Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.8 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:
23 mg/m³
Explanation for the modification of the dose descriptor starting point:
A fully reliable toxicity study is available for oral route of administration (carcinogenicity study, Kitahori et al. 1997). In this study groups of 50 male and 50 female rats were exposed to levels of 0, 0.25 % and 0.5 % L-Cysteine hydrochloride (0, 133 and 235 mg/kg bw. for males and 0, 148 and 180 mg /kg bw. for females) in the drinking water for 108 weeks. Although no no-effect level was identified, the clear decline of toxic effects between the 2 dosages allows the estimation that a level of at least 13 mg/kg bw /day for both sexes should be a no-effect level. Even if an inhalative exposure may occur the most suitable way to determine the systemic toxicity of a solid test substance is normally the oral administration. Additionally the experiences with inhalative administration of dusts of solid substances, i.e. drugs, to humans revealed that such an inhalative exposure leads to a mainly oral ingestion of the substances. This is especially true for L-Cysteine hydrochloride as (1) the substance has a very low vapour pressure and (2) as the measurement of the particle size distribution revealed, that the mean particle size (of the marketed monohydrate form) is relatively high with no particles < 3 µm which otherwise represent the respirable fraction. In consequence an inhalative exposure will result in an oral uptake of nearly 100 % of the administered dosage. The dose descriptor starting point was derived as follows: NOAEL of 13 mg/kg bw. x 1/0.38 m3/kg/bw x 6.7 m3 / 10 m3 /person = 23 mg/m3 (according to REACH ECHA GD, Example R. 8-2 Workers (Chapter R.8: Characterisation of dose [concentration]-response for human health).
AF for dose response relationship:
1
Justification:
Derived no-effect level from a carcinogenicity study (see details above).
AF for differences in duration of exposure:
1
Justification:
DNEL based on a fully reliable carcinogenicity study (with oral administration of the test article to rats), which is regarded as chronic study. Therefore no AF for differences in duration to be applied.
AF for interspecies differences (allometric scaling):
1
Justification:
According to ECHA guidance no assessment factor used for inhalation route.
AF for other interspecies differences:
2.5
Justification:
"Remaining differences"
AF for intraspecies differences:
5
Justification:
Standard factor according to ECHA REACH guidance.
AF for the quality of the whole database:
1
Justification:
A fully reliable study is used for the derivation of the hazard via oral route
AF for remaining uncertainties:
1
Justification:
A fully reliable study is used for the derivation of the hazard via oral route
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
282 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:
3 526 mg/m³
Explanation for the modification of the dose descriptor starting point:
The Dose descriptor starting point was derived as follows: LD50 > 2000 mg/kg bw. x 1/0.38 m3/kg/bw x 6.7 m3 / 10 m3 /person =3526 mg/m3 (according to REACH ECHA GD, Example R. 8-2 Workers (Chapter R.8: Characterisation of dose [concentration]-response for human health).
AF for dose response relationship:
1
Justification:
No higher factor applicable because no effects were observed up to the highest dose.
AF for interspecies differences (allometric scaling):
1
Justification:
AF not used for inhalation route
AF for other interspecies differences:
2.5
Justification:
"Remaining differences"
AF for intraspecies differences:
5
Justification:
Standard factor for worker according to ECHA REACH guidance.
AF for the quality of the whole database:
1
Justification:
A fully reliable acute oral toxicity study is availiable
AF for remaining uncertainties:
1
Justification:
AF based on a fully reliable acute oral toxicity study with rats.

