Cyanamide

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.35 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

other: MAK-Begründung Cyanamid, 52. Lieferung 2012

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:

medium hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.67 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

7

Dose descriptor starting point:

NOAEL

Value:

1 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

4.67 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

For risk characterisation a dermal NOEL was derived by route to route extrapolation. The oral NOAEL of 1 mg/kg bw/day, obtained from chronic repeated dose toxicity testing in dogs by Osheroff (1991), was considered reliable and was chosen as key value for the chemical safety assessment and therefore, most relevant starting point. Based on the results obtained from dermal absorption testing (see IUCLID section 7.1) a dermal absorption rate of 30 % through skin was deduced.

 

Oral absorption of the dog/ dermal absorption of humans (ABS oral-dog / ABS derm-human): 1/0.3

Correction for difference between human and experimental exposure conditions: 7 d dog/5 d worker

Corrected NOAEL (dermal) for workers:

NOAELcorr = NOAELoral x 7d/5d x ABSoral/ABSderm

NOAELcorr = 1 mg/kg bw/day x 7d/5d x 1/0.3

AF for dose response relationship:

1

Justification:

The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for differences in duration of exposure:

1

Justification:

No time extrapolation factor is needed since a chronic toxicity study is available.

AF for interspecies differences (allometric scaling):

1.4

Justification:

The default allometric scaling factor for the differences between dog and humans is used.

AF for other interspecies differences:

1

Justification:

Substance-specific information shows specific susceptibility differences between species, which are not related to differences in basal metabolic rate, the additional factor of 2.5 for ‘remaining differences’ was reduced to 1. For more details and justification please refer to IUCLID section 7.1.

AF for intraspecies differences:

5

Justification:

The default value for the relatively homogenous group "worker" is used.

AF for the quality of the whole database:

1

Justification:

The quality of the whole data base is considered to be sufficient and uncritical.

AF for remaining uncertainties:

1

Justification:

The approach used for DNEL derivation is conservative. No further assessment factors are required.

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

2.01 mg/kg bw/day

Most sensitive endpoint:

acute toxicity

Route of original study:

Dermal

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

0.33

DNEL extrapolated from long term DNEL

Dose descriptor starting point:

other: DNEL

Value:

0.67 mg/kg bw/day

Local effects

Long term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

Most sensitive endpoint:

sensitisation (skin)

Acute/short term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

Most sensitive endpoint:

sensitisation (skin)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

medium hazard (no threshold derived)

Additional information - workers

General

Cyanamide revealed toxic systemic effects during acute and long-term toxicity testing. Adverse effects occurred during acute oral and dermal application as well as long-term oral, inhalation and dermal application. Moreover, the substance was tested corrosive to skin and eyes as well as skin sensitising. DNELs were derived for acute dermal as well as long-term dermal and long-term inhalation exposure but limited to systemic effects.

DNEL derivation for the test item is performed under consideration of the recommendations of ECHA (2010). In view of the data used for evaluation, the "quality of whole database factors" and "dose-response factors" are considered to amount each to a value of 1, and are thus not shown in the calculations presented below.

 

Systemic long-term DNEL for inhalation exposure

For the the DNEL long-term, inhalation the conservative German MAK-value of 0.35 mg/m³ (MAK-Begründung Cyanamid, 52. Lieferung 2012) derived from the one year dog study was applied.

