Reaction products of N-methyldiethanolamine and Boric Acid (1:1.5)

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.544 mg/m³

Most sensitive endpoint:

developmental toxicity / teratogenicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

225

Dose descriptor starting point:

LOAEL

Value:

100 mg/kg bw/day

Modified dose descriptor starting point:

LOAEC

Value:

1 960 mg/m³

Explanation for the modification of the dose descriptor starting point:

No long-term exposure data is available for the inhalation route, therefore, the NOAEL/LOAEL resulted from an animal study after an oral administration of the substance for at least 28 days to rats, is used. Route-to-route extrapolation is therefore needed from the oral to the inhalation route. The most sensitive value was found in the Reproductive/Developmental Screening Test combined with Repeated Dose Toxicity test. The lowest dose administered to treatment animals was 100 mg/kg bw/day, which was subsequently associated with developmental toxicity of offspring. Therefore, the LOAEL value is considered 100 mg/kg bw/day and the NOAEL value is less than 100 mg/kg bw/day, therefore, it is implied that the NOAEL value cannot be extrapolated from this study.

As the LOAEL value was particular to rats, it is necessary to divide the LOAEL value by a factor of 4 to consider inter-species differences; the standard body weight considered for workers is 70 kg, therefore, the LOAEL is multiplied by a factor of 70 kg. A worker is considered to be exposed to 10 m³ for 8 hours per day for 5 days out of 7, therefore, the LOAEL value is multiplied by 10 m³ and a factor of 1.4 to account for weekends. Finally, absorption of a substance by the inhalation route is considered to be 100 % once it reaches the alveolar level, whereas absorption via the oral route is considered generically to be 50 %, therefore, the LOAEL value is multiplied by 0.5 to account for absorption differences.

Based on these considerations, the following formula is applied:

LOAEC_{human, inhalation} = LOAEL_{rat, oral} ÷ 4 × 70 kg ÷ 10 m³ × 1.4 × 0.5 = 122.5 mg/m³

Subsequent assessment factors (AF) are then applied as detailed below. The overall assessment factor was found to be 225.

AF for dose response relationship:

3

Justification:

AF for dose response relationship is considered 3 as the source study does not specify a NOAEL and the LOAEL is extrapolated from the lowest dose tested

AF for differences in duration of exposure:

6

Justification:

AF for differences in duration of exposure is considered 6 as the source study is a sub-acute toxicity study (51-day reproductive/developmental screening combined with repeated dose toxicity; OECD 422)

AF for interspecies differences (allometric scaling):

1

Justification:

Interspecies differences are already considered in the original formula (above), whereby the LOAEL was multiplied by a factor of 4 to allow for differences between rats and humans

AF for other interspecies differences:

2.5

Justification:

Default factor of 2.5 is applied for other interspecies differences (toxicokinetic differences not related to metabolic rate and toxicodynamic differences)

AF for intraspecies differences:

5

Justification:

AF for intraspecies differences is considered 5 to allow for potential differences in the population of workers

AF for the quality of the whole database:

1

Justification:

Good standard of quality of database

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties

Acute/short term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

Most sensitive endpoint:

sensitisation (skin)

Route of original study:

Dermal

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

developmental toxicity / teratogenicity

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

skin irritation/corrosion

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.556 mg/kg bw/day

Most sensitive endpoint:

developmental toxicity / teratogenicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

900

Dose descriptor starting point:

LOAEL

Value:

100 mg/kg bw/day

Modified dose descriptor starting point:

LOAEL

Value:

1 400 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

No long-term exposure data is available for the dermal route, therefore, the NOAEL/LOAEL value used resulted from an animal study whereby the substance was administered orally for at least 28 days to rats. Route-to-route extrapolation is therefore needed from the oral to the dermal route.The most sensitive value was found in the Reproductive/Developmental Screening Test combined with Repeated Dose Toxicity test.

The lowest dose administered to treatment animals was 100 mg/kg bw/day, which was subsequently associated with developmental toxicity of offspring. Therefore, the LOAEL value is considered 100 mg/kg bw/day and the NOAEL value is less than 100 mg/kg bw/day, therefore, it is implied that the NOAEL value cannot be extrapolated from this study.

A worker is considered to be exposed to a substance for 5 days out of 7, therefore, the LOAEL value is multiplied by a factor of 1.4. Although the mean molecular weight of the main structures of the substance are slightly lower than the minimum cut-off value for low skin absorption, polyborate species complexed with N-methyldiethanolamine may be in fact much larger than the 500 g/mol cut-off; therefore, the skin absorption value allocated is 10 % as the octanol-water partition coefficient value satisfies the requirements for 10 % dermal absorption (below -1 or above 4) and the known dermal absorption values of the two main structures of the substance are 0.5 % and 17 to 21 %.

