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Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
5.9 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):
12.5
Dose descriptor starting point:
NOAEL
Value:
50 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
73.4 mg/m³
Explanation for the modification of the dose descriptor starting point:

For the inhalation route there is no animal study available. Therefore, oral rat data is used to calculate a corresponding air concentration for humans and a route-to-route extrapolation for systemic effects is necessary to derive the correct starting point. In the case of oral-to-inhalation the inclusion of a default factor of 2 is recommended according to chapter R.8.4.2 of the ECHA guidance on information requirements and chemical safety assessment, chapter R.8: Characterisation of dose [concentration]-response for human health (version 2.1, November 2012). According to Figure R. 8-3 in the ECHA guidance on information requirements and chemical safety assessment, chapter R.8: Characterisation of dose [concentration]-response for human health (version 2.1, November 2012) additional correction is needed for scaling issues: Corrected inhalatory NOAEC = oral NOAEL * 50%/100% * 1/0.38 m³ per kg and day * 6.7 m³/10 m³ * 1.4 (differences in experimental/human exposure conditions were considered with the factor 1.4 (7 days/week in animal study versus 5 days/week for workers  in subchronic and chronic studies), based on the oral NOAEL of 50 mg/kg bw/day for systemic toxicity obtained in several subchronic feeding studies on rats and mice the starting point is calculated with 61.7 mg/m³ for MBT.

The precise composition of ZMBT has to be taken into account to derive a corrected inhalatory NOAEC for ZMBT based on the read-across approach with MBT. The MBT mass content in ZMBT is 84%, consequently the corrected inhalatory NOAEC for MBT of 61.7 mg/m³ corresponds to 73.4 mg/m³ for ZMBT (61.7/0.84 = 73.4 mg/m³).

AF for dose response relationship:
1
Justification:
Since the starting point for the DNEL calculation is a NOAEL according to chapter R.8.4.3.1 of ECHA guidance R.8 the default assessment factor for dose response relationship is 1.
AF for differences in duration of exposure:
1
Justification:
No difference in the experimental exposure duration (= subchronic) and the duration of exposure for the population and scenario under consideration (= chronic) according to Table R.8-5 of ECHA guidance R.8 is included in this assessment, since several repeated dose toxicity studies with subchronic and chronic exposure are available for MBT that show NOAEL and LOAEL values in the same dose range. This procedure is supported by consistent toxicological findings in subchronic, chronic, and reproduction/developmental toxicity studies.
AF for interspecies differences (allometric scaling):
1
Justification:
Allometric scaling is already included in the route-to-route extrapolation for dose descriptor calculation as described in ECHA guidance R.8.
AF for other interspecies differences:
2.5
Justification:
A factor of 2.5 for remaining interspecies differences is suggested in ECHA guidance R.8.
AF for intraspecies differences:
5
Justification:
According to chapter R.8.4.3.1 of ECHA guidance R.8 the default assessment factor to be applied for intraspecies differences in workers is 5.
AF for the quality of the whole database:
1
Justification:
Default assessment factor for good/standard quality of database as suggested by ECHA guidance R.8.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
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:
3.3 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):
50
Dose descriptor starting point:
NOAEL
Value:
50 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
166.7 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

For the dermal route there is no animal study available. Therefore, oral rat data are used to calculate a corresponding dermal exposure dose of ZMBT for humans. The dermal absorption of MBT is low. In topically treated rats percutaneous absorption rates of 16.1 % to 17% were measured, in guinea pigs 38.4% (CMA 1986, 1987). Therefore, a default factor of 2 is considered appropriate for dermal versus oral MBT absorption. Since ZMBT has a much higher molecular weight than MBT, this factor also applied to MBT. Differences in experimental/human exposure conditions were considered with the factor 1.4 (7 days/week in animal study versus 5 days/week for workers) . The corrected dermal NOAEL for workers = 50 mg/kg bw/day * 2*  1.4 =  140 mg/kg bw/day for MBT. The precise composition of ZMBT has to be taken into account to derive a corrected dermal NOAEL for ZMBT based on the read-across approach with MBT. The MBT mass content in ZMBT is 84%, consequently the corrected dermal NOAEL for MBT of 140 mg/kg bw/day corresponds to 166.7 mg/kg bw/day for ZMBT (140/0.84 = 166.7 mg/kg bw).