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information
DNEL derivation method:
ECHA REACH Guidance

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.26 mg/kg bw/day
Most sensitive endpoint:
carcinogenicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
50
Modified dose descriptor starting point:
NOAEL
Value:
13 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
A fully reliable carcinogenicity study with rats is available for the oral route of administration (carcinogenicity study, Kitahori et al. 1997). Appropriate species and dosages were used in this study. Although no no-effect level was identified, the clear decline of toxic effects between the 2 dosages allows the estimation that a level of at least 13 mg/kg bw /day for both sexes should be a no-effect level. Additionally an acute dermal toxicity study revealed no effects up to and including dosages of 2000 mg/kg bw. It is assumed that the resorption after dermal application is similar to the resorption after oral administration.
AF for dose response relationship:
1
Justification:
Derived no-effect level from a carcinogenicity study.
AF for differences in duration of exposure:
1
Justification:
Derived no-effect level from a carcinogenicity study.
AF for interspecies differences (allometric scaling):
4
Justification:
According to ECHA guidance a factor of 4 is used for allometric scaling from rat to human.
AF for other interspecies differences:
2.5
Justification:
"Remaining differences"
AF for intraspecies differences:
5
Justification:
Standard factor for worker according to ECHA REACH guidance.
AF for the quality of the whole database:
1
Justification:
A fully reliable study is availiable
AF for remaining uncertainties:
1
Justification:
A fully reliable study is availiable
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
40 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):
50
Modified dose descriptor starting point:
NOAEL
Value:
2 000 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
no route to route extrapolation necessary
AF for dose response relationship:
1
Justification:
No higher factor necessary because no effects were observed up to the highest dose
AF for interspecies differences (allometric scaling):
4
Justification:
According to ECHA guidance a factor of 4 is used for allometric scaling from rat to human.
AF for other interspecies differences:
2.5
Justification:
"Remaining differences"
AF for intraspecies differences:
5
Justification:
Standard factor for worker according to ECHA REACH guidance.
AF for the quality of the whole database:
1
Justification:
A fully reliable study is availiable
AF for remaining uncertainties:
1
Justification:
A fully reliable study is availiable

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.9 mg/cm²
Most sensitive endpoint:
acute toxicity
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
12.5
Dose descriptor starting point:
other: NOAEL
AF for dose response relationship:
1
Justification:
No higher factor applicable because no effects were observed up to the highest dose
AF for interspecies differences (allometric scaling):
1
Justification:
AF for allometric scaling of 1, " ... since local effects are independent of the basal metabolic rate, allometric scaling should not be applied (allometric scaling factor of 1)" (ECHA REACH Guidance Chapter R8)
AF for other interspecies differences:
2.5
Justification:
"Remaining differences"
AF for intraspecies differences:
5
Justification:
Standard factor for worker according to ECHA REACH guidance.
AF for the quality of the whole database:
1
Justification:
AF based on a fully reliable dermal toxicity study with rats
AF for remaining uncertainties:
1
Justification:
AF based on a fully reliable dermal toxicity study with rats

