAEL

AF for differences in duration of exposure:

1

Justification:

The DNEL is based on a chronic study

AF for interspecies differences (allometric scaling):

1

Justification:

AF not used for inhalation route

AF for other interspecies differences:

2.5

Justification:

Default AF

AF for intraspecies differences:

5

Justification:

Default AF for workers

AF for the quality of the whole database:

1

Justification:

DNEL is based on a high-quality study

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

acute toxicity

Route of original study:

By inhalation

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

hazard unknown (no further information necessary)

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

acute toxicity

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.67 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Dermal

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

300

Modified dose descriptor starting point:

NOAEL

Value:

500 mg/kg bw/day

AF for dose response relationship:

1

Justification:

The dose descriptor starting point is based on a NOAEL

AF for differences in duration of exposure:

6

Justification:

The DNEL is based on a subacute study

AF for interspecies differences (allometric scaling):

4

Justification:

The starting point has been derived in rats

AF for other interspecies differences:

2.5

Justification:

Default AF

AF for intraspecies differences:

5

Justification:

Default AF for workers

AF for the quality of the whole database:

1

Justification:

DNEL is based on a high-quality study

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

acute toxicity

Route of original study:

Dermal

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

repeated dose toxicity

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

acute toxicity

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

Additional information - workers

The inhalation DNEL was derived from an oral combined chronic toxicity and carcinogenicity study according to OECD 453 (M-446454-02-1). Triafamone, was administered to Wistar rats (70 animals/sex/dose group) via the diet at 50, 250 and 1500 ppm, corresponding to 1.96, 9.86 and 60.4 mg/kg bw/day in males and 2.81, 14.2 and 84.2 mg/kg bw/day in females, over a 24-month period. After 52 weeks, 10 males and 10 females from each group allocated to the chronic (12 month) phase were necropsied at the scheduled interim sacrifice. The remaining 60 animals/sex/group, allocated to the carcinogenicity (24-month) phase of the study, continued treatment until final sacrifice of the study after at least 104 weeks of treatment, when surviving animals were necropsied.

The liver was confirmed to be the main target organ in both sexes, females appearing to be more susceptible than males. Dietary administration of Triafamone over a 24-month period to the Wistar rat induced neoplastic changes in the liver consisting of a higher incidence of hepatocellular adenoma in both sexes compared to controls at the highest dose level tested of 1500 ppm (equivalent to 60.4 mg/kg bw/day in males and 84.2 mg/kg bw/day in females).

The mode of action behind the liver toxicity and therefore, behind liver tumours formation, may be explained by the results of the 28-day hepatotoxicity studies in rodents which showed that Triafamone is able to induce the activity of the liver P-450 isoenzymes CYP 2B, CYP 3A which is the typical response triggered by the activation of CAR/PXR nuclear receptors. Repeat exposure to compounds known to activate CAR/PXR (like the drug phenobarbital) results in liver enlargement, hypertrophy and hyperplasia/cell proliferation, which with chronic exposure can lead to altered hepatic foci and ultimately liver tumor formation. Rats have been shown to be more sensitive than mice to the pleiotropic liver response to Triafamone. This explains also why hepatocellular adenoma occurred only in the rat carcinogenicity study with Triafamone. The human relevance of this mode of action for hepatic tumor formation has been extensively discussed in the literature, with the weight of evidence indicating that this type of carcinogenic response is not relevant to humans. In fact epidemiological data support the absence of a correlation between human hepatic tumorigenesis of the CAR/PXR activator phenobarbital, which is the most widely used anticonvulsant worldwide and the oldest (was brought into the market in 1912) still commonly used. In conclusion, the hepatocellular adenomas observed in the rat carcinogenicity study after administration of doses equivalent to about 60 and 84 mg/kg bw/day for the entire lifespan of the animals, are not relevant to human.

In the liver, a higher incidence and severity of eosinophilic focus (i) of hepatocellular alteration was noted in both sexes (p ≤ 0.001), in association with minimal to slight hepatocellular hypertrophy in both sexes (p ≤ 0.001), minimal to moderate hepatocellular macrovacuolation mainly in females (p ≤ 0.001 in females), a higher incidence and/or severity of hepatocellular brown pigment in both sexes (p ≤ 0.001 or p ≤ 0.05) and a higher incidence of hepatocellular single cell necrosis in females only (p ≤ 0.05). In the thyroid gland, a higher incidence and severity of colloid alteration (p ≤ 0.01) and a slightly higher incidence of follicular cell hypertrophy were observed in both sexes. In the urinary bladder, a slightly higher incidence and severity of diffuse transitional cell hyperplasia was observed in females and a slightly higher incidence and/or severity of suburothelial mononuclear cell infiltrate was observed in both sexes. These non-neoplastic findings were mainly noted at the top dose level.

The NOEL for neoplastic changes was 250 ppm in both sexes (equivalent to 9.86 mg/kg bw/day in males and 14.2 mg/kg bw/day in females). Over a 24-month period of dietary administration with Triafamone to the Wistar rat, the dose level of 50 ppm (equivalent to 1.96 mg/kg bw/day in males and 2.81 mg/kg bw/day in females) was a NOEL in both sexes.

The dermal DNEL was derived from a 28-day dermal toxicity study according to OECD 410 (M-446559-01-1). Triafamone was dermally applied for 6 hour a day to Wistar rats. 80 Wistar rats of both sexes were involved in the study. Each experimental group consisted of 10 animals/sex. Test item was applied to the rat skin (shaved flank) by a semi-occluded application at dose of 250, 500 and 1000 mg/kg bw/day using special jackets.

Treatment-related effects were observed at 1000 mg/kg bw/day and consisted of minimal/mild, periportal/diffuse hepatocellular vacuolation (3/10 males and 3/10 females) and minimal centrilobular hepatocellular hypertrophy (3/10 males and 2/10 females) correlated with increased liver weight (approximately 11-14%) and increased cholesterol in both sexes and slight increase in the thyroid weight in females without morphological changes. No adverse effects or test item related histopathological findings were observed at the low or mid-dose levels. In conclusion, the NOAEL of this 28-day dermal toxicity study was 500 mg/kg bw/day.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Acute/short term exposure

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

hazard unknown but no further hazard information necessary as no exposure expected

Additional information - General Population

The general population is not exposed to the test substance, based on its identified uses.