Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
8.8 mg/m³
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
70.4 mg/m³
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:
5 mg/kg bw/day
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
40 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

Additional information - workers

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

The test substance is not skin and eye irritating.

Data from animal studies and data from human volunteers as well as data from epidemiological studies demonstrated a skin sensitizing potential of MBT (for review SCCP 2005, BG Chemie 2000). In consequence, an existing classification with R43 (22 ATP)/ GHS Skin Sensitizer category 1 is confirmed. According to criteria published in REACH guidance document chapter R.8, MBT was categorised as moderate skin sensitizer.

Acute/short-term exposure systemic effects:

The acute dermal and oral toxicity of the test substance MBT is very low, indicated by oral LD50 values greater than 2000 mg/kg. The acute oral LD50 value in rats is >= 2830 mg/kg bw (Monsanto Co. 1973, 1974) and the dermal LD50 value in rabbits is greater than 7940 mg/kg bw (Monsanto Co. 1973, 1974). Due to the very low oral and dermal acute toxicity of MBT 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).

DNEL short-term systemic dermal: 5 mg/kg bw/day x 8 = 40 mg/kg bw/day

DNEL short-term systemic inhalation: 8.8 mg/m3 x 8 = 70.4 mg/m3

DNEL long-term exposure systemic

The data discussed under repeated dose toxicity were used in a weight of evidence to assess a NOAEL in rats (for more details see chapter 5.6.). Mild toxic effects, like body weight reduction and/or increase in kidney and liver weights were noted in a concentration range of 150 to 375 mg/kg bw and day in rats. Following the recommendation given in MAK (1999) a NOAEL of 50 mg/kg bw and day was suggested, which based on data from the two-generation toxicity study and the observed LOAEL of 2500 ppm (ca. 150 to 250 mg/kg bw and day)(CMA 1990).

Worker DNEL long-term systemic for oral route

Start point: NOAEL 50 mg/mg bw and day 2-generation study with Sprague-Dawley rats (CMA 1990 according to MAK 1999).

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

=> Corrected NOAEL 50 mg/kg bw/day

Interspecies differences: Allometric scaling: 4

Remaining interspecies differences: 1*

Intraspecies differences: 5

Differences in duration of exposure (2-generation study to chronic): 1**

Dose response and endpoint specific/severity issues: 1

Quality of database: 1

Overall factor (product of individual factors): 20

=>Worker DNEL long-term for oral route-systemic: 2.5 mg/kg bw/day

* Repeated dose toxicity data from different rat and mice strains available

** In several repeated dose studies the NOAEL and or LOAEL are in the same range; consistent findings in subchronic, chronic and reproduction/ developmental toxicity study

Worker DNEL long-term sytemic for dermal route

Start point: NOAEL 50 mg/mg bw and day 2-generation study with Sprague-Dawley rats (CMA 1990 according to MAK 1999).

Differences in absorption Abs (oral-rat) / Abs (dermal-human): 2*

=> Corrected NOAEL 100 mg/kg bw/day

Interspecies differences: Allometric scaling: 4

Remaining interspecies differences: 1**

Intraspecies differences: 5

Differences in duration of exposure (2-generation study to chronic): 1***

Dose response and endpoint specific/severity issues: 1

Quality of database: 1

Overall factor (product of individual factors): 20

=>Worker DNEL long-term for dermal route-systemic: 5 mg/kg bw/day

* Toxicokinetic data revealed low dermal absorption

** Repeated dose toxicity data from different rat and mice strains available

*** In several repeated dose studies the NOAEL and or LOAEL are in the same range; consistent findings in subchronic, chronic and reproduction/ developmental toxicity study

Worker DNEL long-term systemic for inhalation route

Start point: NOAEL 50 mg/mg bw and day 2-generation study with Sprague-Dawley rats (CMA 1990 according to MAK 1999).

