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
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
70 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
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
Most sensitive endpoint:
repeated dose toxicity
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
40 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information

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:
no hazard identified

Additional information - workers

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

The test substance MBTS showed a practically non-irritating potential to rabbit skin (Monsanto Co. 1973). This negative finding was confirmed in a Repeated Insult Patch Test with human volunteers (Monsanto Co. 1982). A low eye irritation potential of MBTS was revealed in an eye irritation study with New Zealand albino rabbits (Monsanto Co 1973).

The skin sensitizing potential of MBTS was confirmed in a modified Local Lymph Node Assay (LLNA) (De Jong 2002) and in guinea pig maximization tests (Kaniwa 1992, Nakamura 1994). However, no skin sensitizing potential of MBTS was revealed in a Repeated Insult Patch Test with human volunteers (Monsanto Co. 1982); whereas several case report data indicated a skin sensitizing potential of MBTS in human (BUA report 1995). The above discussed data demonstrated a skin sensitization potential of MBTS. In consequence, according to CLP classification criteria (Regulation (EC) No 1272/2008) a classification as Skin Sens. 1B is justified.

Acute/short-term exposure systemic effects

The acute dermal and oral toxicity of the test substance MBTS is very low, indicated by LD50 values greater than 5000 mg/kg bw. The acute oral LD50 value in rats is greater than 7940 mg/kg bw (Monsanto Co. 1973) and the dermal LD50 value in rabbits is greater than 7940 mg/kg bw (Monsanto Co. 1973). 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 long-term systemic dermal: 5 mg/kg bw/day x 8 = 40 mg/kg bw/day

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

DNEL long-term exposure systemic

There are only limited data from an early cancer study available for MBTS that can not be used as starting point for DNEL calculation. MBTS consists of two MBT molecules. As discussed by El Dareer (1989) MBT and MBTS have remarkable similarities in their kinetics and extent of absorption, distribution, excretion, and metabolism and since the identified metabolites of both derivates of MBT, it is apparent that MBTS is readily converted to MBT under in vivo conditions. Based on these findings it is assumed that MBT is the determining factor for the biological activities of MBTS

The DNEL calculation is based on a read-across approach with MBT. The following strategy was followed: 1) derive a DNEL for MBT 2) adopt the DNEL for MBT to MBTS.

For MBT several repeated dose toxicity data were used in a weight of evidence approach to assess a NOAEL for DNEL calculation (for more details see chapter repeated dose toxicity). 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. 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 MBT: 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 based on the MBT content for oral route-systemic: 2.5 mg/kg bw/day

Based on the assumption that MBTS is readily converted into MBT under in vivo conditions no additional factors are needed to derive the systemic DNEL for MBTS.

Consequently, based on the read-across to MBT the worker DNEL long-term of MBTS for oral route-systemic is 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 MBT: 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 based on the MBT content for dermal route-systemic: 5 mg/kg bw/day

Based on the assumption that MBTS is readily converted into MBT under in vivo conditions no additional factors are needed to derive the systemic DNEL for MBTS.

Consequently, based on the read-across to MBT the worker DNEL long-term of MBTS for dermal route-systemic is 5 mg/kg bw/day.

* Toxicokinetic data revealed low dermal absorption of MBT and MBTS

** 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 MBT: 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 based on the MBT content for inhalation route-systemic: 8.8 mg/m3

Based on the assumption that MBTS is readily converted into MBT under in vivo conditions no additional factors are needed to derive the systemic DNEL for MBTS.

Consequently, based on the read-across to MBT the worker DNEL long-term of MBTS for inhalation route-systemic is 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 MBT: no valid data available

DNEL fertility

There is no reproduction/developmental toxicity screening study (OECD TG 421) and no two-generation reproduction toxicity study available for MBTS. A read across approach was conducted with study data from MBT (benzothiazole-2-thiol) (see discussion endpoint summary toxicokinetics).

