Registration Dossier

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.044 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

375

Dose descriptor starting point:

LOAEL

Value:

18.75 mg/kg bw/day

Modified dose descriptor starting point:

LOAEC

Value:

16.53 mg/m³

Explanation for the modification of the dose descriptor starting point:

Regarding absorption, in the absence of reliable data for both the starting route (oral) and the end route (inhalation), worst case assumptions were made. It was assumed that a limited absorption occurs through the oral route, leading to a low (conservative) internal LOAEL. To secure a conservative external LOAEL, a maximum absorption should be assumed for the inhalation route (i.e.; 100%) leading to a low external LOAEL. Thus, in the case of oral-to- inhalation extrapolation, it is proposed to include a default factor of 2, i.e. the absorption percentage by oral route is half that of the inhalation absorption as suggested in ECHA Guidance on Information Requirements and Chemical Safety Assessment, Chapter R.8 (2012).

To convert the oral LOAEL into inhalatory LOAEC, a rat default respiratory volume was used corresponding to the daily duration of human exposure (sRVrat: 0.38 m3/kg bw/8 h). For workers a correction was added for the difference between respiratory rates under standard conditions (sRVhuman: 6.7 m3 for an 8-h exposure period) and under conditions of light activity (wRV: 10 m3 for an 8-h exposure period). Thus, the corrected dose descriptor for inhalation is [18.75 mg/kg bw/day] X [1/0.38 m3/kg bw/day] X [2/1] X [6.7 m3/10m3]. Thus, the corrected dose descriptor for inhalation is 16.53 mg/m3 for workers.

AF for dose response relationship:

1

Justification:

The dose-descriptor is a NOAEL. Table R.8-6 ECHA REACH Guidance

AF for differences in duration of exposure:

6

Justification:

Default factor for a sub-acute study. Table R.8-5 ECHA REACH Guidance

AF for interspecies differences (allometric scaling):

1

Justification:

Table R.8-4 ECHA REACH Guidance. Assessment factor not to be used for inhalation route since the differences in the metabolic rate/bw has already been taken into account in the corrected dose descriptor.

AF for other interspecies differences:

2.5

Justification:

Default factor for other interspecies differences. Table R.8-6 ECHA REACH Guidance

AF for intraspecies differences:

5

Justification:

Default factor for worker. Table R.8-6 ECHA REACH Guidance

AF for the quality of the whole database:

5

Justification:

Assessment factor considered for the extrapolation of LOAEL to NOAEL and for poor/standard quality of the database taken into account completeness of the standard information requirements for the tonnage band

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.013 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

1 500

Dose descriptor starting point:

LOAEL

Value:

18.75 mg/kg bw/day

Modified dose descriptor starting point:

LOAEL

Value:

18.75 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

For potential dermal exposure, route-to-route extrapolation from the oral LOAEL value was considered appropriate. Since a maximal absorption already occurred by oral route, no additional factor was introduced.

AF for dose response relationship:

1

Justification:

The dose-descriptor is a NOAEL. Table R.8-6 ECHA REACH Guidance.

AF for differences in duration of exposure:

6

Justification:

Default factor for a sub-acute study. Table R.8-5 ECHA REACH Guidance.

AF for interspecies differences (allometric scaling):

4

Justification:

Default allometric scaling factor for rats. Table R.8-4 ECHA REACH Guidance.

AF for other interspecies differences:

2.5

Justification:

Default factor for other interspecies differences. Table R.8-6 ECHA REACH Guidance

AF for intraspecies differences:

5

Justification:

Default factor for worker. Table R.8-6 ECHA REACH Guidance

AF for the quality of the whole database:

5

Justification:

Assessment factor considered for the extrapolation of LOAEL to NOAEL and for poor/standard quality of the database taken into account completeness of the standard information requirements for the tonnage band

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

high hazard (no threshold derived)

Hazard assessment conclusion:

high hazard (no threshold derived)

Hazard assessment conclusion:

low hazard (no threshold derived)

For risk assessment conservative approached was taken using a LOAEL (systemic toxicity) = 375ppm equivalent of 18.75 mg/kg bw/day; OECD 453. Furthermore the assessment factor (AF) of 5 was taken into consideration for the extrapolation of LOAEL to NOAEL.

In a 104-week chronic carcinogenicity study using methods equivalent or similar to the requirements of OECD Guideline 453, to evaluate the potential carcinogenicity of the test item via the dietary route. Chronic toxicity tests were conducted with both Fisher 344 rats and B6C3F1 mice. F344 male/female rats were distributed among two treatment groups of low: 375 ppm and high: 750 ppm, each consisting of fifty males and fifty females. B6C3F1 strain male/female mice were distributed among two treatment groups of low: 750 ppm and high: 1500 ppm, each consisting of fifty males and fifty females. Negative controls consisted of twenty rats, and/or mice untreated with plain diet.

