Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
7.1 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):
12.5
Dose descriptor starting point:
NOAEL
Value:
7.1 mg/m³
Modified dose descriptor starting point:
NOAEC
Value:
7.1 mg/m³
Explanation for the modification of the dose descriptor starting point:

Using the standard equation as outlined in ECHA R8 guidance document, corrected Inhalatory NOAEC = oral NOAEL x (1/ sRVrat) x (ABSoral-rat/ ABSinh-rat) x (sRVhuman/ wRV)

Corrected Inhalatory NOAEC = 50 mg/kg (bw)/day x (1/ 0.38m³ /kg/d) x (100 %/ 100 %) x (6.7 m³(8h) / 10 m³(8h))

Corrected Inhalatory NOAEC = 88.16 mg/m³

sRV: standard Respiratory Volume

ABS: Absorption,

wRV: worker Respiratory Volume

sRVrat= 0,38 m³/day

sRVhuman= 6,7 m³/day (8h);

sRVhuman, moderate work= 10 m³/day (8h)

ABSoral-rat= ABSinh-human= 100 %

Note The oral absorption of dilithium tetraborate is expected to be circa 100% in both test animals and humans. Based on the water solubility of dilithium tetraborate a 'worse case' of 100% absorption by the inhalation route is also assumed.

AF for dose response relationship:
1
Justification:
Default value
AF for differences in duration of exposure:
1
Justification:
Combined reproductive/devlopmental/repeated dose toxicity study
AF for interspecies differences (allometric scaling):
1
Justification:
Respiratory interspecies differences are fully covered by the factors used for route to route extrapolation.
AF for other interspecies differences:
2.5
Justification:
1 - the allometric scaling is covered in the formula which is used
AF for intraspecies differences:
5
Justification:
Default value for workers according to ECHA REACH Guidance (R8, 2012).
AF for the quality of the whole database:
1
Justification:
Standard default value according to ECHA REACH Guidance (R8, 2012).
AF for remaining uncertainties:
1
Justification:
Standard default value according to ECHA REACH Guidance (R8, 2012).
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
7.1 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):
12.5
DNEL extrapolated from long term DNEL

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
333 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):
30
Dose descriptor starting point:
NOAEL
Value:
333 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
333 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

An estimate of 0.5% is proposed for dermal absorption, which is a reasonable worse case approach (SCCS, 2010). The DNEL for dermal exposure is therefore adjusted to take this into consideration.

[We would therefore have 50/30 = 1.67/0.5% = 333 mg/kg (bw) as the DNEL (worker, long term,systemic, dermal)]

AF for dose response relationship:
1
Justification:
Default value used
AF for differences in duration of exposure:
1
Justification:
Reproductive/screening developmental toxicity study
AF for other interspecies differences:
5
Justification:
Default worker value (ECHA guidance document) - There is currently insufficient chemical specific data to amend the default assessment factor for interspecies variation and therefore for workers it remains at 5 and for the general population it is 10. (Doursonet al.,1998)
AF for intraspecies differences:
6
Justification:
Based on available data, the pregnant female is the most susceptible of the human population which is associated with the critical effect of dilithium tetraborate. Absorption and distribution within the humans is expected to be similar, with no metabolism predicted.

However, elimination/excretion during pregnancy is likely to be different. This is based on an increase in glomerular filtration rate (GFR) as a known physiological adaptation during pregnancy (Doursonet al.,1998)

Therefore, by use of the mean GFR from healthy humans in late pregnancy minus two standard deviations to take into account the variation for approximately 95% of the human population, a value of 1.8 is derived. This is then put forward as the toxicokinetic part of the intraspecies assessment factor (the default value is 3.2). (EFSA,2013; US EPA, 2004)

The default value of 3.2 for intraspecies variation (toxicodynamics) is used as a default value.
This gives a total of 1.8 x 3.2 for the intraspecies variation = 5.76 (i.e. 6)

AF for the quality of the whole database:
1
Justification:
Standard default value according to ECHA REACH Guidance (R8, 2012).
AF for remaining uncertainties:
1
Justification:
Standard default value according to ECHA REACH Guidance (R8, 2012).
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

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
high hazard (no threshold derived)

Additional information - workers

It is necessary to wear appropriate eye protection and have access to eye wash stations in the areas where dilithium tetraborate is handled/stored.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.74 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):
25
Dose descriptor starting point:
NOAEL
Value:
1.74 mg/m³
Modified dose descriptor starting point:
NOAEC
Value:
1.74 mg/m³
Explanation for the modification of the dose descriptor starting point:

In line with ECHA guidance document (R8, 2008,p58)

Divide the NOAEL (oral dose, rat) by 1.15 m3 /kg bw to obtain the no adverse effect concentration (24 hours, general population), i.e. 50/1.15 = 43.48 mg/m3.

