Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
14.79 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
6
Acute/short term exposure
DNEL related information

Local effects

Acute/short term exposure
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
6.9 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
24
Acute/short term exposure
DNEL related information

Workers - Hazard for the eyes

Additional information - workers

DNEL Acute Oral

Calculation of a DNEL Acute oral is not necessary as the substance is not classified as toxic or very toxic

DNEL Acute Dermal

Calculation of a DNEL Acute dermal is not necessary as the substance is not classified as toxic or very toxic

DNEL Acute Inhalation

Calculation of a DNEL Acute inhalation is not necessary as the substance is not classified as toxic or very toxic

DNEL Skin irritation

Available data do not permit calculation of a DNEL skin irritation

DNEL Eye Irritation

Available data do not permit calculation of a DNEL eye irritation

DNEL Skin Sensitization

Available data do not permit calculation of a DNEL skin sensitization

 

DNELs Repeat Dose Toxicity

The calculations of long term worker exposure DNELs for systemic and local toxicity (oral exposure) and systemic effects (dermal and inhalation) are shown below. The reason for two calculations of systemic and local effects for oral exposures is based on the results of the 90-day oral toxicity study, (Stebbins et al., 2007), which showed that the NOEL (10 mg/kg/day) for the local effect, (i.e. gastric irritation based on local site of first contact in the stomach), occurred at a lower dose than that producing the systemic effect (i.e. 50 mg/kg/day). As the local effect was stomach irritation associated with oral dosing the DNEL calculations for dermal and inhalation exposures are based on the NOEL identified for systemic toxicity.

As there are no consumer exposures to this substance (with the exception of the biocidal uses which do not fall under REACH), DNELs for consumers have not been calculated. 

 

Worker DNEL Oral (Local)

The NOEL of 10 mg/kg/day for local (stomach irritation) from the repeat dose 90-day study was taken as the starting point (Stebbinset al,2007).

Assessment factor for inter-species differences, (local effect) is 1. This based on the fact that a direct irritant effect does not involve a toxicokinetic component therefore it is not necessary to apply an allometric scaling factor to take account of differences in basal metabolic rates between animals and humans. According to ECETOC the additional assessment factor of 2.5 to quantify other differences between animals and humans that could affect interspecies extrapolation is scientifically not justified and a factor of 1 is appropriate. Based on these considerations an assessment factor of 1 to account for inter-species differences is considered to be justified.

Assessment factor for intra-species differences is 3. For intra-species variability the assessment factor proposed by ECETOC (2003, 2010) is used. There are no data to quantify variability in susceptibility to the effects of long-term exposure to CS-1246 in the human population. The default factor of 3 for workers as proposed by ECETOC will therefore be used to take account of intra-species variability.

Assessment factor for conversion from sub-chronic to chronic exposure is 2

1 x 3 x 2 = 6

Worker DNEL oral (local) = 10/6 = 1.6 mg/kg/day

 

Worker DNEL Oral (systemic)

The NOEL of 50 mg/kg/day for systemic toxicity from the repeat dose 90-day study was taken as the starting point (Stebbinset al,2007).

Assessment factor for inter-species differences, (systemic effect) is 4. For interspecies variability the assessment factors proposed by ECETOC (2003, 2010) are used. The starting point is derived from the internal rat dose in mg/kg/day and the allometric scaling factor of 4 is used to take account of differences in basal metabolic rates between animals and humans. According to ECETOC the additional assessment factor of 2.5 to quantify other differences between animals and humans that could affect interspecies extrapolation is scientifically not justified and a factor of 4 is appropriate. Based on these considerations an assessment factor of 4 to account for inter-species differences is considered to be justified.

Assessment factor for intra-species differences is 3. For intra-species variability the assessment factor proposed by ECETOC (2003, 2010) is used. There are no data to quantify variability in susceptibility to the effects of long-term exposure to CS-1246 in the human population. The default factor of 3 for workers as proposed by ECETOC will therefore be used to take account of intra-species variability.

Assessment factor for conversion from sub-chronic to chronic exposure is 2

4 x 3 x1 x2 = 24

Worker DNEL oral systemic = 50/24 = 2.1 mg/kg/day

 

Worker DNEL Dermal 

The NOEL of 50 mg/kg/day for systemic toxicity from the repeat dose 90-day study was taken as the starting point (Stebbinset al,2007).

The corrected dermal NOEL = oral NOEL x oral absorption/dermal absorption.

Based on a kinetic and metabolism study, (Saghir et al, 2008), oral absorption is 100% of applied dose while dermal absorption is approximately 30% of applied dose.

The corrected NOEL dermal is thus 50 x (1/0.3) = 166 mg/kg/day.

The DNEL dermal is calculated by applying an assessment factor of 24

Assessment factor for inter-species differences, (systemic effect) is 4. For interspecies variability the assessment factors proposed by ECETOC (2003, 2010) are used. The starting point is derived from the internal rat dose in mg/kg/day and the allometric scaling factor of 4 is used to take account of differences in basal metabolic rates between animals and humans. According to ECETOC the additional assessment factor of 2.5 to quantify other differences between animals and humans that could affect inter-species extrapolation is scientifically not justified and a factor of 4 is appropriate. Based on these considerations an assessment factor of 4 to account for inter-species differences is considered to be justified.