Calculations according to ECHA Guidance Document on Information Requirement, Chapter R8, based on the available chonic dog study by Osheroff (1991) result in slightly higher figures:

Standard body weight human: 70 kg

Allometric scaling factor (ASF) dog: 1,4

Worker respiratory volume (wRV) for 8 hours with light physical activity per person: 10 m³

Oral absorption of the dog/ inhalation absorption of humans (ABS oral-dog / ABS inh.-human): 1/2

Correction for difference between human and experimental exposure conditions: 7 d dog/5 d worker

 

Corrected NOAEC (inhalation) for workers:

NOAEC_corr = NOAEL_oral / ASF x 70 kg / 10m³ x 7d/5d x ABS_oral/ABS_inh

NOAEC_corr = 1 mg/kg bw/d / 1,4 x 70 kg / 10m³ x 7d/5d x 1/2

                  = 3.5 mg/m³

(NOAEC_corr/ SF= 3.5 mg/ m³ / 5* = 0.7 mg/m³ )

*intraspecies default factor for population "worker"

 

 

Systemic acute DNEL for inhalation exposure

A reliable acute inhalation toxicity study in rats resulted in a LC50 of 1000 mg/m³. Based on this result, cyanamide is not classified and labelled for acute inhalation systemic toxicity, according to Regulation EC 1272/2008 (CLP). Systemic effects through high peak-inhalation exposure are therefore not likely to occur, so that no hazard could be identified.

 

Local long-term and acute DNELs for inhalation exposure

Due to classification of cyanamide as skin corrosive, Cat. 1B, eye damage Cat. 1 and skin sensitising Cat. 1 according to Regulation (EC) No 1272/2008 (CLP) and association to the medium hazard band, local long-term effects are likely to occur.

No local long-term systemic DNEL for inhalation was derived as the possibly occurring effects are fully covered by the long-term risk assessment using the long-term systemic inhalation DNEL.

 

Systemic long-term DNEL for dermal exposure

The oral NOAEL of 1 mg/kg bw/day from a chronic oral dog study by Osheroff (1991) was used as POD. A route-to-route extrapolation to a dermal NOEL was conducted. Based on the results obtained from dermal absorption testing (see IUCLID section 7.1) a dermal absorption rate of 30 % through skin was deduced. It was additionally modified using a correction for difference between human and experimental exposure conditions (7 days exposure of the rats/5 days exposure of worker per week) to 4.67 mg/kg bw/day using the equation provided in the Guidance Document on Information Requirement, Chapter R8:

NOAEL_corr = NO(A)EL_dermal x 7d/5d x ABSoral/ABSderm

Using assessment factors of (i) 1.4 for interspecies differences (allometric scaling), (ii) 1 for remaining interspecies differences and (iii) 5 for intraspecies extrapolation, a DNEL of 0.67 mg/kg bw/day for long-term, systemic dermal exposure was calculated.

 

Systemic acute DNEL for dermal exposure

In an acute dermal toxicity study, the NOAEL was 848 mg/kg bw/day. Therefore hazard could be identified and the determination of a DNEL for acute oral toxicity triggered. The DNEL was derived on the basis of a long-term DNEL of 0.67 mg/kg bw/day and in accordance with ECHA Guidance R.8 Dose- or concentration-response characterisation (2012).

dermal DNEL_acute = long-term DNEL x 1-5

To derive a dermal DNEL for acute toxicity a reasonable worst case assumption for the AF of 3 has been made and a dermal DNEL_acute of 2 mg/kg bw/day was determined.

 

Local long-term and acute DNELs for dermal exposure

Hazard was identified in skin sensitisation studies. Thus, long-term and acute local dermal effects are likely to occur. The long-term inhalation and dermal DNELs for local effects were not derived. A potency categorisation into high hazard (> 80 % animals responding at > 1 % intradermal induction dose) applies for the neat substance or mixtures containing the substance in quantities of equal to or more than 1 %, taking into account the generic concentration limits that trigger classification of a mixture as given in Table 3.4.5 of Commission Regulation (EU) No 286/2011.

 

Hazard to the eyes:

Cyanamid is classified as eye damage Cat. 1. according to Regulation (EC) No 1272/2008 (CLP) and associated to the medium Hazard Band. A qualitative risk assessment is conducted.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.125 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

10

Dose descriptor starting point:

NOAEL

Value:

1 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

1.25 mg/m³

Explanation for the modification of the dose descriptor starting point:

The DNEL long-term, inhalation was derived by route to route extrapolation from the oral NOAEL of 1 mg/kg bw/day.