AF for dose response relationship:
1
Justification:
As the starting point for the DNEL calculation is a NOAEL according to chapter R.8.4.3.1 of ECHA guidance R.8 the default assessment factor for dose response relationship is 1.
AF for differences in duration of exposure:
1
Justification:
No difference in the experimental exposure duration (= subchronic) and the duration of exposure for the population and scenario under consideration (= chronic) according to Table R.8-5 of ECHA guidance R.8 is included in this assessment, since several repeated dose toxicity studies with subchronic and chronic exposure are available that show NOAEL and LOAEL values in the same dose range. This procedure is supported by consistent toxicological findings in subchronic, chronic, and reproduction/developmental toxicity studies.
AF for interspecies differences (allometric scaling):
4
Justification:
According to Table R.8-3 of ECHA guidance R.8 the allometric scaling factor for the rat when compared with humans is 4.
AF for other interspecies differences:
2.5
Justification:
A factor of 2.5 for remaining interspecies differences is suggested in ECHA guidance R.8.
AF for intraspecies differences:
5
Justification:
According to chapter R.8.4.3.1 of ECHA guidance R.8 the default assessment factor to be applied for intraspecies differences in workers is 5.
AF for the quality of the whole database:
1
Justification:
Default assessment factor for good/standard quality of database as suggested by ECHA guidance R.8.
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:
sensitisation (skin)
Acute/short term exposure
Hazard assessment conclusion:
medium 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

There are only limited data from an early cancer study available for ZMBT repeated dose toxicity that are not suitable as starting point for DNEL calculation. ZMBT is composed of two MBT molecules associated with zinc ion (mass content ZMBT: 84% MBT, 16% Zn2+). It was shown in hydrolysis studies that under acidic conditions (pH 3) a rapid degradation to ZMBT to the MBT and to zinc ions Zn2+ was observed. A read-across with toxicological data for MBT as source is thus considered adequate. For justification of the read-across see separate Read-Across Justification Document attached to the IUCLID.

For MBT there are several repeated dose toxicity studies available. Based on the recommendation of MAK (1999) the most relevant study for the assessment of repeated dose toxicity is the two-generation reproduction toxicity feeding study (CMA 1990) in rats with a LOAEL of 2500 ppm (ca. 150 mg to 250 mg/kg bw/day). Following MAK (1999) an overall NOAEL of 50 mg/kg bw and day is suggested for this study and this NOAEL is taken forward for DNEL derivation. This NOAEL is supported as worst-case consideration by consistent findings in several additional repeated dose toxicity studies with subchronic and chronic oral MBT exposure of rats and mice (NTP 1988) that show NOAELs and/or LOAELs in the same range as in the 2-generation study. The ‘human biomonitoring’ commission of the German Federal Environmental Agency (2015) derived an overall NOAEL of 94 mg/kg bw/day for MBT, taking the subchronic study in mice (NTP 1988) as basis.

In the 2-generation study (CMA 1990) with MBT minimal to mild toxic effects (reduced body weights, increase in absolute and relative kidney and liver weights combined with histopathological changes in the kidneys and liver) were observed in parental animals from all MBT groups. These effects were more prominent in the Fl generation due to a greater intake and longer exposure to the test article. Liver was also the target organ in the subchronic NTP studies in rats and mice (increase in liver weight). Effects were observed at daily doses of ≥ 150 mg/kg bw throughout all subchronic studies.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1 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):
25
Dose descriptor starting point:
NOAEL
Value:
50 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
25.9 mg/m³
Explanation for the modification of the dose descriptor starting point:

For the inhalation route there is no animal study available. Therefore, oral rat data is used to calculate a corresponding air concentration for humans and a route-to-route extrapolation for systemic effects is necessary to derive the correct starting point. In the case of oral-to-inhalation the inclusion of a default factor of 2 is recommended according to chapter R.8.4.2 of ECHA guidance R.8. According to Figure R. 8-3 in ECHA guidance R.8 additional correction is needed for scaling issues: Corrected inhalatory NOAEC = oral NOAEL * 50%/100% * 1/1.15 m³ per kg and day, based on the oral NOAEL of 50 mg/kg bw/day for systemic toxicity obtained in several feeding studies on rats and mice the starting point is calculated with 21.7 mg/m³ for MBT. The precise composition of ZMBT has to be taken into account to derive a corrected inhalatory NOAEC for ZMBT based on the read-across approach with MBT. The MBT mass content in ZMBT is 84%, consequently the corrected inhalatory NOAEC for MBT of 21.7 mg/m³ corresponds to 25.9 mg/m³ for ZMBT (21.7/0.84 = 25.9 mg/m³).