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: 88.2 mg/m3

Interspecies differences: Allometric scaling: 1

Remaining interspecies differences: 1*

Intraspecies differences: 5

Differences in duration of exposure (2-generation study to chronic): 1**

Dose response and endpoint specific/severity issues: 1

Quality of database: 2***

Overall factor (product of individual factors): 10

=>Worker DNEL long-term for inhalation route-systemic: 8.8 mg/m3

* Repeated dose toxicity data from different rat and mice strains available

** In several repeated dose studies the NOAEL and or LOAEL are in the same range; consistent findings in subchronic, chronic and reproduction/ developmental toxicity study

* ** Repeated dose toxicity inhalation study: no valid data available

DNEL fertility:

A two-generation reproduction toxicity study (CMA 1990) was performed to evaluate the potential of MBT on reproduction toxicity. No adverse effects on reproductive functions of the F0 or F1 generation were indicated up to highest dose evaluated (15000 ppm, ca 778 to 2633 mg/kg bw/d F0 and F1 males, ca. 745 to 1770 mg/kg bw/d F0 and F1 females). Minimal to mild toxic effects occurred in all treated groups in both F0 and F1 parental animals. Based on the reduction of body weight noted in F0 males and F1 males and females at the lowest dose group a LOAEL of 2500 ppm (ca. 150 to 250 mg/kg bw and day) was suggested. These data were used in a weight of evidence approach for systemic DNEL calculation (as discussed above). No additional DNEL fertility was calculated because the systemic DNEL covers the maternal toxic effects.

DNEL developmental toxicity:

The developmental toxicity of MBT was evaluated in a teratology study with New Zealand White rabbits (CMA 1989). The oral administration of MBT up to the highest dose group evaluated (300 mg/kg bw and day) during major organogenesis did not induce any developmental toxicity or teratogenicity. Maternal toxicity was evident only at 300 mg/kg bw and day as slightly decreased body weight gain and slightly elevated liver weight. Based on these findings a NOAEL maternal/foetal of 300 mg/kg bw and day was suggested. Both NOAELs are above the suggested NOAEL systemic (50 mg/kg bw/and day) and thus it was concluded that the DNEL for long-term exposure 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:
2.2 mg/m³
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
17.6 mg/m³
DNEL related information

Local effects

Acute/short term exposure
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.5 mg/kg bw/day
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
20 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:
1.25 mg/kg bw/day
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
10 mg/kg bw/day
DNEL related information

General Population - Hazard for the eyes

Additional information - General Population

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

The test substance is not skin and eye irritating.

Data from animal studies and data from human volunteers as well as data from epidemiological studies demonstrated a skin sensitizing potential of MBT (for review SCCP 2005, BG Chemie 2000). In consequence, an existing classification with R43 (22 ATP)/ GHS Skin Sensitizer category 1 is confirmed. According to criteria published in REACH guidance document chapter R.8, MBT was categorised as moderate skin sensitizer.

Acute/short-term exposure systemic effects:

The acute dermal and oral toxicity of the test substance MBT is very low, indicated by oral LD50 values greater than 2000 mg/kg. The acute oral LD50 value in rats is >= 2830 mg/kg bw (Monsanto Co. 1973, 1974) and the dermal LD50 value in rabbits is greater than 7940 mg/kg bw (Monsanto Co. 1973, 1974). Due to the very low oral and dermal acute toxicity of DCBS 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).

DNEL short-term systemic oral: 1.25 mg/kg bw/day x 8 = 10 mg/kg bw/day

DNEL short-term systemic dermal: 2.5 mg/kg bw/day x 8 = 20 mg/kg bw/day

DNEL short-term systemic inhalation: 2.2 mg/m3 x 8 = 17.6 mg/m3

General public long-term exposure systemic

General public long-term systemic for oral route

Start point: NOAEL 50 mg/mg bw and day 2-generation study with Sprague-Dawley rats (CMA 1990 according to MAK 1999).