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 potential of MBTS was evaluated in Wistar rats (Ema 1989). Pregnant rats (15 to 19 per dose) were given MBTS at a dosage of 0, 0.04, 0.2 or 1% in the diet from day 0 to day 20 of pregnancy. The dams were scheduled sacrificed on day 20 of pregnancy. In an additional approach dams (5 to 6 per dose group) were allowed to deliver spontaneously. These dams were killed on day 21 after birth. The offspring of these dams were scheduled sacrificed seven weeks after birth. No significant compound–related effects on the incidences of pre- and post-implantation losses and the number, sex ratio and body weight of live foetuses were noted. Morphological examinations of the foetuses revealed no evidence of teratogenesis. In the postnatal development of the offspring from dams treated with MBTS, a high survival rate and good growth of the offspring were observed. The authors suggested a NOAEL developmental toxicity of 596 mg/kg bw/ day (highest dose evaluated). Maternal toxicity was indicated by a reduction in body weight gain during day 0 to day 14 of pregnancy at the highest dose group, thus a NOAEL of 127 mg/kg bw and day is suggested for maternal toxicity. Both NOAEL values 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.

Read across with MBT

Additionally, a developmental toxicity study in rabbits for MBT, CAS no. 149-30-4 (read-across from supporting substance (structural analogue or surrogate)) is available.

The experimental design consisted of three MBT treated groups and a concurrent control group. Each group was comprised of 20 artificially inseminated New Zealand White rabbits. Dosage levels selected for this teratology study were 50, 150, and 300 mg/kg/day. MBT was suspended in 1% methylcellulose and administered at a volume of 2 ml/kg. Control animals received 1% aqueous solution of methylcellulose at an equivalent dosage volume. Treatment was performed from gestation day 6 through gestation day 18. All rabbits were observed daily for signs of overt toxicity. Body weights were measured on gestation days 0, 6, 9, 12, 15, 19, 24, and 29. Food consumption was measured daily and reported for the specified intervals. Cesarean section was performed on gestation day 29. Intrauterine survival was evaluated and fetuses were examined for external, visceral, and skeletal anomalies.

The oral administration of 50, 150, or 300 mg/kg/day (highest applied dose) of MBT to pregnant New Zealand White rabbits during major organogenesis did not induce any developmental toxicity or teratogenicity. Maternal toxicity was evident only at a level of 300 mg/kg/day as slightly decreased body weight gain and slightly elevated liver weight.

General Population - Hazard via inhalation route

Systemic effects

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

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
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:
2.5 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
20 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information

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:
1.25 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
10 mg/kg bw/day
Most sensitive endpoint:
sensitisation (skin)
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 MBTS showed a practically non-irritating potential to rabbit skin (Monsanto Co. 1973). This negative finding was confirmed in a Repeated Insult Patch Test with human volunteers (Monsanto Co. 1982). A low eye irritation potential of MBTS was revealed in an eye irritation study with New Zealand albino rabbits (Monsanto Co 1973).

The skin sensitizing potential of MBTS was confirmed in a modified Local Lymph Node Assay (LLNA) (De Jong 2002) and in guinea pig maximization tests (Kaniwa 1992, Nakamura 1994). However, no skin sensitizing potential of MBTS was revealed in a Repeated Insult Patch Test with human volunteers (Monsanto Co. 1982); whereas several case report data indicated a skin sensitizing potential of MBTS in human (BUA report 1995). The above discussed data demonstrated a skin sensitization potential of MBTS. In consequence, existing classification with Skin Sens. category 1 is confirmed. According to criteria published in REACH guidance document chapter R. 8, MBTS was categorised as strong skin sensitizer.

Acute/short-term exposure systemic effects

The acute dermal and oral toxicity of the test substance MBTS is very low, indicated by LD50 values greater than 5000 mg/kg bw. The acute oral LD50 value in rats is greater than 7940 mg/kg bw (Monsanto Co. 1973) and the dermal LD50 value in rabbits is greater than 7940 mg/kg bw (Monsanto Co. 1973). 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: 2.5 mg/kg bw/day x 8 = 20 mg/kg bw/day

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

DNEL short-term systemic inhalation: 2.2 mg/m3x 8 = 17.6 mg/m3

DNEL long-term exposure systemic

There are only limited data from an early cancer study available for MBTS that can not be used as starting point for DNEL calculation. MBTS consists of two MBT molecules. As discussed by El Dareer (1989) MBT and MBTS have remarkable similarities in their kinetics and extent of absorption, distribution, excretion, and metabolism and since the identified metabolites of both derivates of MBT, it is apparent that MBTS is readily converted to MBT under in vivo conditions. Based on these findings it is assumed that MBT is the determining factor for the biological activities of MBTS

The DNEL calculation is based on a read-across approach with MBT. The following strategy was followed: 1) derive a DNEL for MBT 2) adopt the DNEL for MBT to MBTS.