AF for dose response relationship:
1
Justification:
As the starting point for the DNEL calculation is a NOAEL according to chapter R.8.4.3.1 of ECHA guidance R.8 the default assessment factor for dose response relationship is 1.
AF for differences in duration of exposure:
1
Justification:
No difference in the experimental exposure duration (= subchronic) and the duration of exposure for the population and scenario under consideration (= chronic) according to Table R.8-5 of ECHA guidance R.8 is included in this assessment, since several repeated dose toxicity studies with subchronic and chronic exposure are available for MBT that show NOAEL and LOAEL values in the same dose range. This procedure is supported by consistent toxicological findings in subchronic, chronic, and reproduction/developmental toxicity studies.
AF for interspecies differences (allometric scaling):
1
Justification:
Allometric scaling is already included in the route-to-route extrapolation for dose descriptor calculation as described in ECHA guidance R.8.
AF for other interspecies differences:
2.5
Justification:
A factor of 2.5 for remaining interspecies differences is suggested in ECHA guidance R.8.
AF for intraspecies differences:
10
Justification:
According to chapter R.8.4.3.1 of ECHA guidance R.8 the default assessment factor to be applied for intraspecies differences in the general population is 10.
AF for the quality of the whole database:
1
Justification:
Default assessment factor for good/standard quality of database as suggested by ECHA guidance R.8.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
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:
1.2 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):
100
Dose descriptor starting point:
NOAEL
Value:
50 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
119 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

For the dermal route there is no animal study available. Therefore, oral rat data are used to calculate a corresponding dermal exposure dose of ZMBT for humans. The dermal absorption of MBT is low. In topically treated rats percutaneous absorption rates of 16.1 % to 17% were measured, in guinea pigs 38.4% (CMA 1986, 1987). Therefore, a default factor of 2 is considered appropriate for dermal versus oral MBT absorption. Since ZMBT has a much higher molecular weight than MBT, this factor also applied to MBT. The corrected dermal NOAEL for workers = 50 mg/kg bw/day * 2 =  100 mg/kg bw/day for MBT. The precise composition of ZMBT has to be taken into account to derive a corrected dermal NOAEL for ZMBT based on the read-across approach with MBT. The MBT mass content in ZMBT is 84%, consequently the corrected dermal NOAEL for MBT of 100 mg/kg bw/day corresponds to 119 mg/kg bw/day for ZMBT (100/0.84 = 119 mg/kg bw).

AF for dose response relationship:
1
Justification:
As the starting point for the DNEL calculation is a NOAEL according to chapter R.8.4.3.1 of ECHA guidance R.8 the default assessment factor for dose response relationship is 1.
AF for differences in duration of exposure:
1
Justification:
No difference in the experimental exposure duration (= subchronic) and the duration of exposure for the population and scenario under consideration (= chronic) according to Table R.8-5 of ECHA guidance R.8 is included in this assessment, since several repeated dose toxicity studies with subchronic and chronic exposure are available that show NOAEL and LOAEL values in the same dose range. This procedure is supported by consistent toxicological findings in subchronic, chronic, and reproduction/developmental toxicity studies.
AF for interspecies differences (allometric scaling):
4
Justification:
According to Table R.8-3 of ECHA guidance R.8 the allometric scaling factor for the rat when compared with humans is 4.
AF for other interspecies differences:
2.5
Justification:
A factor of 2.5 for remaining interspecies differences is suggested in ECHA guidance R.8.
AF for intraspecies differences:
10
Justification:
According to chapter R.8.4.3.1 of ECHA guidance R.8 the default assessment factor to be applied for intraspecies differences in the general population is 10.
AF for the quality of the whole database:
1
Justification:
Default assessment factor for good/standard quality of database as suggested by ECHA guidance R.8.
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:
sensitisation (skin)
Acute/short term exposure
Hazard assessment conclusion:
medium 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:
0.6 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):
100
Dose descriptor starting point:
NOAEL
Value:
50 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
59.5 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Oral data from the rat are used to decide on a corresponding oral dose for humans. Therefore a route-to-route extrapolation is not necessary and the NOAEL from the rat study is used as starting point. However, the precise composition of ZMBT has to be taken into account to derive an oral NOAEL for ZMBT based on the read-across approach with MBT. The MBT mass content in ZMBT is 84%, consequently the corrected oral NOAEL for MBT of 50 mg/kg bw/day corresponds to 59.5 mg/kg bw/day for ZMBT (50/0.84 = 59.5 mg/kg bw).