Then apply the appropriate assessment factors = 43.48/ 25 = 1.74 mg/m3

AF for dose response relationship:
1
Justification:
Default value
AF for differences in duration of exposure:
1
Justification:
Combined reproductive/developmental/repeated dose toxicity study
AF for interspecies differences (allometric scaling):
1
Justification:
Respiratory interspecies differences are fully covered by the factors used for route to route extrapolation.
AF for other interspecies differences:
2.5
Justification:
Standard default value according to ECHA REACH Guidance (R8, 2012).
AF for intraspecies differences:
10
Justification:
Standard default value according to ECHA REACH Guidance (R8, 2012).
AF for the quality of the whole database:
1
Justification:
Standard default value according to ECHA REACH Guidance (R8, 2012).
AF for remaining uncertainties:
1
Justification:
Standard default value according to ECHA REACH Guidance (R8, 2012).
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.74 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):
25
DNEL extrapolated from long term DNEL
Value:
1.74 mg/m³
Modified dose descriptor starting point:
other: NOAEL
Value:
1.74 mg/m³

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
166 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):
60
Dose descriptor starting point:
NOAEL
Value:
166 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
166 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

An estimate of 0.5% is proposed for dermal absorption, which is a reasonable worse case approach (SCCS, 2010). The DNEL for dermal exposure is therefore adjusted to take this into consideration.

Therfore, DNEL (Systemic, long term, dermal, general population) = 50/60 = 0.83/0.5% = 166 mg/kg (bw)

AF for dose response relationship:
1
Justification:
Default value
AF for differences in duration of exposure:
1
Justification:
Combined reproductive/developmental toxicity/repeated dose screening study
AF for other interspecies differences:
10
Justification:
Default value (ECHA guidance document) - There is currently insufficient chemical specific data to amend the default assessment factor for interspecies variation and therefore for the general population it is 10. (Doursonet al.,1998)
AF for intraspecies differences:
6
Justification:
Based on available data, the pregnant female is the most susceptible of the human population which is associated with the critical effect of dilithium tetraborate. Absorption and distribution within the humans is expected to be similar, with no metabolism predicted.However, elimination/excretion during pregnancy is likely to be different. This is based on an increase in glomerular filtration rate (GFR) as a known physiological adaptation during pregnancy (Doursonet al.,1998)

Therefore, by use of the mean GFR from healthy humans in late pregnancy minus two standard deviations to take into account the variation for approximately 95% of the human population, a value of 1.8 is derived. This is then put forward as the toxicokinetic part of the intraspecies assessment factor (the default value is 3.2). (EFSA,2013; US EPA, 2004)

The default value of 3.2 for intraspecies variation (toxicodynamics) is used as a default value.
This gives a total of 1.8 x 3.2 for the intraspecies variation = 5.76 (i.e. 6)
AF for the quality of the whole database:
1
Justification:
Standard default value according to ECHA REACH Guidance (R8, 2012).
AF for remaining uncertainties:
1
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information
DNEL extrapolated from long term DNEL

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.83 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):
60
Dose descriptor starting point:
NOAEL
Value:
0.83 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
0.83 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

The study upon which the DNEL is based was a repeated dose oral study (OECD TG422)

AF for dose response relationship:
1
Justification:
Standard default value according to ECHA REACH Guidance (R8, 2012).
AF for differences in duration of exposure:
1
Justification:
Standard default value according to ECHA REACH Guidance (R8, 2012).
AF for other interspecies differences:
10
Justification:
There is currently insufficient chemical specific data to amend the default assessment factor for interspecies variation and therefore for workers it remains at 5 and for the general population it is 10. (Doursonet al.,1998)
AF for intraspecies differences:
6
Justification:
Based on available data, the pregnant female is the most susceptible of the human population which is associated with the critical effect of dilithium tetraborate. Absorption and distribution within the humans is expected to be similar, with no metabolism predicted.

However, elimination/excretion during pregnancy is likely to be different. This is based on an increase in glomerular filtration rate (GFR) as a known physiological adaptation during pregnancy (Doursonet al.,1998)

Therefore, by use of the mean GFR from healthy humans in late pregnancy minus two standard deviations to take into account the variation for approximately 95% of the human population, a value of 1.8 is derived. This is then put forward as the toxicokinetic part of the intraspecies assessment factor (the default value is 3.2). (EFSA,2013; US EPA, 2004)
AF for the quality of the whole database:
1
Justification:
Standard default value according to ECHA REACH Guidance (R8, 2012).
AF for remaining uncertainties:
1
Justification:
Standard default value according to ECHA REACH Guidance (R8, 2012).
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.83 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):
60
DNEL extrapolated from long term DNEL
Explanation for the modification of the dose descriptor starting point:

It is assumed that the long term DNEL (consumer, oral, long term) will protect against any potential short term acute oral exposures.

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
high hazard (no threshold derived)

Additional information - General Population

Appropriate labelling to highlight the need to avoid eye contact