Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
11 mg/m³
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
11 mg/m³
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
11 mg/m³
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
11 mg/m³
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
67 mg/kg bw/day
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
534 mg/kg bw/day
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
Most sensitive endpoint:
sensitisation (skin)
Acute/short term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
Most sensitive endpoint:
sensitisation (skin)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

Acute/short-term local effects/ Long-term exposure local effects:

The test substance CBS caused skin sensitization in a well conducted human Repeated Insult Patch Test study which clearly demonstrated contact sensitization in humans (Monsanto Co. 1982). In consequence, existing classification with R 43/ skin sens. cat.1 is confirmed. Based on the findings of the Repeated Insult Patch Test with human volunteers and the data from the guinea pig assay (Monsanto Co. 1982) a moderate skin sensitizing potential of CBS is suggested according to the categorization criteria published in REACH guidance document chapter R. 8.

In the limited inhalation study (Monsanto Co. 1981) exposed rats exhibited occasional nasal irritation which appeared to be concentration related (no more data). This finding was observed immediately after the 6 hour exposure period and disappeared by the next morning. Since the animals recovered from this lesion within 24 hours and this finding could not be correlated to histopathologic effects observed, the observation of nasal irritation in CBS-exposed animals was not considered to be toxicologically adverse. No relevant local effects on the respiratory tract were observed up to 48 mg/m3. Thus, the DNEL inhalation (long-term exposure systemic: 11.3 mg/m³) covers the highest dose tested in this limited study.

Acute/short-term exposure systemic effects:

The acute toxicity of the test substance CBS in rodents is very low after oral and dermal administration; LD50 values of >5000 mg/kg bw were obtained. Due to the very low oral and dermal acute toxicity of CBS it is proposed to limit exposure peaks to a factor of 8. This approach is generally in line with the regulatory procedure in Germany (see Technical Rule for Hazardous Substances 900 and equivalent to REACH guidance document chapter 8, page 110)

DNEL short-term systemic dermal: 66.7 mg/kg bw/day x 8 = 533.6 mg/kg bw/day

To consider possible effects of nasal irritation it was concluded that the DNEL inhalation (long-term exposure systemic: 11.3 mg/m³) covers the DNEL acute/short-term systemic effects.

DNEL long-term exposure systemic

Worker DNEL long-term systemic for oral route

The 28-day gavage study with Crj: CD (SD) rats (MHWJ 1997) was considered to be the most relevant oral toxicity study for NOAEL determination. In this subacute toxicity study signs of coagulopathy of the blood were observed in both male and female rats. In males shortening of the prothrombine time (statistically significant) was noted after oral administration of >= 250 mg/kg bw and day CBS, and in females statistically significant decreased platelet count was noted at 800 mg/kg bw and day. CBS-related effects were present in male and female Crj: CD (SD) rats at >= 250 mg/kg bw and day. There were signs of a coagulopathy of the blood in both sexes and effects in the kidney of male rats. No relevant systemic effects were observed in male and female rats after repeated oral administration of 80 mg/kg bw and day CBS. Thus, the NOAEL is considered to be 80 mg/kg bw and day.

Startpoint: NOAEL 80 mg/kg bw and day

Differences in absorption Abs (oral-rat) / Abs (oral-human): 1

=> Corrected NOAEL 80 mg/kg bw/day

Interspecies differences: Allometric scaling: 4

Remaining interspecies differences: 2.5

Intraspecies differences: 5

Differences in duration of exposure (subacute to chronic): 1*

Dose response and endpoint specific/severity issues: 1

Quality of database: 1

Overall factor (product of individual factors): 50

=>Worker DNEL long-term for oral route-systemic: 1.6 mg/kg bw/day

*No additional factor used as the NOAEL from the chronic study (18 months, NTP 1968) is in the same range as the NOAEL from the subacute toxicity study

Worker DNEL long-term sytemic for dermal route

In a subacute dermal toxicity study using doses of 125, 500 and 2000 mg/kg bw and day no systemic or local effects were noted in New Zealand White rabbits after repeated dermal exposure for three weeks with 2000 mg/kg bw and day (Monsanto 1981). Thus, the NOAEL is considered to be 2000 mg/kg bw and day.

