A mixture of: N,N-diethylpropane-1,3-diamine 6-methyl-2-(4-(2,4,6-triaminopyrimidin-5-ylazo)phenyl)benzothiazole-7-sulfonate; 2,2-iminodiethanol 6-methyl-2-(4-(2,4,6-triaminopyrimidin-5-ylazo)phenyl)benzothiazole-7-sulfonate; 2-methylaminoethanol 6-methyl-2-(4-(2,4,6-triaminopyrimidin-5-ylazo)phenyl)benzothiazole-7-sulfonate

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

11.75 mg/m³

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Overall assessment factor (AF):

30

Modified dose descriptor starting point:

NOAEC

Acute/short term exposure

DNEL related information

Local effects

Acute/short term exposure

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.67 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Overall assessment factor (AF):

300

Modified dose descriptor starting point:

NOAEL

Acute/short term exposure

DNEL related information

Additional information - workers

According to the REACH “Guidance on information requirements and chemical safety assessment”, a leading DN(M)EL needs to be derived for every relevant human population and every relevant route, duration and frequency of exposure, if feasible.  

OVERVIEW OF DATA

Toxicokinetics (absorption, metabolism, distribution and elimination)

Direct Yellow 166 is an orange powder with a density of 1.38 g/cm³at 23 °C, which decomposes before melting. The molecular weight is about 767 g/mol. The vapour pressure is <0.0019 Pa at 25°C (extrapolated), the substance is soluble in water, and the log Pow is 0.19 at 25 °C (pH 9.1). These physico-chemical properties considered together with the available toxicological data provide evidence that no significant dermal absorption of Direct Yellow 166 has to be expected, and that, when systemically bioavailable, e.g., following oral uptake, the substance would most likely be subjected to metabolisation in the liver, and excretion, mainly via feces and urine, and therefore, bioaccumulation seems to be rather improbable (for details, see IUCLID chapter 7.1).

According to the REACH “Guidance on information requirements and chemical safety assessment”, a leading DN(M)EL needs to be derived for every relevant human population and every relevant route, duration and frequency of exposure, if feasible. Nevertheless, for DNEL derivation the default values for absorption as reported in the ECHA guidance document, chapter R8 were considered.

Direct Yellow 166 is an orange powder with a density of 1.38 g/cm³at 23 °C, which decomposes before melting. The molecular weight is about 767 g/mol. The vapour pressure is <0.0019 Pa at 25°C (extrapolated), the substance is soluble in water, and the log Pow is 0.19 at 25 °C (pH 9.1). These physico-chemical properties considered together with the available toxicological data provide evidence that no significant dermal absorption of Direct Yellow 166 has to be expected, and that, when systemically bioavailable, e.g., following oral uptake, the substance would most likely be subjected to metabolisation in the liver, and excretion, mainly via feces and urine, and therefore, bioaccumulation seems to be rather improbable (for details, see IUCLID chapter 7.1).

According to the REACH “Guidance on information requirements and chemical safety assessment”, a leading DN(M)EL needs to be derived for every relevant human population and every relevant route, duration and frequency of exposure, if feasible. Nevertheless, for DNEL derivation the default values for absorption as reported in the ECHA guidance document, chapter R8 were considered.

 

Acute toxicity

Direct Yellow 166 is neither classified for acute oral nor for acute dermal toxicity. With respect to acute inhalation toxicity, no data are available; however, Direct Yellow 166 is an amorphous powder and vapour pressure measured by thermogravimetry revealed that volatiles at temperatures ranging from 25 to 100°C were about 6. Moreover, particle size distribution analysis had revealed that 77% particles were > 10 µm and only 7.2% were < 4 µm. Therefore, the majority of generated particles will not penetrate into the broncho-alveolar tract. Due to these physicochemical characteristics, and taking into account the low acute toxic potential showed by other routes (oral and dermal), no acute risk for the inhalation route is to be expected. Nevertheless, even if the dermal route of exposure is the most relevant one during manufacture, handling and use of the substance, the inhalation route can not be ignored since the professional worker may inhale, e.g., dust generated during cutting of dyed paper. Therefore and in contrast to both the oral and dermal route, DNEL derivation for the acute inhalation is needed. Since no acute inhalation data are available, neither a systemic nor a local DNEL for short-term inhalation exposure can be derived; however, the derived long-term systemic inhalation DNEL is expected to cover both, the short systemic and local DNEL for the inhalation route. Thus, summarizing, no acute systemic DNELs are needed for Direct Yellow 166 for the oral and dermal route of exposure, and for the inhalation, this will be covered by the long-term systemic DNEL.

Irritation

Direct Yellow 166 is neither classified for skin nor for eye irritation. Thus, no DNEL calculation referring to local effects is needed.

Sensitisation

Direct Yellow 166 is classified as sensitising to skin according to the EU Directive 67/548/EEC (Xi, R43) as well as to the CLP Regulation EC/1272/2008 (Cat. 1B). Classification refers to a valid GPMT study, which revealed that the test article is a sensitizer, and thus, a qualitative approach has to be considered since it is not possible to derive a DNEL for skin sensitisation.  