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.9 mg/m³
Most sensitive endpoint:
carcinogenicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
25
Modified dose descriptor starting point:
NOAEC
Value:
23 mg/m³
Explanation for the modification of the dose descriptor starting point:
A fully reliable toxicity study is available for oral route of administration (carcinogenicity study, Kitahori et al. 1997). In this study groups of 50 male and 50 female rats were exposed to levels of 0, 0.25 % and 0.5 % L-Cysteine hydrochloride (0, 133 and 235 mg/kg bw. for males and 0, 148 and 180 mg /kg bw. for females) in the drinking water for 108 weeks. Although no no-effect level was identified, the clear decline of toxic effects between the 2 dosages allows the estimation that a level of at least 13 mg/kg bw /day for both sexes should be a no-effect level. Even if an inhalative exposure may occur the most suitable way to determine the systemic toxicity of a solid test substance is normally the oral administration. Additionally the experiences with inhalative administration of dusts of solid substances, i.e. drugs, to humans revealed that such an inhalative exposure leads to a mainly oral ingestion of the substances. This is especially true for L-Cysteine hydrochloride as (1) the substance has a very low vapour pressure and (2) as the measurement of the particle size distribution revealed, that the mean particle size (of the marketed monohydrate form) is relatively high with no particles < 3 µm which otherwise represent the respirable fraction. In consequence an inhalative exposure will result in an oral uptake of nearly 100 % of the administered dosage. The dose descriptor starting point was derived as follows: NOAEL of 13 mg/kg bw. x 1/0.38 m3/kg/bw x 6.7 m3 / 10 m3 /person = 23 mg/m3 (according to REACH ECHA GD, Example R. 8-2 Workers (Chapter R.8: Characterisation of dose [concentration]-response for human health).
AF for dose response relationship:
1
Justification:
Derived no-effect level from a carcinogenicity study.
AF for differences in duration of exposure:
1
Justification:
DNEL based on a fully reliable carcinogenicity study with oral administration of the test article to rats.
AF for interspecies differences (allometric scaling):
1
Justification:
According to ECHA guidance no assessment factor used for inhalation route.
AF for other interspecies differences:
2.5
Justification:
"Remaining differences"
AF for intraspecies differences:
10
Justification:
Standard factor for the general public according to ECHA REACH guidance.
AF for the quality of the whole database:
1
Justification:
A fully reliable study is used for the derivation of the hazard via oral route
AF for remaining uncertainties:
1
Justification:
A fully reliable study is used for the derivation of the hazard via oral route
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
141 mg/m³
Most sensitive endpoint:
acute toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
25
Modified dose descriptor starting point:
NOAEC
Value:
3 526 mg/m³
Explanation for the modification of the dose descriptor starting point:
The Dose descriptor starting point was derived as follows: LD50 > 2000 mg/kg bw. x 1/0.38 m3/kg/bw x 6.7 m3 / 10 m3 /person =3526 mg/m3 (according to REACH ECHA GD, Example R. 8-2 Workers (Chapter R.8: Characterisation of dose [concentration]-response for human health).
AF for dose response relationship:
1
Justification:
No higher factor applicable because no effects were observed up to the highest dose
AF for interspecies differences (allometric scaling):
1
Justification:
According to ECHA guidance no assessment factor used for inhalation route.
AF for other interspecies differences:
2.5
Justification:
"Remaining differences"
AF for intraspecies differences:
10
Justification:
Standard factor for the general public according to ECHA REACH guidance.
AF for the quality of the whole database:
1
Justification:
A fully reliable study is used for the derivation of the hazard.
AF for remaining uncertainties:
1
Justification:
A fully reliable study is used for the derivation of the hazard.

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.13 mg/kg bw/day
Most sensitive endpoint:
carcinogenicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
100
Modified dose descriptor starting point:
NOAEL
Value:
13 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
A fully reliable carcinogenicity study with rats is available for the oral route of administration (carcinogenicity study, Kitahori et al. 1997). Appropriate species and dosages were used in theis study. Although no no-effect level was identified, the clear decline of toxic effects between the 2 dosages allows the estimation that a level of at least 13 mg/kg bw /day for both sexes should be a no-effect level. Additionally an acute dermal toxicity study revealed no effects up to and including dosages of 2000 mg/kg bw. It is assumed that the resorption after dermal application is similar to the resorption after oral administration.
AF for dose response relationship:
1
Justification:
Derived no-effect level from a carcinogenicity study.
AF for differences in duration of exposure:
1
Justification:
DNEL based on a fully reliable carcinogenicity study with oral administration of the test article to rats.
AF for interspecies differences (allometric scaling):
4
Justification:
According to ECHA guidance a factor of 4 is used for allometric scaling from rat to human.
AF for other interspecies differences:
2.5
Justification:
"Remaining differences"
AF for intraspecies differences:
10
Justification:
Standard factor for the general public according to ECHA REACH guidance.
AF for the quality of the whole database:
1
Justification:
A fully reliable study is used for the derivation of the hazard via dermal route
AF for remaining uncertainties:
1
Justification:
A fully reliable study is used for the derivation of the hazard via dermal route
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
20 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):
100
Modified dose descriptor starting point:
NOAEL
Value:
2 000 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
no route to route extrapolation necessary
AF for dose response relationship:
1
Justification:
No higher factor necessary because no effects were observed up to the highest dose.
AF for interspecies differences (allometric scaling):
4
Justification:
According to ECHA guidance a factor of 4 is used for allometric scaling from rat to human.
AF for other interspecies differences:
2.5
Justification:
"Remaining differences
AF for intraspecies differences:
10
Justification:
Standard factor for the general public according to ECHA REACH guidance.
AF for the quality of the whole database:
1
Justification:
A fully reliable study is used for the derivation of the hazard via dermal route
AF for remaining uncertainties:
1
Justification:
A fully reliable study is used for the derivation of the hazard via dermal route