Based on these considerations, the following formula is applied:

LOAEC_{human, dermal} = LOAEL_{rat, oral} × 1.4 / 10 % = 1400 mg/kg

Subsequent assessment factors (AF) are then applied as detailed below. The overall assessment factor was found to be 900.

AF for dose response relationship:

3

Justification:

AF for dose response relationship is considered 3 as the source study does not specify a NOAEL and the LOAEL is extrapolated from the lowest dose tested

AF for differences in duration of exposure:

6

Justification:

AF for differences in duration of exposure is considered 6 as the source study is a sub-acute toxicity study (51-day reproductive/developmental screening combined with repeated dose toxicity; OECD 422)

AF for interspecies differences (allometric scaling):

4

Justification:

An AF value of 4 is provided for interspecies differences between the rat and human

AF for other interspecies differences:

2.5

Justification:

Default factor of 2.5 is applied for other interspecies differences (toxicokinetic differences not related to metabolic rate and toxicodynamic differences)

AF for intraspecies differences:

5

Justification:

AF for intraspecies differences is considered 5 to allow for potential differences in the population of workers

AF for the quality of the whole database:

1

Justification:

Good standard of quality of database

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties

Acute/short term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

Most sensitive endpoint:

sensitisation (skin)

Route of original study:

Dermal

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

developmental toxicity / teratogenicity

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

skin irritation/corrosion

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.083 mg/m³

Most sensitive endpoint:

developmental toxicity / teratogenicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

450

Dose descriptor starting point:

LOAEL

Value:

100 mg/kg bw/day

Modified dose descriptor starting point:

LOAEC

Value:

37.5 mg/m³

Explanation for the modification of the dose descriptor starting point:

No long-term exposure data is available for the inhalation route, therefore, the NOAEL/LOAEL resulted from an animal study after an oral administration of the substance for at least 28 days to rats, is used. Route-to-route extrapolation is therefore needed from the oral to the inhalation route. The most sensitive value was found in the Reproductive/Developmental Screening Test combined with Repeated Dose Toxicity test. The lowest dose administered to treatment animals was 100 mg/kg bw/day, which was subsequently associated with developmental toxicity of offspring. Therefore, the LOAEL value is considered 100 mg/kg bw/day and the NOAEL value is less than 100 mg/kg bw/day, therefore, it is implied that the NOAEL value cannot be extrapolated from this study.

As the LOAEL value was particular to rats, it is necessary to divide the LOAEL value by a factor of 4 to consider inter-species differences; the standard body weight considered for the general population is 60 kg, therefore, the LOAEL is multiplied by a factor of 60 kg. The general population is considered to be exposed to 20 m³ for 24 hours per day, 7 days out of 7, therefore, the LOAEL value is multiplied by 20 m³. Finally, absorption of a substance by the inhalation route is considered to be 100 % once it reaches the alveolar level, whereas absorption via the oral route is considered generically to be 50 %, therefore, the LOAEL value is multiplied by 0.5 to account for absorption differences.

Based on these considerations, the following formula is applied:

LOAEC_{human, inhalation} = LOAEL_{rat, oral} ÷ 4 × 60 kg ÷ 20 m³ × 0.5 = 37.5 mg/m³

Subsequent assessment factors (AF) are then applied as detailed below. The overall assessment factor was found to be 450.

AF for dose response relationship:

3

Justification:

AF for dose response relationship is considered 3 as the source study does not specify a NOAEL and the LOAEL is extrapolated from the lowest dose tested

AF for differences in duration of exposure:

6

Justification:

AF for differences in duration of exposure is considered 6 as the source study is a sub-acute toxicity study (51-day reproductive/developmental screening combined with repeated dose toxicity; OECD 422)

AF for interspecies differences (allometric scaling):

1

Justification:

Interspecies differences are already considered in the original formula (above), whereby the LOAEL was multiplied by a factor of 4 to allow for differences between rats and humans

AF for other interspecies differences:

2.5

Justification:

Default factor of 2.5 is applied for other interspecies differences (toxicokinetic differences not related to metabolic rate and toxicodynamic differences)

AF for intraspecies differences:

10

Justification:

AF for intraspecies differences is considered 10 to allow for potential differences in the general population such as age, health, race

AF for the quality of the whole database:

1

Justification:

Good/standard quality data base

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties

Acute/short term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

Most sensitive endpoint:

sensitisation (skin)

Route of original study:

Dermal

DNEL related information

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

developmental toxicity / teratogenicity

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

skin irritation/corrosion

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.555 mg/kg bw/day

Most sensitive endpoint:

developmental toxicity / teratogenicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

1 800

Dose descriptor starting point:

LOAEL

Value:

100 mg/kg bw/day

Modified dose descriptor starting point:

LOAEL

Value:

1 000 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

No long-term exposure data is available for the dermal route, therefore, the NOAEL/LOAEL value used resulted from an animal study whereby the substance was administered orally for at least 28 days to rats. Route-to-route extrapolation is therefore needed from the oral to the dermal route. The most sensitive value was found in the Reproductive/Developmental Screening Test combined with Repeated Dose Toxicity test.