There were no significant positive associations between the concentrations of the substance administered and mortality in rats or mice of either sex.

Adequate numbers of animals (rats and mice) in all groups survived sufficiently long to be at risk from late-developing tumours. Distinct dose-related mean body weight depression was observed among rats, indicating that the dosages of the substance administered to the animals in this bioassay may have approximated the maximum tolerated concentrations. While no distinct or consistent dose-related mean body weight depression was apparent in either male or female mice, dosed groups of both sexes did weigh slightly less than their controls throughout a major portion of the bioassay. No other clinical signs were recorded in the bioassay.

Tumours of the urinary bladder occurred only in dosed rats and with female rats being more susceptible. Transitional-Cell Papilloma observed in 2/46 male and 4/44 female in high dose groups, Transitional-Cell Carcinoma was observed in 1/43 and 7/44 female in low and high dose while no incidence was observed in male rats. Incident of squamous-cell carcinomas also reported in one female from the low dose group. Statistical analysis (Cochran-Armitage test and Fisher extract) indicated a significant positive association between compound administration and tumour incidence in female rats only.

Kidney tumours were found only in male rats. There was one transitional-cell papilloma of the renal pelvis in a low dose male and one tubular-cell adenocarcinoma and two tubular-cell adenomas in the high dose animals. The papilloma of the renal pelvis was unilateral and well-differentiated. The tubular neoplasms were well delineated from surrounding tissue and showed a compact glandular arrangement of plump, tubular epithelial cells. None of the neoplasms of the urinary system showed metastasis from their primary sites and were not statistically significant. The low observed effect level (LOAEL) for carcinogenicity was considered as 375 ppm (eq: 18.75 mg/kg bw/day) based on the observation of transitional-cell carcinoma in the urinary bladder of female rats.

In mice, the most commonly observed neoplasms were of the lungs and liver. Both benign and malignant alveolar/bronchiolar and hepatocellular neoplasms were present in dosed and control animals of each sex. Vascular neoplasms of the spleen were observed only in dosed animals. These included hemangioma (in 1 low dose male, 3 high dose males, 2 low dose females and 1 high dose female) and hemangiosarcoma (in 2 low dose males). These observations were not statistically significant, and the overall data failed to give conclusive evidence of carcinogenicity for the substance administered at the given doses in B6C3F1 mice.

In female mice, there was a significant positive association between chemical administration and the incidence of hepatocellular neoplasms. However, the Fisher exact comparisons were not significant. The historical control incidence for this combination of liver neoplasms in female B6C3F1 mice maintained by this laboratory for the NCI Carcinogenesis Testing Program is 4% with incidences as high as 17%, while 8/50 (16%) of the high dose female mice in this bioassay had one of these tumours. The difference between the historical data and the results obtained in this bioassay, do not support an association between the administration of the substance and the incidence of a combination of neoplastic nodules and hepatocellular carcinomas. There were no other statistical tests for tumours at any site in mice of either sex that indicated a significant positive association between compound administration and tumour incidence. As such no observed effect level (NOAEL) for carcinogenicity in mice was considered as 1500 ppm (eq. 225 mg/kg bw/day).

Under the conditions of this bioassay, dietary administration of the substance was carcinogenic to female Fischer 344 rats, causing neoplasms of the urinary bladder. The compound was not carcinogenic to male Fischer 344 rats or B6C3F1 mice of either sex. The LOAEL and NOAEL for carcinogenicity was considered as 375 ppm (eq: 18.75 mg/kg bw/day) in female rats and 1500 ppm (eq. 225 mg/kg bw/day) in mice, respectively.

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.011 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

750

Dose descriptor starting point:

LOAEC

Value:

18.75 mg/kg bw/day

Modified dose descriptor starting point:

LOAEC

Value:

8.15 mg/m³

Explanation for the modification of the dose descriptor starting point:

Concerning absorption, in the absence of reliable data for both the starting route (oral) and the end route (inhalation), worst case assumptions were made. It was assumed that a limited absorption occurs by the oral route, leading to a low (conservative) internal LOAEL. To secure a conservative external LOAEL, a maximum absorption should be assumed for the inhalation route (i.e.; 100%) leading to a low external LOAEL. Thus, in the case of oral-to- inhalation extrapolation, it is proposed to include a default factor of 2, i.e. the absorption percentage by oral route is half that of the inhalation absorption as suggested in ECHA Guidance on Information Requirements and Chemical Safety Assessment, Chapter R.8 (2012).

To convert the oral LOAEL into inhalatory LOAEC, a rat default respiratory volume was used corresponding to the daily duration of human exposure (sRVrat: 1.15 m3/kg bw/24 h).

The corrected dose descriptor for inhalation is determined using the following equation:

Corrected Inhalator LOAEC = 1/sRVrat x ABSoral-rat/ABSinh-rat x ABSinh-rat/ABSinh-human

= [18.75 mg/kg bw/day] x [1/1.15 m3/kg bw/ day] x [1/2] x [1/1]

Thus, the corrected dose descriptor for inhalation is 8.15 mg/m3 for the general population.

