Registration Dossier

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Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.

The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.

Diss Factsheets

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
14 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
Modified dose descriptor starting point:
NOAEC
Value:
176 mg/m³
AF for dose response relationship:
1
AF for differences in duration of exposure:
1
Justification:
The NOAEL and LOAEL of the subacute, subchronic and combined repeated dose and reproduction/developmental screening study (TG 422) showed similarities in dose range and effects, because of this a factor of 1 for risk assessment is suggested.
AF for interspecies differences (allometric scaling):
1
Justification:
Default value (ECHA) for worker
AF for other interspecies differences:
5
Justification:
Default value (ECHA) for worker
AF for intraspecies differences:
2.5
Justification:
Default value (ECHA) for worker
AF for the quality of the whole database:
1
Justification:
Equivalent or similar to guideline study
AF for remaining uncertainties:
1
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
14 mg/m³
Most sensitive endpoint:
acute toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: To cover possible irritating effects on the respiratory tract it was concluded that the DNEL inhalation (long-term exposure systemic: 14 mg/m3) covers the DNEL acute/short-term systemic effects.
DNEL extrapolated from long term DNEL

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
14 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information
DNEL derivation method:
other: No relevant local effects on the respiratory tract were observed up to 84 mg/m3. Thus, the DNEL inhalation (long-term exposure systemic: 14 mg/m3) covers the DNEL local effects.
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
14 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information
DNEL derivation method:
other: No relevant local effects on the respiratory tract were observed up to 84 mg/m3. Thus, the DNEL inhalation (long-term exposure systemic: 14 mg/m3) covers the DNEL local effects.

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
67 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Dermal
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
30
Modified dose descriptor starting point:
NOAEL
Value:
2 000 mg/kg bw/day
AF for dose response relationship:
1
AF for differences in duration of exposure:
1
Justification:
No specific systemic effects noted for the dermal route, thus a factor of 1 as recommended for the oral route is suggested (the NOAEL and LOAEL of the subacute, subchronic and combined repeated dose and reproduction/developmental screening study (TG 422) showed similarities in dose range and effects, because of this a factor of 1 for risk assessment is suggested).
AF for interspecies differences (allometric scaling):
2.4
Justification:
Default value (ECHA) for worker
AF for other interspecies differences:
2.5
Justification:
Default value (ECHA) for worker
AF for intraspecies differences:
5
Justification:
Default value (ECHA) for worker
AF for the quality of the whole database:
1
Justification:
Equivalent or similar to guideline study
AF for remaining uncertainties:
1
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
534 mg/kg bw/day
Most sensitive endpoint:
acute toxicity
Route of original study:
Dermal
DNEL related information
DNEL derivation method:
other: Due to the very low oral and dermal acute toxicity of TBBS 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 TRGS 900 and equivalent to REACH guidance document).
DNEL extrapolated from long term DNEL

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

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

The test substance TBBS (60% in pet.) caused skin sensitization in a well conducted human Repeated Insult Patch Test study which clearly demonstrated contact sensitization in humans (Monsanto Co. 1983). Based on the findings of the Repeated Insult Patch Test with human volunteers (Monsanto Co 1983) and the data from the guinea pig assays (Monsanto Co. 1982) a moderate skin sensitizing potential of TBBS is suggested according to the categorization criteria published in REACH guidance document chapter R. 8.

The test substance is not skin and eye irritating.

In the limited inhalation study (Monsanto Co. 1981) exposed rats exhibited occasional nasal irritation which appeared to be concentration related in term of severity and number of animals exhibiting the sign (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 few TBBS-exposed animals was not considered to be toxicologically adverse. No relevant local effects on the respiratory tract were observed up to 84 mg/m3. Thus, the DNEL inhalation (long-term exposure systemic: 14 mg/m3) covers the DNEL local effects.

Acute/short-term exposure systemic effects:

The acute toxicity of the test substance TBBS 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 TBBS 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: 2 mg/kg bw/day x 8 = 16 mg/kg bw/day

DNEL short-term systemic dermal: 66.7 mg/kg bw/day x 8 = 534 mg/kg bw/day

To cover possible irritating effects on the respiratory tract it was concluded that the DNEL inhalation (long-term exposure systemic: 14 mg/m3) covers the DNEL acute/short-term systemic effects.

DNEL long-term exposure systemic

Worker DNEL long-term systemic for oral route

The NOAEL of 100 mg/kg bw and day is taken for the risk assessment which based on the findings from the subchronic gavage toxicity study (Monsanto Co 1985).