AF for dose response relationship:
1
Justification:
As the starting point for the DNEL calculation is a NOAEL according to chapter R.8.4.3.1 of ECHA guidance R.8 the default assessment factor for dose response relationship is 1.
AF for differences in duration of exposure:
1
Justification:
No difference in the experimental exposure duration (= subchronic) and the duration of exposure for the population and scenario under consideration (= chronic) according to Table R.8-5 of ECHA guidance R.8 is included in this assessment, since several repeated dose toxicity studies with subchronic and chronic exposure are available that show NOAEL and LOAEL values in the same dose range. This procedure is supported by consistent toxicological findings in subchronic, chronic, and reproduction/developmental toxicity studies.
AF for interspecies differences (allometric scaling):
4
Justification:
According to Table R.8-3 of ECHA guidance R.8 the allometric scaling factor for the rat when compared with humans is 4.
AF for other interspecies differences:
2.5
Justification:
A factor of 2.5 for remaining interspecies differences is suggested in ECHA guidance R.8
AF for intraspecies differences:
10
Justification:
According to chapter R.8.4.3.1 of ECHA guidance R.8 the default AF to be applied for intraspecies differences in the general population is 10.
AF for the quality of the whole database:
1
Justification:
Default assessment factor for good/standard quality of database as suggested by ECHA guidance R.8.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population

There are only limited data from an early cancer study available for ZMBT repeated dose toxicity that are not suitable as starting point for DNEL calculation. ZMBT is composed of two MBT molecules associated with zinc ion (mass content ZMBT: 84% MBT, 16% Zn2+). It was shown in hydrolysis studies that under acidic conditions (pH 3) a rapid degradation to ZMBT to the MBT and to zinc ions Zn2+ was observed. A read-across with toxicological data for MBT as source is thus considered adequate. For justification of the read-across see separate Read-Across Justification Document attached to the IUCLID.

For MBT there are several repeated dose toxicity studies available. Based on the recommendation of MAK (1999) the most relevant study for the assessment of repeated dose toxicity is the two-generation reproduction toxicity feeding study (CMA 1990) in rats with a LOAEL of 2500 ppm (ca. 150 mg to 250 mg/kg bw/day). Following MAK (1999) an overall NOAEL of 50 mg/kg bw and day is suggested for this study and this NOAEL is taken forward for DNEL derivation. This NOAEL is supported as worst-case consideration by consistent findings in several additional repeated dose toxicity studies with subchronic and chronic oral MBT exposure of rats and mice (NTP 1988) that show NOAELs and/or LOAELs in the same range as in the 2-generation study. The ‘human biomonitoring’ commission of the German Federal Environmental Agency (2015) derived an overall NOAEL of 94 mg/kg bw/day for MBT, taking the subchronic study in mice (NTP 1988) as basis. US EPA determined the NOAEL for parenteral/systeim toxicity with 194 mg/kg bw/day, based on the 2 -generation study of CMA (1990) and derived a Reference Dose (RfD) of 0.65 mg/kg bw/day for long term oral uptake of the general population for MBT (EPA 1994).

In the 2-generation study (CMA 1990) with MBT minimal to mild toxic effects (reduced body weights, increase in absolute and relative kidney and liver weights combined with histopathological changes in the kidneys and liver) were observed in parental animals from all MBT groups. These effects were more prominent in the Fl generation due to a greater intake and longer exposure to the test article. Liver was also the target organ in the subchronic NTP studies in rats and mice (increase in liver weight). Effects were observed at daily doses of ≥ 150 mg/kg bw throughout all subchronic studies.