Startpoint: 2000 mg/kg bw and day

Differences in absorption Abs (dermal-rabbit) / Abs (dermal-human): 1

=> Corrected NOAEL 2000 mg/kg bw/day

Interspecies differences: Allometric scaling: 2.4

Remaining interspecies differences: 2.5

Intraspecies differences: 5

Differences in duration of exposure (subacute to chronic): 1*

Dose response and endpoint specific/severity issues: 1

Quality of database: 1

Overall factor (product of individual factors): 30

=>Worker DNEL long-term for dermal route-systemic: 66.7 mg/kg bw/day

*No specific systemic effects noted for the dermal route, thus purpose of the assessment factor from the oral route (No additional factor used as the NOAEL from the chronic study (18 months, NTP 1968) is in the same range as the NOAEL from the subacute toxicity study)

Worker DNEL long-term systemic for inhalation route

A limited inhalation study is available (Monsanto Co. 1981). However, the study is limited concerning the recommended particle-size distribution given in current guidelines and thus an exposure of all relevant regions of the respiratory tract might not have been given. The biologically relevance of sporadic findings reported, especially systemic effects are questionable. In light of these limitations the data from the oral subacute toxicity study (NOAEL: 80 mg/kg bw and day, MHWJ 1997) will be used for calculation of the systemic DNEL.

Startpoint: NOAEL 80 mg/kg bw and day

Respiratory volume rat (sRV) (worker (8 h): 1/0.38): 2.632

Differences in respiratory volume (default factor "light activity worker"): 0.67

Differences in absorption Abs (oral-rat) / Abs (inhalation-human): 1*

=> Corrected NOAEC 141 mg/m3

Interspecies differences: Allometric scaling: 1

Remaining interspecies differences: 2.5

Intraspecies differences: 5

Differences in duration of exposure (subacute to chronic): 1**

Dose response and endpoint specific/severity issues: 1

Quality of database: 1

Overall factor (product of individual factors): 12.5

=>Worker DNEL long-term for inhalation route-systemic: 11.3 mg/m3

* Limited inhalation study available (Monsanto 1981)

** No additional factor used as the NOAEL from the chronic study (18 months, NTP 1968) is in the same range as the NOAEL from the subacute toxicity study

DNEL fertility

There is no fertility study available. From an oral 28-day repeated dose toxicity test with CBS in rats data on reproductive organ toxicity were available (MHWJ 1997). Atrophy of seminiferous tubuli, hyperplasia of interstitial cells and decrease in epididymal sperm (each of 1/6 males, respectively were found at a dose of 800 mg/kg bw and day (14 day recovery period). No histopathological abnormalities were detected in ovary from females of 800 mg/kg groups. Based on the findings from this subacute toxicity study, the NOAEL for males concerning adverse effects on the reproductive organs is considered to be 250 mg/kg bw and day and for females 800 mg/kg bw and day (highest dose tested). Based on the findings of the 28-day gavage study (MHWJ 1997) which indicate adverse effects on the testes it was concluded that the DNEL long-term exposure systemic covers the DNEL fertility.

DNEL developmental toxicity

The findings from the three available oral developmental toxicity studies consistently demonstrated that CBS induces maternal toxicity in terms of impairment of maternal weight gain during gestation and signs of fetal growth retardation in terms of reduced mean fetal body weight. Fetal body weight impairment, however, was exclusively observed at oral dosages associated with significantly reduced maternal weight. A substance-related specific embryotoxic and or/ teratogenic potential was not revealed from available studies. The guideline-consistent developmental toxicity study (Monsanto 1981) was considered as the most relevant developmental toxicity study. A NOAEL derived from this study for maternal toxicity is 100 mg/kg bw and day and is based on a decrease in mean body weight gain. The NOAEL for the offspring is 300 mg/kg bw and day and is based on a decrease mean fetal body weight. Based on the findings of the developmental toxicity study (Monsanto 1981) which indicate maternal toxicity in terms of reduced mean body weight gain and fetal toxicity in the range of maternal toxicity it was concluded that the DNEL long-term exposure systemic covers the DNEL developmental toxicity.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.8 mg/m³
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.8 mg/m³
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.8 mg/m³
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.8 mg/m³
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
33 mg/kg bw/day
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
266 mg/kg bw/day
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
Most sensitive endpoint:
sensitisation (skin)
Acute/short term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
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:
0.8 mg/kg bw/day
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
6.4 mg/kg bw/day
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population