Long-term toxicity

Referring to long-term toxicity, a 28-day oral repeated dose study (RCC 205571), including a 5-day range finder pretest (RCC 205582), is available. In the range finding pretest, Direct Yellow 166 was administered to rats by repeated oral gavage, for a period of 5 days, to provide a basis for dose selection for a 28-day oral toxicity study. The pretest comprised 3 test groups, with 3 animals per sex each, and the dose levels tested were 0, 200 and 1000 mg/kg bw/d. Based on the results of this test, the following dose levels were selected as appropriate for the main 28-day study: 0, 50, 200 and 1000 mg/kg bw/d. The 28-day study was conducted according to the OECD TG 407, and the test item was administered daily by gavage to Wistar rats of both sexes. The rats were assigned to test and recovery groups.

No mortality occurred. All animals of the high dose group showed orange discoloured feces from day 5 to 28 of treatment. The animals of the recovery group showed the same discoloration between day 1 and 3 of recovery period but had recovered from day 4 of recovery. The evaluation of hematological data revealed some treatment-related changes reflecting slight anemia for both sexes of the high dose group at 4 weeks of treatment. At the end of the recovery period the findings were found to be reversible but still slightly below that of the controls. The evaluation of clinical chemical parameters revealed some slightly modified parameters

reflecting of stress induced metabolic adaptation due to treatment in the high dose group at test ending; these changes were fully reversible. A slightly decreased overnight urinary output for males and slight proteinuria for females of the high dose group after 4 weeks of treatment also was seen; the findings were reversible at the end of the recovery period. However, it remains unclear whether these findings were treatment-related. Statistically significant increased absolute and/or relative kidney weights were observed in male and female rats of the mid dose group (females only) and the high dose group 4 after 4 weeks of treatment and also after recovery. In addition the high dose females showed statistically significant increased absolute and/or relative liver weights upon sacrifice at test ending (4 weeks) and after recovery. These findings were indicative of metabolic adaptation and therefore not significant in toxicological terms. All other parameters considered, such as body weight and food consumption were inconspicuous.

Since treatment-related effects were seen in the high dose group treated with 1000 mg/kg bw/d, the LOAEL was set at 1000 mg/kg bw/d. The NOAEL was therefore set at 200 mg/kg bw/d for both, male and female Wistar rats treated orally by gavage with Direct Yellow 166 for 28 days.

 Mutagenicity

Direct Yellow 166 is assessed as being non-mutagenic, based on a series of in vitro and in in vivo tests. Thus, no risk characterisation for mutagenicity is needed.

Carcinogenicity

Carcinogenicity studies have not been conducted.

Reproduction toxicity

A reproduction/developmental toxicity screening test according to OECD TG 421 in compliance with GLP was conducted for assessment of toxicity to reproduction. Direct Yellow 166 was offered to male and female Wistar Han rats by oral gavage at dose levels of 100, 300 and 1000 mg/kg bw/d. Males were exposed for 2 weeks prior to mating, during mating, and up to termination (for 30 days). The females were exposed for 2 weeks prior to mating, during mating, during post-coitum, and at least 4 days of lactation (for 42-55 days). Based on the significantly reduced fertility and conception index, and a gestation index of 0% at the high dose level (1000 mg/kg bw/d), the classification of the substance as R62 (Repr. Cat. 3) according to EU Directive 67/548/EEC and in Repro Cat. 2 according to CLP Regulation EC/1272/2008 is proposed. No reproduction toxicity was observed at 100 and 300 mg/kg bw/d as revealed by mating, fertility and conception indices, precoital time, and numbers of corpora lutea and implantation sites, which all were normal. The parental systemic NOAEL was set at 300 mg/kg bw/d, the reproductive NOAEL also was set at 300 mg/kg bw/d. The NOAEL for developmental toxicity also was set at 300 mg/kg bw/d since at 1000 mg/kg bw/d, no pups had been delivered.

 

DERIVATION OF DNELS:

Taking into account the data mentioned above and the more relevant industrial exposure routes, DNEL derivation for systemic effects is needed for long-term exposure via dermal route and long-term exposure via inhalation. As Direct Yellow 166 is classified as sensitizer, a qualitative approach is to be considered since DNEL derivation for skin sensitisation is not feasible. For both the dermal and inhalation systemic DNEL derivation for worker, The NOAEL of 200 mg/kg bw/d obtained from the 28 day oral repeated dose study was selected, and route-to-route extrapolation was done; the NOAEL was modified accordingly as recommended by the ECHA Guidance Document, Chapter R8 (version 2, 2010). The assessment factors were selected as already described above, according to the ECHA Guidance Document, Chapter R8. For purpose of comparison, dermal and inhalation systemic DNEL derivation for worker also was done using the NOAEL of 300 mg/kg bw/d obtained from the reproduction screening test (OECD 421) since this study had led to a classification proposal.