General public long-term systemic for oral route

Start point MBT: 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 based on the MBT content for oral route-systemic: 1.25 mg/kg bw/day

Based on the assumption that MBTS is readily converted into MBT under in vivo conditions no additional factors are needed to derive the systemic DNEL for MBTS.

Consequently, based on the read-across approach to MBT the general public DNEL long-term MBTS oral route-systemic is 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 MBT: 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 based on the MBT content for dermal route-systemic: 2.5 mg/kg bw/day

Based on the assumption that MBTS is readily converted into MBT under in vivo conditions no additional factors are needed to derive the systemic DNEL for MBTS.

Consequently, based on the read-across approach to MBT the general public DNEL long-term of MBTS for dermal route-systemic is 2.5 mg/kg bw/day.

* Toxicokinetic data revealed low dermal absorption of MBT and MBTS

** 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 MBT: 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 based on the MBT content for inhalation route-systemic: 2.2 mg/m3

Based on the assumption that MBTS is readily converted into MBT under in vivo conditions no additional factors are needed to derive the systemic DNEL for MBTS.

Consequently, based on the read-across approach to MBT the general public DNEL long-term MBTS inhalation route-systemic is 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 MBT: no valid data available

DNEL fertility

There is no reproduction/developmental toxicity screening study (OECD TG 421) and no two-generation reproduction toxicity study available for MBTS. A read across approach was conducted with study data from MBT (benzothiazole-2-thiol) (see discussion endpoint summary toxicokinetics).

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 potential of MBTS was evaluated in Wistar rats (Ema 1989). Pregnant rats (15 to 19 per dose) were given MBTS at a dosage of 0, 0.04, 0.2 or 1% in the diet from day 0 to day 20 of pregnancy. The dams were scheduled sacrificed on day 20 of pregnancy. In an additional approach dams (5 to 6 per dose group) were allowed to deliver spontaneously. These dams were killed on day 21 after birth. The offspring of these dams were scheduled sacrificed seven weeks after birth. No significant compound–related effects on the incidences of pre- and post-implantation losses and the number, sex ratio and body weight of live foetuses were noted. Morphological examinations of the foetuses revealed no evidence of teratogenesis. In the postnatal development of the offspring from dams treated with MBTS, a high survival rate and good growth of the offspring were observed. The authors suggested a NOAEL developmental toxicity of 596 mg/kg bw/ day (highest dose evaluated). Maternal toxicity was indicated by a reduction in body weight gain during day 0 to day 14 of pregnancy at the highest dose group, thus a NOAEL of 127 mg/kg bw and day is suggested for maternal toxicity. Both NOAEL values 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.

Read across with MBT

Additionally, a developmental toxicity study in rabbits for MBT, CAS no. 149-30-4 (read-across from supporting substance (structural analogue or surrogate)) is available.

The experimental design consisted of three MBT treated groups and a concurrent control group. Each group was comprised of 20 artificially inseminated New Zealand White rabbits. Dosage levels selected for this teratology study were 50, 150, and 300 mg/kg/day. MBT was suspended in 1% methylcellulose and administered at a volume of 2 ml/kg. Control animals received 1% aqueous solution of methylcellulose at an equivalent dosage volume. Treatment was performed from gestation day 6 through gestation day 18. All rabbits were observed daily for signs of overt toxicity. Body weights were measured on gestation days 0, 6, 9, 12, 15, 19, 24, and 29. Food consumption was measured daily and reported for the specified intervals. Cesarean section was performed on gestation day 29. Intrauterine survival was evaluated and fetuses were examined for external, visceral, and skeletal anomalies.

The oral administration of 50, 150, or 300 mg/kg/day (highest applied dose) of MBT to pregnant New Zealand White rabbits during major organogenesis did not induce any developmental toxicity or teratogenicity. Maternal toxicity was evident only at a level of 300 mg/kg/day as slightly decreased body weight gain and slightly elevated liver weight.