Startpoint: NOAEL 100 mg/kg bw and day

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

=> Corrected NOAEL 100 mg/kg bw/day

Interspecies differences: Allometric scaling: 4

Remaining interspecies differences: 2.5

Intraspecies differences: 5

Differences in duration of exposure (subchronic 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: 2 mg/kg bw/day

*The NOAEL and LOAEL of the subacute, subchronic and combined repeated dose and reproduction/developmental screening study (TG 422) showed similarities in dose range and effects, because of this a factor of 1 for risk assessment is suggested.

Worker DNEL long-term sytemic for dermal route

The NOAEL of 2000 mg/kg bw and day is taken for the risk assessment which based on the findings from the 21-day dermal toxicity study (Monsanto Co 1981).

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 a factor of 1 as recommended for the oral route is suggested (the NOAEL and LOAEL of the subacute, subchronic and combined repeated dose and reproduction/developmental screening study (TG 422) showed similarities in dose range and effects, because of this a factor of 1 for risk assessment is suggested).

Worker DNEL long-term systemic for inhalation route-systemic

The NOAEL of 100 mg/kg bw and day is taken for the risk assessment which based on the findings from the subchronic gavage toxicity study (Monsanto Co 1985).

Startpoint: NOAEL 100 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 176 mg/m3

Interspecies differences: Allometric scaling: 1

Remaining interspecies differences: 2.5

Intraspecies differences: 5

Differences in duration of exposure (subchronic 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: 14 mg/m3

* Limited inhalation study available (Monsanto 1981)

**The NOAEL and LOAEL of the subacute, subchronic and combined repeated dose and reproduction/developmental screening study (TG 422) showed similarities in dose range and effects, because of this a factor of 1 for risk assessment is suggested.

DNEL fertility:

The effects of the test substance TBBS on fertility was evaluated in a combined repeat dose and reproductive/developmental toxicity screening study (MHWJ 1997). Maternal toxicity was revealed by slight histopathological changes in the kidney and in the liver at 200 mg/kg bw and higher, and a decrease of food consumption and body weight gain in treated females at 1000 mg/kg bw day. The changes noted in kidney and liver are slight in severity and the incidences were only slightly elevated compared to control. Based on this finding, a LOAEL for maternal toxicity of 200 mg/kg bw and day was suggested. The authors of this study suggested a NOAEL maternal of 40 mg/kg bw and day, whereas the 90-day gavage study revealed a NOAEL of 100 mg/kg bw and day. Thus, the value used for DNEL calculation was above the NOAEL maternal of this study but below the LOAEL. Because of the rather weak changes in liver and kidney seen in this study at 200 mg/kg bw and day (LOAEL) it was concluded that the systemic DNEL, derived from the 90 day study (start point NOAEL 100 mg/kg bw and day) also covers the DNEL maternal toxicity.

The decrease in the fertility index noted in this study at 40 and 1000 mg/ kg bw and day (TG 422) was not dose-dependent and was not supported by other fertility parameter. The biological relevance of this decrease is questionable. A NOAEL fertility of 1000 mg/kg bw and day was suggested and thus the DNEL long-term exposure systemic covered the DNEL fertility toxicity.

DNEL developmental toxicity:

The developmental toxicity of the test substance TBBS was evaluated in a TG 414 (Monsanto Co. 1981). No biologically relevant adverse effects were noted in dams treated up to the highest concentration evaluated (500 mg/kg bw and day). There were no biologically relevant differences in appearance or behaviour, maternal or foetal body weight, mean number of viable foetuses or post-implantation losses in any of the treatment groups compared to the control group. In addition, there were no biologically relevant differences in the total numbers of foetuses with malformation in any of the treated groups. Based on these findings a NOAEL maternal/foetal of 500 mg/kg bw and day was suggested. Both NOAELs are clearly above the NOAEL systemic (100 mg/kg bw/and day) and thus it was concluded that the DNEL long-term exposure systemic covered the DNEL developmental toxicity.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
3.5 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
Modified dose descriptor starting point:
NOAEC
Value:
87 mg/m³
AF for dose response relationship:
1
AF for differences in duration of exposure:
1
Justification:
The NOAEL and LOAEL of the subacute, subchronic and combined repeated dose and reproduction/developmental screening study (TG 422) showed similarities in dose range and effects, because of this a factor of 1 for risk assessment is suggested.
AF for interspecies differences (allometric scaling):
1
Justification:
Default value (ECHA) for general population
AF for other interspecies differences:
2.5
Justification:
Default value (ECHA) for general population
AF for intraspecies differences:
10
Justification:
Default value (ECHA) for general population
AF for the quality of the whole database:
1
Justification:
Equivalent or similar to guideline study
AF for remaining uncertainties:
1
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
3.5 mg/m³
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: To cover possible irritating effects on the respiratory tract it was concluded that the DNEL inhalation (long-term exposure systemic: 3.5 mg/m3) covers the DNEL acute/short-term systemic effects.
DNEL extrapolated from long term DNEL