The lowest dose administered to treatment animals was 100 mg/kg bw/day, which was subsequently associated with developmental toxicity of offspring. Therefore, the LOAEL value is considered 100 mg/kg bw/day and the NOAEL value is less than 100 mg/kg bw/day, therefore, it is implied that the NOAEL value cannot be extrapolated from this study.

The general population is considered to be exposed to a substance 7 days a week (100 %). Although the mean molecular weight of the main structures of the substance are slightly lower than the minimum cut-off value for low skin absorption, polyborate species complexed with N-methyldiethanolamine may be in fact much larger than the 500 g/mol cut-off; therefore, the skin absorption value allocated is 10 % as the octanol-water partition coefficient value satisfies the requirements for 10 % dermal absorption (below -1 or above 4) and the known dermal absorption values of the two main structures of the substance are 0.5 % and 17 to 21 %.

Based on these considerations, the following formula is applied:

LOAEC_{human, dermal}= LOAEL_{rat, oral} / 10 % = 1000 mg/kg

Subsequent assessment factors (AF) are then applied as detailed below. The overall assessment factor was found to be 1800.

AF for dose response relationship:

3

Justification:

AF for dose response relationship is considered 3 as the source study does not specify a NOAEL and the LOAEL is extrapolated from the lowest dose tested

AF for differences in duration of exposure:

6

Justification:

AF for differences in duration of exposure is considered 6 as the source study is a sub-acute toxicity study (51-day reproductive/developmental screening combined with repeated dose toxicity; OECD 422)

AF for interspecies differences (allometric scaling):

4

Justification:

An AF value of 4 is provided for interspecies differences between the rat and human

AF for other interspecies differences:

2.5

Justification:

Default factor of 2.5 is applied for other interspecies differences (toxicokinetic differences not related to metabolic rate and toxicodynamic differences)

AF for intraspecies differences:

10

Justification:

AF for intraspecies differences is considered 10 to allow for potential differences in the general population

AF for the quality of the whole database:

1

Justification:

Good/standard quality of database

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties

Acute/short term exposure

Hazard assessment conclusion:

high hazard (no threshold derived)

Most sensitive endpoint:

sensitisation (skin)

Route of original study:

Oral

DNEL related information

Explanation for the modification of the dose descriptor starting point:

No study for the acute dermal toxicity is available for the substance. The substance is classified in Category 1 for skin sensitisation potential without further subclassification based on the skin sensitising potential observed in two out of three in vitro experimental studies and using a Weight of Evidence approach.

Local effects

Long term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

developmental toxicity / teratogenicity

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

skin irritation/corrosion

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.056 mg/kg bw/day

Most sensitive endpoint:

developmental toxicity / teratogenicity

Route of original study:

Oral

DNEL related information

DNEL derivation method:

ECHA REACH Guidance

Overall assessment factor (AF):

1 800

Dose descriptor starting point:

LOAEL

Value:

100 mg/kg bw/day

Modified dose descriptor starting point:

LOAEL

Value:

100 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

The NOAEL/LOAEL value used resulted from an animal study whereby the substance was administered orally for at least 28 days to rats. The most sensitive value was found in the Reproductive/Developmental Screening Test combined with Repeated Dose Toxicity test. The lowest dose administered to treatment animals was 100 mg/kg bw/day, which was subsequently associated with developmental toxicity of offspring. Therefore, the LOAEL value is considered 100 mg/kg bw/day and the NOAEL value is less than 100 mg/kg bw/day, therefore, it is implied that the NOAEL value cannot be extrapolated from this study.

Subsequent assessment factors (AF) are then applied as detailed below. The overall assessment factor was found to be 1800.

AF for dose response relationship:

3

Justification:

AF for dose response relationship is considered 3 as the source study does not specify a NOAEL and the LOAEL is extrapolated from the lowest dose tested

AF for differences in duration of exposure:

6

Justification:

AF for differences in duration of exposure is considered 6 as the source study is a sub-acute toxicity study (51-day reproductive/developmental screening combined with repeated dose toxicity; OECD 422)

AF for interspecies differences (allometric scaling):

4

Justification:

An AF value of 4 is provided for interspecies differences between the rat and human

AF for other interspecies differences:

2.5

Justification:

Default factor of 2.5 is applied for other interspecies differences (toxicokinetic differences not related to metabolic rate and toxicodynamic differences)

AF for intraspecies differences:

10

Justification:

AF for intraspecies differences is considered 10 to allow for potential differences in the general population

AF for the quality of the whole database:

1

Justification:

Good/standard quality database

AF for remaining uncertainties:

1

Justification:

No remaining uncertainties

Acute/short term exposure

Hazard assessment conclusion:

no hazard identified

Most sensitive endpoint:

acute toxicity

Route of original study:

Oral

DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:

no hazard identified