Standard body weight human: 70 kg

Allometric scaling factor (ASF) dog: 1,4

General population respiratory volume (wRV) per person for 24 hours: 20 m³

Oral absorption of the dog/ inhalation absorption of humans (ABS oral-dog / ABS inh.-human): ½ (default)

 

Corrected NOAEC (inhalation) for the general population:

NOAEC_corr = NOAEL_oral / ASF x 70 kg / 20m³ x ABS_oral/ABS_inh

NOAEC_corr = 1 mg/kg bw/d / 1,4 x 70 kg / 20m³ x 1/2

AF for dose response relationship:

1

Justification:

The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for differences in duration of exposure:

1

Justification:

No time extrapolation factor is needed since a chronic toxicity study is available.

AF for interspecies differences (allometric scaling):

1

Justification:

Respiratory interspecies differences are fully covered by the factors used for route to route extrapolation.

AF for other interspecies differences:

1

Justification:

There is no evidence for species differences in the general mode of action or kinetics.

AF for intraspecies differences:

10

Justification:

The default value for the more heterogenous group "general population" is used.

AF for the quality of the whole database:

1

Justification:

The quality of the whole data base is considered to be sufficient and uncritical.

AF for remaining uncertainties:

1

Justification:

The approach used for DNEL derivation is conservative. No further assessment factors are required.

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

Acute/short term exposure

Hazard assessment conclusion:

medium hazard (no threshold derived)

Most sensitive endpoint:

skin irritation/corrosion

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.24 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

14

Dose descriptor starting point:

NOAEL

Value:

1 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

3.33 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

For risk characterisation a dermal NOEL was derived by route to route extrapolation. The oral NOAEL of 1 mg/kg bw/day, obtained from chronic repeated dose toxicity testing in dogs by Osheroff (1991), was considered as key value for the chemical safety assessment and therefore, most relevant starting point. Based on the results obtained from dermal absorption testing (see IUCLID section 7.1) a dermal absorption rate of 30 % through skin was deduced.

 

Oral absorption of the dog/ dermal absorption of humans (ABS oral-dog / ABS derm-human): 1/0.3

 

Corrected NOAEL (dermal) for general population:

 

NOAELcorr = NOAELoral x ABSoral/ABSinh

 

NOAELcorr = 1 mg/kg bw/day x 1/0.3

AF for dose response relationship:

1

Justification:

The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for differences in duration of exposure:

1

Justification:

No time extrapolation factor is needed since a chronic toxicity study is available.

AF for interspecies differences (allometric scaling):

1.4

Justification:

The default allometric scaling factor for the differences between dog and humans is used.

AF for other interspecies differences:

1

Justification:

Substance-specific information shows specific susceptibility differences between species, which are not related to differences in basal metabolic rate, the additional factor of 2.5 for ‘remaining differences’ was modified. For more details and justification please refer to IUCLID section 7.1.

AF for intraspecies differences:

10

Justification:

The default value for the more heterogenous group "general population" is used.

AF for the quality of the whole database:

1

Justification:

The quality of the whole data base is considered to be sufficient and uncritical.

AF for remaining uncertainties:

1

Justification:

The approach used for DNEL derivation is conservative. No further assessment factors are required.

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.72 mg/kg bw/day

Most sensitive endpoint:

acute toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

0.33

DNEL extrapolated from long term DNEL

Dose descriptor starting point:

other: DNEL

Value:

0.24 mg/kg bw/day

Local effects

Long term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

Most sensitive endpoint:

sensitisation (skin)

Acute/short term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

Most sensitive endpoint:

sensitisation (skin)

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.072 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

14

Dose descriptor starting point:

NOAEL

Value:

1 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

No route to route extrapolation is necessary since a repeated dose oral toxicity study is available.

AF for dose response relationship:

1

Justification:

The dose response relationship is considered unremarkable, therefore no additional factor is used.