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
3.5 mg/m³
DNEL related information
DNEL derivation method:
other: No relevant local effects on the respiratory tract were observed up to 84 mg/m3. Thus, the DNEL inhalation (long-term exposure systemic: 3.5 mg/m3) covers the DNEL local effects.
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
3.5 mg/m³
DNEL related information
DNEL derivation method:
other: No relevant local effects on the respiratory tract were observed up to 84 mg/m3. Thus, the DNEL inhalation (long-term exposure systemic: 3.5 mg/m3) covers the DNEL local effects.

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
Route of original study:
Dermal
DNEL related information
DNEL derivation method:
other: No relevant local effects on the respiratory tract were observed up to 84 mg/m³. Thus, the DNEL inhalation (long-term exposure systemic: 3.5 mg/m³) covers the DNEL local effects.
Overall assessment factor (AF):
60
Modified dose descriptor starting point:
NOAEL
Value:
2 000 mg/kg bw/day
AF for dose response relationship:
1
AF for differences in duration of exposure:
1
Justification:
No specific systemic effects noted for the dermal route, thus a factor of 1 as recommended for the oral route is suggested (the NOAEL and LOAEL of the subacute, subchronic and combined repeated dose and reproduction/developmental screening study (TG 422) showed similarities in dose range and effects, because of this a factor of 1 for risk assessment is suggested).
AF for interspecies differences (allometric scaling):
2.4
Justification:
Default value (ECHA) for general population
AF for other interspecies differences:
2.5
Justification:
Default value (ECHA) for general population
AF for intraspecies differences:
10
Justification:
Default value (ECHA) for general population
AF for the quality of the whole database:
1
AF for remaining uncertainties:
1
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
266 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Dermal
DNEL related information
DNEL derivation method:
other: Due to the very low oral and dermal acute toxicity of TBBS 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 TRGS 900 and equivalent to REACH guidance document).
DNEL extrapolated from long term DNEL

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:
1 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
Modified dose descriptor starting point:
NOAEL
Value:
100 mg/kg bw/day
AF for dose response relationship:
1
AF for differences in duration of exposure:
1
Justification:
The NOAEL and LOAEL of the subacute, subchronic and combined repeated dose and reproduction/developmental screening study (TG 422) showed similarities in dose range and effects, because of this a factor of 1 for risk assessment is suggested.
AF for interspecies differences (allometric scaling):
4
Justification:
Default value (ECHA) for general population
AF for other interspecies differences:
2.5
Justification:
Default value (ECHA) for general population
AF for intraspecies differences:
10
Justification:
Default value (ECHA) for general population
AF for the quality of the whole database:
1
Justification:
Equivalent or similar to guideline study
AF for remaining uncertainties:
1
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
8 mg/kg bw/day
Most sensitive endpoint:
acute toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: Due to the very low oral and dermal acute toxicity of TBBS 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 extrapolated from long term DNEL

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 TBBS (60% in pet.) caused skin sensitization in a well conducted human Repeated Insult Patch Test study which clearly demonstrated contact sensitization in humans (Monsanto Co. 1983). Based on the findings of the Repeated Insult Patch Test with human volunteers (Monsanto Co 1983) and the data from the guinea pig assays (Monsanto Co. 1982) a moderate skin sensitizing potential of TBBS is suggested according to the categorization criteria published in REACH guidance document chapter R. 8.

The test substance is not skin and eye irritating.

In the limited inhalation study (Monsanto Co. 1981) exposed rats exhibited occasional nasal irritation which appeared to be concentration related in term of severity and number of animals exhibiting the sign (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 few TBBS-exposed animals was not considered to be toxicologically adverse. No relevant local effects on the respiratory tract were observed up to 84 mg/m3. Thus, the DNEL inhalation (long-term exposure systemic: 3.5 mg/m3) covers the DNEL local effects.