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

=> Corrected NOAEL 50 mg/kg bw/day

Interspecies differences: Allometric scaling: 4

Remaining interspecies differences: 1*

Intraspecies differences: 10

Differences in duration of exposure (2-generation study to chronic): 1**

Dose response and endpoint specific/severity issues: 1

Quality of database: 1

Overall factor (product of individual factors): 40

=> General Public long-term for oral route-systemic: 1.25 mg/kg bw/day

* Repeated dose toxicity data from different rat and mice strains available

** In several repeated dose studies the NOAEL and or LOAEL are in the same range; consistent findings in subchronic, chronic and reproduction/ developmental toxicity study

General public long-term systemic for dermal route

Start point: NOAEL 50 mg/mg bw and day 2-generation study with Sprague-Dawley rats (CMA 1990 according to MAK 1999).

Differences in absorption Abs (oral-rat) / Abs (dermal-human): 2*

=> Corrected NOAEL 100 mg/kg bw/day

Interspecies differences: Allometric scaling: 4

Remaining interspecies differences: 1**

Intraspecies differences: 10

Differences in duration of exposure (2-generation study to chronic): 1***

Dose response and endpoint specific/severity issues: 1

Quality of database: 1

Overall factor (product of individual factors): 40

=>General public long-term for dermal route-systemic: 2.5 mg/kg bw/day

* Toxicokinetic data revealed low dermal absorption

** Repeated dose toxicity data from different rat and mice strains available

*** In several repeated dose studies the NOAEL and or LOAEL are in the same range; consistent findings in subchronic, chronic and reproduction/ developmental toxicity study

General public long-term systemic for inhalation route

Start point: NOAEL 50 mg/mg bw and day 2-generation study with Sprague-Dawley rats (CMA 1990 according to MAK 1999).

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

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

=> Corrected NOAEC: 43.5 mg/m3

Interspecies differences: Allometric scaling: 1

Remaining interspecies differences: 1*

Intraspecies differences: 10

Differences in duration of exposure (2-generation study to chronic): 1**

Dose response and endpoint specific/severity issues: 1

Quality of database: 2***

Overall factor (product of individual factors): 20

=>General Public DNEL long-term for inhalation route-systemic: 2.2 mg/m3

* Repeated dose toxicity data from different rat and mice strains available

** In several repeated dose studies the NOAEL and or LOAEL are in the same range; consistent findings in subchronic, chronic and reproduction/ developmental toxicity study

* ** Repeated dose toxicity inhalation study: no valid data available

DNEL fertility:

A two-generation reproduction toxicity study (CMA 1990) was performed to evaluate the potential of MBT on reproduction toxicity. No adverse effects on reproductive functions of the F0 or F1 generation were indicated up to highest dose evaluated (15000 ppm, ca 778 to 2633 mg/kg bw/d F0 and F1 males, ca. 745 to 1770 mg/kg bw/d F0 and F1 females). Minimal to mild toxic effects occurred in all treated groups in both F0 and F1 parental animals. Based on the reduction of body weight noted in F0 males and F1 males and females at the lowest dose group a LOAEL of 2500 ppm (ca. 150 to 250 mg/kg bw and day) was suggested. These data were used in a weight of evidence approach for systemic DNEL calculation (as discussed above). No additional DNEL fertility was calculated because the systemic DNEL covers the maternal toxic effects.

DNEL developmental toxicity:

The developmental toxicity of MBT was evaluated in a teratology study with New Zealand White rabbits (CMA 1989). The oral administration of MBT up to the highest dose group evaluated (300 mg/kg bw and day) during major organogenesis did not induce any developmental toxicity or teratogenicity. Maternal toxicity was evident only at 300 mg/kg bw and day as slightly decreased body weight gain and slightly elevated liver weight. Based on these findings a NOAEL maternal/foetal of 300 mg/kg bw and day was suggested. Both NOAELs are above the suggested NOAEL systemic (50 mg/kg bw/and day) and thus it was concluded that the DNEL for long-term exposure covers the DNEL developmental toxicity.