Acute/short-term local effects/ Long-term exposure local effects:

The test substance CBS caused skin sensitization in a well conducted human Repeated Insult Patch Test study which clearly demonstrated contact sensitization in humans (Monsanto Co. 1982). In consequence, existing classification with R 43/ skin sens. cat. 1 is confirmed. Based on the findings of the Repeated Insult Patch Test with human volunteers and the data from the guinea pig assay (Monsanto Co. 1982) a moderate skin sensitizing potential of CBS is suggested according to the categorization criteria published in REACH guidance document chapter R. 8.

In the limited inhalation study (Monsanto Co. 1981) exposed rats exhibited occasional nasal irritation which appeared to be concentration related (no more data). This finding was observed immediately after the 6 hour exposure period and disappeared by the next morning. Since the animals recovered from this lesion within 24 hours and this finding could not be correlated to histopathologic effects observed, the observation of nasal irritation in CBS-exposed animals was not considered to be toxicologically adverse. No relevant local effects on the respiratory tract were observed up to 48 mg/m3. Thus, the DNEL inhalation (long-term exposure systemic: 2.8 mg/m3) covers the highest dose tested in this limited study.

Acute/short-term exposure systemic effects:

The acute toxicity of the test substance CBS in rodents is very low after oral and dermal administration; LD50 values of >5000 mg/kg bw were obtained. Due to the very low oral and dermal acute toxicity of CBS it is proposed to limit exposure peaks to a factor of 8. This approach is generally in line with the regulatory procedure in Germany (see Technical Rule for Hazardous Substances 900 and equivalent to REACH guidance document chapter 8, page 110)

DNEL short-term systemic oral: 0.8 mg/kg bw/day x 8 = 6.4 mg/kg bw/day

DNEL short-term systemic dermal: 33.3 mg/kg bw/day x 8 = 266 mg/kg bw/day

To consider possible effects of nasal irritation it was concluded that the DNEL inhalation (long-term exposure systemic: 2.8 mg/m3) covers the DNEL acute/short-term systemic effects.

DNEL long-term exposure systemic

General public DNEL long-term systemic for oral route

The 28-day gavage study with Crj: CD (SD) rats (MHWJ 1997) was considered to be the most relevant oral toxicity study for NOAEL determination. In this subacute toxicity study signs of coagulopathy of the blood were observed in both male and female rats. In males shortening of the prothrombine time (statistically significant) was noted after oral administration of >= 250 mg/kg bw and day CBS, and in females statistically significant decreased platelet count was noted at 800 mg/kg bw and day. CBS-related effects were present in male and female Crj: CD (SD) rats at >= 250 mg/kg bw and day. There were signs of a coagulopathy of the blood in both sexes and effects in the kidney of male rats. No relevant systemic effects were observed in male and female rats after repeated oral administration of 80 mg/kg bw and day CBS. Thus, the NOAEL is considered to be 80 mg/kg bw and day.

Startpoint: NOAEL 80 mg/kg bw and day

Differences in absorption Abs (oral-rat) / Abs (oral-human): 1

=> Corrected NOAEL 80 mg/kg bw/day

Interspecies differences: Allometric scaling: 4

Remaining interspecies differences: 2.5

Intraspecies differences: 10

Differences in duration of exposure (subacute to chronic): 1*

Dose response and endpoint specific/severity issues: 1

Quality of database: 1

Overall factor (product of individual factors): 100

=>General Public DNEL long-term for oral route-systemic: 0.8 mg/kg bw/day

*No additional factor used as the NOAEL from the chronic study (18 months, NTP 1968) is in the same range as the NOAEL from the subacute toxicity study

General public DNEL long-term sytemic for dermal route

In a subacute dermal toxicity study using doses of 125, 500 and 2000 mg/kg bw and day no systemic or local effects were noted in New Zealand White rabbits after repeated dermal exposure for three weeks with 2000 mg/kg bw and day (Monsanto 1981). Thus, the NOAEL is considered to be 2000 mg/kg bw and day.