Assessment factor for intra-species differences is 3. For intra-species variability the assessment factor proposed by ECETOC (2003, 2010) is used. There are no data to quantify variability in susceptibility to the effects of long-term exposure to CS-1246 in the human population. The default factor of 3 for workers as proposed by ECETOC will therefore be used to take account of intra-species variability.

Assessment factor for conversion from sub-chronic to chronic exposure is 2

4 x 3 x2 = 24

Worker DNEL dermal is 166/24 = 6.9 mg/kg/day

 

Worker DNEL Inhalation

The NOEL of 50 mg/kg/day for systemic toxicity from the repeat dose 90-day study (Stebbinset al,2007) was taken as the starting point.

The corrected inhalation NOEL = oral NOEL x (1/sRVrat) x (oral absorption/inhalation absorption) x (sRVhuman/wRV).

(Note for the calculation oral absorption is 100% of applied dose based on the kinetic and metabolic study by Saghir et al., (2008) while default for human inhalation absorption is 100% of applied dose.

The corrected NOEL inhalation is thus 50 x (1/0.38) x (100/100) (6.7/10) = 88 mg/kg/day.

The DNEL inhalation is calculated by applying an assessment factor of 6

Assessment factor for inter-species differences, (systemic effect) is 1. The default parameters for human inhalation allometric scaling are included in the calculation. According to ECETOC the additional assessment factor of 2.5 to quantify other differences between animals and humans that could affect interspecies extrapolation is scientifically not justified and a factor of 1 is appropriate. Based on these considerations an assessment factor of 1 to account for inter-species differences is considered to be justified.

Assessment factor for intra-species differences is 3. For intra-species variability the assessment factor proposed by ECETOC (2003, 2010) is used. There are no data to quantify variability in susceptibility to the effects of long-term exposure to CS-1246 in the human population. The default factor of 3 for workers as proposed by ECETOC will therefore be used to take account of intra-species variability.

Assessment factor for conversion from sub-chronic to chronic exposure is 2

1 x 3 x 2 = 6

Worker DNEL dermal is 88/6 = 14.79 mg/m3

 

Endpoint specific DNEL for Reproductive Toxicity

To derive a DNEL for reproductive toxicity two study have been used, i.e. the 2-generation reproductive study in the rat (Carney et al., 2008) and the developmental (teratology) study in the rat (Nemec, 1989).

DNEL based on 2-Generation reproductive Toxicity Study

A guideline 2-generation study in the rat (Carney et al., 2008) showed no evidence of reproductive toxicity or fertility at the highest dose tested, i.e. 150 mg/kg/day.

Although no adverse effects were seen the NOEC derived from the study (i.e. 150 mg/kg/day) has been used for the DNEL (reproduction) calculations.

The methodology for deriving a worker DNEL (reproduction) is similar to the methodology for repeat dose testing. As DNEL calculations use results from a 2-generation study an assessment factor of 1 is appropriate for differences in duration of exposure.

Worker DNEL Reproduction (oral) = 6.25 mg/kg/day

Worker DNEL Reproduction (dermal) = 18.75 mg/kg/day

Worker DNEL Reproduction (inhalation) is 44 mg/m3

 

DNEL based on Developmental (Teratology) Toxicity Study

A guideline developmental (teratology) study in the rat (Nemec, 1989) reported some evidence of a delayed ossification at a dose 250 mg/kg/day. While the delay in growth was not considered to represent a selective developmental the NOEC of 250 mg/kg/day is used for the DNEL calculations

The methodology for deriving a worker DNEL (developmental) is similar to the methodology for repeat dose testing. As DNEL calculations use results from a developmental (teratology) study an assessment factor of 1 is appropriate for differences in duration of exposure .

Worker DNEL Reproduction (oral) = 10.4 mg/kg/day

Worker DNEL Reproduction (dermal) = 30.75 mg/kg/day

Worker DNEL Reproduction (inhalation) is 73.3 mg/m3

 

 

References

 

Carney, E.W., Zablotny, C. L., Stebbins, K. E., Thomas, J. (2008)BIOBANCS-1246: Two Generation Oral Gavage Reproduction Study CRL-CD(SD) Rats

The Dow Chemical Company Report No:DR-0365-7827-008 GLP, Unpublished

 

ECETOC Derivation of Assessment Factors for Human Health Risk Assessment. Technical Report No 86 (2003)

 

ECETOC Guidance on Assessment Factors to Derive DNELs (unpublished)

 

Nemec, M.D. (1989) A Teratology Study in Rats with AMINE CS-1246. 

WIL Research Laboratories, Inc. The Dow Chemical Company Report No: DR-0365-7725-011 GLP, Unpublished

 

Saghir,, Clark, A. J., Beuthin, D.J., McClymont, E. L. and Staley, J. L. (2008)BIOBANÔCS-1246BIOCIDE: Pharmacokinetics and Metabolism in Crl: CD(SD) Rats. The Dow Chemical Company Report No: DR-0365-7827-010 GLP, Unpublished

 

General Population - Hazard via inhalation route

Systemic effects

Acute/short term exposure
DNEL related information

Local effects

Acute/short term exposure
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Acute/short term exposure
DNEL related information

General Population - Hazard via oral route

Systemic effects

Acute/short term exposure
DNEL related information

General Population - Hazard for the eyes

Additional information - General Population

Since no consumer exposure will occur from the identified REACH uses of this substance, the DNELs for the general population have not been calculated.