AF for differences in duration of exposure:

1

Justification:

No time extrapolation factor is needed since a chronic toxicity study is available.

AF for interspecies differences (allometric scaling):

1.4

Justification:

The default allometric scaling factor for the differences between dog and humans is used.

AF for other interspecies differences:

1

Justification:

Substance-specific information shows specific susceptibility differences between species, which are not related to differences in basal metabolic rate, the additional factor of 2.5 for ‘remaining differences’ was modified. For more details and justification please refer to IUCLID section 7.1.

AF for intraspecies differences:

10

Justification:

The default value for the more heterogenous group "general population" is used.

AF for the quality of the whole database:

1

Justification:

The quality of the whole data base is considered to be sufficient and uncritical.

AF for remaining uncertainties:

1

Justification:

The approach used for DNEL derivation is conservative. No further assessment factors are required.

Acute/short term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.216 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

0.33

DNEL extrapolated from long term DNEL

Dose descriptor starting point:

other: DNEL systemic, oral, long-term

Value:

0.072 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

No modification was necessary as the starting point (DNEL oral, systemic, long-term) was obtained from an oral toxicity study.

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

medium hazard (no threshold derived)

Additional information - General Population

General

Cyanamide revealed toxic systemic effects during acute and long-term toxicity testing. Adverse effects occurred during acute oral and dermal application as well as long-term oral, inhalation and dermal application. Moreover, the substance was tested corrosive to skin and eyes as well as skin sensitising. DNELs were derived for acute dermal as well as long-term dermal and long-term inhalation exposure but limited to systemic effects.

 

DNEL derivation for the test item is performed under consideration of the recommendations of ECHA (2010). In view of the data used for evaluation, the "quality of whole database factors" and "dose response factors" are considered to amount each to a value of 1, and are thus not shown in the calculations presented below.

 

Systemic long-term DNEL for inhalation exposure

The oral NOAEL of 1 mg/kg bw/day from a chronic oral dog study by Osheroff (1991) was used as POD. This NOEL was confirmed by the recent RAC evaluation. For risk characterisation a dermal NOEL was derived by route to route extrapolation. It was modified using the ASF of 1,4 for the differences between the dog and a human, a human standard respiratory volume (sRV) of 20 m³ for 24 hours, default body weight of 70 kg for an adult and the default quotient of ½ for oral absorption of the dog and inhalation absorption of humans (ABS oral-dog / ABS inh-human) to 0.125 mg/m³ using the equation provided in the Guidance Document on Information Requirement, Chapter R8.

 

NOECcorr = NOAELoral x 1.4 / 20 m³ x 70 kg x ABSoral/ABSinh

 

Using assessment factors of (i) 1 for remaining interspecies differences and (ii) 10 for intraspecies extrapolation, a DNEL of 0.125 mg/m³ for long term, systemic dermal exposure was calculated.

 

Systemic acute DNEL for inhalation exposure

A reliable acute inhalation toxicity study in rats resulted in a LC50 of 1000 mg/m³. Based on this result, cyanamide is not classified and labelled for acute inhalation systemic toxicity, according to Regulation EC 1272/2008 (CLP). Systemic effects through high peak-inhalation exposure are therefore not likely to occur, so that no hazard could be identified.

 

Local long-term and acute DNELs for inhalation exposure

Due to classification of Cyanamide as skin corrosive, Cat. 1B, eye damage Cat. 1 and skin sensitising Cat. 1 according to Regulation (EC) No 1272/2008 (CLP) and association to the medium hazard band, local long-term effects are likely to occur. No local long-term systemic DNEL for inhalation was derived as the possibly occurring effects are fully covered by the long-term risk assessment using the long-term systemic inhalation DNEL.