AF for dose response relationship:

1

Justification:

The dose-descriptor is a N(L)OAEL. Table R.8-6 ECHA REACH Guidance.

AF for differences in duration of exposure:

6

Justification:

Default factor for a sub-acute. Table R.8-5 ECHA REACH Guidance.

AF for interspecies differences (allometric scaling):

1

Justification:

Table R.8-4 ECHA REACH Guidance. Assessment factor not to be used for inhalation route since the differences in metabolic rate/bw has already been taken into account for the corrected dose descriptor.

AF for other interspecies differences:

2.5

Justification:

Default factor for other interspecies differences. Table R.8-6 ECHA REACH Guidance.

AF for intraspecies differences:

10

Justification:

Default factor for general population. Table R.8-6 ECHA REACH Guidance.

AF for the quality of the whole database:

5

Justification:

Assessment factor considered for the extrapolation of LOAEL to NOAEL and for poor/standard quality of the database taken into account completeness of the standard information requirements for the tonnage band

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties.

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.006 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

3 000

Dose descriptor starting point:

LOAEL

Value:

18.75 mg/kg bw/day

Modified dose descriptor starting point:

LOAEL

Value:

18.75 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

For systemic hazard assesment via the dermal route of exposure, route-to-route extrapolation from the oral N(L)OAEL value was considered appropriate. As no data on dermal penetration are available, dermal absorption is considered to be the same as oral absorption (i.e. 100 %). Therefore the oral N(L)OAEL is considered the same as the dermal N(L)OAEL (ECHA Guidance on Information Requirements and Chemical Safety Assessment, Chapter R.8 (2012))

AF for dose response relationship:

1

Justification:

The dose-descriptor is a N(L)OAEL. Table R.8-6 ECHA REACH Guidance.

AF for differences in duration of exposure:

6

Justification:

Default factor for a sub-acute study. Table R.8-5 ECHA REACH Guidance.

AF for interspecies differences (allometric scaling):

4

Justification:

Default allometric scaling factor for rats. Table R.8-4 ECHA REACH Guidance.

AF for other interspecies differences:

2.5

Justification:

Default factor for other interspecies differences. Table R.8-6 ECHA REACH Guidance.

AF for intraspecies differences:

10

Justification:

Default factor for general population. Table R.8-6 ECHA REACH Guidance.

AF for the quality of the whole database:

5

Justification:

Assessment factor considered for the extrapolation of LOAEL to NOAEL and for poor/standard quality of the database taken into account completeness of the standard information requirements for the tonnage band

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties.

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

high hazard (no threshold derived)

Hazard assessment conclusion:

high hazard (no threshold derived)

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.006 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

3 000

Dose descriptor starting point:

LOAEL

Value:

18.75 mg/kg bw/day

Modified dose descriptor starting point:

LOAEL

Value:

18.75 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

No modification of the dose descriptor starting point is required. The endpoint used to derive the DNEL uses the oral route for exposure.

AF for dose response relationship:

1

Justification:

The dose-descriptor is a N(L)OAEL. Table R.8-6 ECHA REACH Guidance.

AF for differences in duration of exposure:

6

Justification:

Default factor for a sub-acute study. Table R.8-5 ECHA REACH Guidance.

AF for interspecies differences (allometric scaling):

4

Justification:

Default allometric scaling factor for rats. Table R.8-4 ECHA REACH Guidance.

AF for other interspecies differences:

2.5

Justification:

Default factor for other interspecies differences. Table R.8-6 ECHA REACH Guidance.

AF for intraspecies differences:

10

Justification:

Default factor for general population. Table R.8-6 ECHA REACH Guidance.

AF for the quality of the whole database:

5

Justification:

Assessment factor considered for the extrapolation of LOAEL to NOAEL and for poor/standard quality of the database taken into account completeness of the standard information requirements for the tonnage band

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties.

Hazard assessment conclusion:

low hazard (no threshold derived)

Explanation for the modification of the dose descriptor starting point:

The acute oral toxicity potential of the test substance to rats and mouse was assessed in various studies, OECD 401, 1964 & 1973 and OECD 474. The reported LD50 in the OECD 401 studies was > 300 and < 2000 mg/kg bw, the substance was classified as acutely toxic category 4 via oral route in accordance to accordance with the Regulation (EC) 1272/2008. No death, clinical signs or any effect on body weight was noted in the OECD 474.

Hazard assessment conclusion:

low hazard (no threshold derived)

For risk assessment conservative approached was taken using a LOAEL (systemic toxicity) = 375ppm equivalent of 18.75 mg/kg bw/day; OECD 453. Furthermore the assessement factor (AF) of 5 was taken into consideration for the extrapolation of LOAEL to NOAEL.