Startpoint: 2000 mg/kg bw and day

Differences in absorption Abs (dermal-rabbit) / Abs (dermal-human): 1

=> Corrected NOAEL 2000 mg/kg bw/day

Interspecies differences: Allometric scaling: 2.4

Remaining interspecies differences: 2.5

Intraspecies differences: 10

Differences in duration of exposure (subacute to chronic): 1*

Dose response and endpoint specific/severity issues: 1

Quality of database: 1

Overall factor (product of individual factors): 60

=>General Public DNEL long-term for dermal route-systemic: 33.3 mg/kg bw/day

*No specific systemic effects noted for the dermal route, thus purpose of the assessment factor from the oral route (No additional factor used as the NOAEL from the chronic study (18 months, NTP 1968) is in the same range as the NOAEL from the subacute toxicity study)

General Public DNEL long-term systemic for inhalation route

A limited inhalation study is available (Monsanto Co. 1981). However, the study is limited concerning the recommended particle-size distribution given in current guidelines and thus an exposure of all relevant regions of the respiratory tract might not have been given. The biologically relevance of sporadic findings reported, especially systemic effects are questionable. In light of these limitations the data from the oral subacute toxicity study (NOAEL: 80 mg/kg bw and day, MHWJ 1997) will be used for calculation of the systemic DNEL.

Startpoint: NOAEL 80 mg/kg bw and day

Respiratory volume rat (sRV) general public 1/1.15: 0.87

Differences in absorption Abs (oral-rat) / Abs (inhalation-human): 1*

=> Corrected NOAEC 70 mg/m3

Interspecies differences: Allometric scaling: 1

Remaining interspecies differences: 2.5

Intraspecies differences: 10

Differences in duration of exposure (subacute to chronic): 1**

Dose response and endpoint specific/severity issues: 1

Quality of database: 1

Overall factor (product of individual factors): 25

=>Worker DNEL long-term for inhalation route-systemic: 2.8 mg/m3

* Limited inhalation study available (Monsanto 1981)

** No additional factor used as the NOAEL from the chronic study (18 months, NTP 1968) is in the same range as the NOAEL from the subacute toxicity study

DNEL fertility

There is no fertility study available. From an oral 28-day repeated dose toxicity test with CBS in rats data on reproductive organ toxicity were available (MHWJ 1997). Atrophy of seminiferous tubuli, hyperplasia of interstitial cells and decrease in epididymal sperm (each of 1/6 males, respectively were found at a dose of 800 mg/kg bw and day (14 day recovery period). No histopathological abnormalities were detected in ovary from females of 800 mg/kg groups. Based on the findings from this subacute toxicity study, the NOAEL for males concerning adverse effects on the reproductive organs is considered to be 250 mg/kg bw and day and for females 800 mg/kg bw and day (highest dose tested). Based on the findings of the 28-day gavage study (MHWJ 1997) which indicate adverse effects on the testes it was concluded that the DNEL long-term exposure systemic covers the DNEL fertility.

DNEL developmental toxicity

The findings from the three available oral developmental toxicity studies consistently demonstrated that CBS induces maternal toxicity in terms of impairment of maternal weight gain during gestation and signs of fetal growth retardation in terms of reduced mean fetal body weight. Fetal body weight impairment, however, was exclusively observed at oral dosages associated with significantly reduced maternal weight. A substance-related specific embryotoxic and or/ teratogenic potential was not revealed from available studies. The guideline-consistent developmental toxicity study (Monsanto 1981) was considered as the most relevant developmental toxicity study. A NOAEL derived from this study for maternal toxicity is 100 mg/kg bw and day and is based on a decrease in mean body weight gain. The NOAEL for the offspring is 300 mg/kg bw and day and is based on a decrease mean fetal body weight. Based on the findings of the developmental toxicity study (Monsanto 1981) which indicate maternal toxicity in terms of reduced mean body weight gain and fetal toxicity in the range of maternal toxicity it was concluded that the DNEL long-term exposure systemic covers the DNEL developmental toxicity.