 

 

Systemic long-term DNEL for dermal exposure

The oral NOAEL of 1 mg/kg bw/day from a chronic oral dog study by Osheroff (1991) was used as POD. A route-to-route extrapolation to a dermal NOEL was conducted. Based on the results obtained from dermal absorption testing (see IUCLID section 7.1) a dermal absorption rate of 30 % through skin was deduced. It was additionally modified using a correction for difference between human and experimental exposure conditions to 3.33 mg/kg bw/ day using the equation provided in the Guidance Document on Information Requirement, Chapter R8:

 

NOAELcorr = NO(A)ELdermal x ABSoral/ABSderm

 

Using assessment factors of (i) 1.4 for interspecies differences (allometric scaling), (ii) 1 for remaining interspecies differences and (iii) 10 for intraspecies extrapolation, a DNEL of 0.24 mg/kg bw/day for long term, systemic dermal exposure was calculated.

 

Systemic acute DNEL for dermal exposure

In an acute dermal toxicity study, the NOAEL was 848 mg/kg bw/day. Therefore hazard could be identified and the determination of a DNEL for acute dermal toxicity triggered. The DNEL was derived on the basis of a long-term DNEL of 0.24 mg/kg bw/day and in accordance with ECHA Guidance R.8 Dose- or concentration-response characterisation (2012).

 

dermal DNEL_acute = long-term DNEL x 1-5

 

To derive a dermal DNEL for acute toxicity a reasonable worst case assumption for the AF of 3 has been made and a dermal DNEL_acute of 0.72 mg/kg bw/day was determined.

 

Local long-term and acute DNELs for dermal exposure

Hazard was identified in skin sensitisation studies. Thus, long-term and acute local dermal effects are likely to occur. The long-term inhalation and dermal DNELs for local effects were not derived. A potency categorisation into high hazard (> 80 % animals responding at > 1 % intradermal induction dose) applies for the neat substance or mixtures containing the substance in quantities of equal to or more than 1 %, taking into account the generic concentration limits that trigger classification of a mixture as given in Table 3.4.5 of Commission Regulation (EU) No 286/2011.

 

 

Systemic long-term DNEL for oral exposure

The oral NOAEL of 1 mg/kg bw/day from a chronic oral dog study by Osheroff (1991) was used as POD. No further modification was necessary.

 

Using assessment factors according to CSA Guidance Document Chapter R.8, December 2010 of (i) 1.4 for interspecies differences (allometric scaling), (ii) 1 for remaining interspecies differences and (iii) 10 for intraspecies extrapolation, a DNEL of 0.972 mg/kg bw/day for long term, systemic oral exposure was calculated.

 

Systemic acute DNEL for oral exposure

In an acute oral toxicity study, the NOAEL was 142 mg/kg bw/day. Therefore hazard could be identified and the determination of a DNEL for acute oral toxicity triggered. The DNEL was derived on the basis of a long-term DNEL of 0.072 mg/kg bw/day and in accordance with ECHA Guidance R.8 Dose- or concentration-response characterisation (2012).

 

oral DNEL_acute = long-term DNEL x 1-5

 

To derive a dermal DNEL for acute toxicity a reasonable worst case assumption for the AF of 3 has been made and a dermal DNEL_acute of 0.216 mg/kg bw/day was determined.

 

Local long-term and acute DNELs for dermal exposure

Hazard was identified in skin sensitisation studies. Thus, long-term and acute local dermal effects are likely to occur. The long-term inhalation and dermal DNELs for local effects were not derived. A potency categorisation into high hazard (> 80 % animals responding at > 1 % intradermal induction dose) applies for the neat substance or mixtures containing the substance in quantities of equal to or more than 1 %, taking into account the generic concentration limits that trigger classification of a mixture as given in Table 3.4.5 of Commission Regulation (EU) No 286/2011.

 

 

Hazard to the eyes:

Cyanamide is classified as eye damage Cat. 1. according to Regulation (EC) No 1272/2008 (CLP) and associated to the medium Hazard Band. A qualitative risk assessment is conducted.