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.45 mg/cm²
Most sensitive endpoint:
acute toxicity
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
25
Dose descriptor starting point:
other: NOAEL
AF for dose response relationship:
1
Justification:
No higher factor necessary because no effects were observed up to the highest dose.
AF for interspecies differences (allometric scaling):
1
Justification:
AF for allometric scaling of 1, " ... since local effects are independent of the basal metabolic rate, allometric scaling should not be applied (allometric scaling factor of 1)" (ECHA REACH Guidance Chapter R8)
AF for other interspecies differences:
2.5
Justification:
"Remaining differences"
AF for intraspecies differences:
10
Justification:
Standard factor for the general public according to ECHA REACH guidance.
AF for the quality of the whole database:
1
Justification:
AF based on a fully reliable study acute dermal toxicity study with rats
AF for remaining uncertainties:
1
Justification:
AF based on a fully reliable study acute dermal toxicity study with rats

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.13 mg/kg bw/day
Most sensitive endpoint:
carcinogenicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
100
Modified dose descriptor starting point:
NOAEL
Value:
13 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
A toxicological study with oral administration is used for extrapolation to the hazard via oral route of the general population. A fully reliable carcinogenicity study with administration in the drinking water to rats is available (Kitahori et al. 1997). Appropriate species and dosages were used in this study. Although no no-effect level was identified, the clear decline of toxic effects between the 2 dosages allows the estimation that a level of at least 13 mg/kg bw /day for both sexes should be a no-effect level.
AF for dose response relationship:
1
Justification:
Derived no-effect level from a carcinogenicity study.
AF for differences in duration of exposure:
1
Justification:
Derived no-effect level from a carcinogenicity study (= chronic study).
AF for interspecies differences (allometric scaling):
4
Justification:
According to ECHA guidance a factor of 4 is used for allometric scaling from rat to human.
AF for other interspecies differences:
2.5
Justification:
"Remaining differences"
AF for intraspecies differences:
10
Justification:
Standard factor for the general public according to ECHA REACH guidance.
AF for the quality of the whole database:
1
Justification:
A fully reliable study is used for the derivation of the hazard via oral route
AF for remaining uncertainties:
1
Justification:
no further AF necessary
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
20 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):
100
Modified dose descriptor starting point:
NOAEL
Value:
2 000 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
no route to route extrapolation necessary
AF for dose response relationship:
1
Justification:
No effects were observed after oral administration of dosages of 2000 mg/kg bw. to rats.
AF for interspecies differences (allometric scaling):
4
Justification:
According to ECHA guidance a factor of 4 is used for allometric scaling from rat to human.
AF for other interspecies differences:
2.5
Justification:
"Remaining differences"
AF for intraspecies differences:
10
Justification:
Standard factor for the general public according to ECHA REACH guidance.
AF for the quality of the whole database:
1
Justification:
A fully reliable acute oral toxicity study is used for the derivation of the hazard via oral route
AF for remaining uncertainties:
1
Justification:
A fully reliable acute oral toxicity study is used for the derivation of the hazard via oral route

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population

An in vitro study was performed to assess the corneal irritation and damage potential of L-Cysteine Hydrochloride Monohydrat. Bovine corneas were incubated for 4 hours with a 20% solution of the test item in 0.9% NaCl solution. Afterwards the change of opacity was measured and compared to negative and positive control groups. The changes in opacity of the control groups, 0.402 and 80.746, met the validity criteria.

L-Cysteine Hydrochloride Monohydrat caused a change in opacity of 9.815.

According to OECD 437 L-Cysteine Hydrochloride Monohydrat is classified as "non corrosive" and/or "no severe irritant".