Acute/short-term exposure systemic effects

The acute toxicity of the test substance TBBS 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 TBBS 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 mg/kg bw/day x 8 = 8 mg/kg bw/day

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

To cover possible irritating effects on the respiratory tract it was concluded that the DNEL inhalation (long-term exposure systemic: 3.5 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 NOAEL of 100 mg/kg bw and day is taken for the risk assessment which based on the findings from the subchronic gavage toxicity study (Monsanto Co 1985).

Startpoint: NOAEL 100 mg/kg bw and day

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

=> Corrected NOAEL 100 mg/kg bw/day

Interspecies differences: Allometric scaling: 4

Remaining interspecies differences: 2.5

Intraspecies differences: 10

Differences in duration of exposure (subchronic 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: 1 mg/kg bw/day

*The NOAEL and LOAEL of the subacute, subchronic and combined repeated dose and reproduction/developmental screening study (TG 422) showed similarities in dose range and effects, because of this a factor of 1 for risk assessment is suggested.

General Public long-term sytemic for dermal route

The NOAEL of 2000 mg/kg bw and day is taken for the risk assessment which based on the findings from the 21-day dermal toxicity study (Monsanto Co 1981).

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 a factor of 1 as recommended for the oral route is suggested (the NOAEL and LOAEL of the subacute, subchronic and combined repeated dose and reproduction/developmental screening study (TG 422) showed similarities in dose range and effects, because of this a factor of 1 for risk assessment is suggested).

General public long-term systemic for inhalation route

The NOAEL of 100 mg/kg bw and day is taken for the risk assessment which based on the findings from the subchronic gavage toxicity study (Monsanto Co 1985).

Startpoint: NOAEL 100 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: 87 mg/m3

Interspecies differences: Allometric scaling: 1

Remaining interspecies differences: 2.5

Intraspecies differences: 10

Differences in duration of exposure (subchronic 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: 3.5 mg/m3

* Limited inhalation study available (Monsanto 1981)

**The NOAEL and LOAEL of the subacute, subchronic and combined repeated dose and reproduction/developmental screening study (TG 422) showed similarities in dose range and effects, because of this a factor of 1 for risk assessment is suggested.

DNEL fertility:

The effects of the test substance TBBS on fertility was evaluated in a combined repeat dose and reproductive/developmental toxicity screening study (MHWJ 1997). Maternal toxicity was revealed by slight histopathological changes in the kidney and in the liver at 200 mg/kg bw and higher, and a decrease of food consumption and body weight gain in treated females at 1000 mg/kg bw day. The changes noted in kidney and liver are slight in severity and the incidences were only slightly elevated compared to control. Based on this finding, a LOAEL for maternal toxicity of 200 mg/kg bw and day was suggested. The authors of this study suggested a NOAEL maternal of 40 mg/kg bw and day, whereas the 90-day gavage study (Monsanto 1985) revealed a NOAEL of 100 mg/kg bw and day. Thus, the value used for DNEL calculation was above the NOAEL maternal of this study but below the LOAEL. Because of the rather weak changes in liver and kidney seen in this study at 200 mg/kg bw and day (LOAEL) it was concluded that the systemic DNEL, derived from the 90 day study (start point NOAEL 100 mg/kg bw and day) also covers the DNEL maternal toxicity.

The decrease in the fertility index noted in this study at 40 and 1000 mg/ kg bw and day (TG 422) was not dose-dependent and was not supported by other fertility parameter. The biological relevance of this decrease is questionable. A NOAEL fertility of 1000 mg/kg bw and day was suggested and thus the DNEL long-term exposure systemic covered the DNEL fertility toxicity.

DNEL developmental toxicity:

The developmental toxicity of the test substance TBBS was evaluated in a TG 414 (Monsanto Co. 1981). No biologically relevant adverse effects were noted in dams treated up to the highest concentration evaluated (500 mg/kg bw and day). There were no biologically relevant differences in appearance or behaviour, maternal or foetal body weight, mean number of viable foetuses or post-implantation losses in any of the treatment groups compared to the control group. In addition, there were no biologically relevant differences in the total numbers of foetuses with malformation in any of the treated groups. Based on these findings a NOAEL maternal/foetal of 500 mg/kg bw and day was suggested. Both NOAELs are clearly above the NOAEL systemic (100 mg/kg bw/and day) and thus it was concluded that the DNEL long-term exposure systemic covered the DNEL developmental toxicity.