Long-term, dermal, systemic effects, DNEL calculation based on route to route extrapolation, starting from a 28 day oral repeated dose study
Description		Value	Remark	Reference
Selected dose descriptor		NOAEL = 200 mg/kg bw/d	28-day oral repeated dose study	ECHA Guidance Doc., R8, version 2, 2010
Modification of starting point		Factor of 1 used	Assuming that dermal absorption will not be higher than oral absorption, no default factor was considered for the route to route extrapolation	ECHA Guidance Doc., R8, version 2, 2010
Assessment factors
	Interspecies	4	Allometric scaling factor (rat versus human)	ECHA Guidance Doc., R8, version 2, 2010
		2.5	Additional factor for remaining differences
	Intraspecies	5	Default factor for worker “subpopulation”	ECHA Guidance Doc., R8, version 2, 2010
	Exposure duration	6	Extrapolation factor, from subacute to chronic exposure	ECHA Guidance Doc., R8, version 2, 2010
	Dose response	1	Standard value for calculation based on NOAEL	ECHA Guidance Doc., R8, version 2, 2010
	Database quality	1	Factor different from 1 to be considered if compensation of potential remaining uncertainties in the derived DNEL is justified. In the present case, even though the tonnage driven data requirements for Direct Yellow 166 are not fully met (e.g., no data for sub chronic repeated dose toxicity), an additional assessment factor for quality of database appears unjustified since the substance is classified for skin sensitisation which will result in very strict RMMs. Furthermore, the DNELs based on the sub acute repeated dose toxicity study are already very low (see below) and it is not expected that the results of further studies will lead to even lower DNELs.	ECHA Guidance Doc., R8, version 2, 2010
DNEL calculation		200 / [1 x 4 x 2.5 x 5 x 6 x 1 x 1]
DNEL value		0.67 mg/kg bw/day

Long-term, inhalation, systemic effects, DNEL calculation based on route to route extrapolation, starting from a 28 day oral repeated dose study
Description		Value	Remark	Reference
Selected dose descriptor		NOAEL = 200 mg/kg bw/d	28-day oral repeated dose study	ECHA Guidance Doc., R8, version 2, 2010
Modification of starting point		1	No default factor for route to route extrapolation	ECHA Guidance Doc., R8, version 2, 2010
		0.38 m3/kg bw	An 8 h respiratory volume of 0.38 m3/kg bw for rat was considered and used for conversion of NOAEL in NOAEC	ECHA Guidance Doc., R8, version 2, 2010
		6.7 m3 /10 m3	Correction factor for conversion rat to human and activity driven differences of respiratory volumes in workers compared to worker in rest	ECHA Guidance Doc., R8, version 2, 2010
Modified dose-descriptor		NOAEC = 200 / 0.38 x [6.7 /10] = 352.6 mg/m3
Assessment factors
	Interspecies	1	No allometric scaling factor needed	ECHA Guidance Doc., R8, version 2, 2010
	Intraspecies	5	Default factor for worker “subpopulation”	ECHA Guidance Doc., R8, version 2, 2010
	Exposure duration	6	Extrapolation factor, from subacute to chronic exposure	ECHA Guidance Doc., R8, version 2, 2010
	Dose response	1	Standard value for calculation based on NOAEL	ECHA Guidance Doc., R8, version 2, 2010
	Database quality	1	Factor different from 1 to be considered if compensation of potential remaining uncertainties in the derived DNEL is justified. In the present case, even though the tonnage driven data requirements for Direct Yellow 166 are not fully met (e.g., no data for sub chronic repeated dose toxicity), an additional assessment factor for quality of database appears unjustified since the substance is classified for skin sensitisation which will result in very strict RMMs. Furthermore, the DNELs based on the sub acute repeated dose toxicity study are already very low (see below) and it is not expected that the results of further studies will lead to even lower DNELs.	ECHA Guidance Doc., R8, version 2, 2010
DNEL calculation		176 / [1 x 5 x 6 x 1 x 1]
DNEL value		11.75 mg/m3

Long-term, dermal, systemic effects, DNEL calculation based on route to route extrapolation starting from reproduction toxicity test (oral)
Description		Value	Remark	Reference
Selected dose descriptor		NOAEL = 300 mg/kg bw/d	OECD 421 screening test: Direct Yellow 166 was administered by daily oral gavage to male and female Wistar Han rats at dose levels of 100, 300 and 1000 mg/kg/d. Males were exposed for 2 weeks prior to mating, during mating, and up to termination (for 30 days). The females were exposed for 2 weeks prior to mating, during mating, during gestation, and at least 4 days of lactation (for 42-55 days).	ECHA Guidance Doc., R8, version 2, 2010
Modification of starting point		1	Assuming that dermal absorption will not be higher than oral absorption, no default factor was considered for the route to route extrapolation	ECHA Guidance Doc., R8, version 2, 2010
Assessment factors
	Interspecies	4	Allometric scaling factor (rat versus human)	ECHA Guidance Doc., R8, version 2, 2010
		2.5	Additional factor for remaining differences
	Intraspecies	5	Default factor for worker “subpopulation”	ECHA Guidance Doc., R8, version 2, 2010
	Exposure duration	6	Since exposure duration ranged between 30 and 55 days, the extrapolation factor was considered as for extrapolation from subacute to chronic exposure.	ECHA Guidance Doc., R8, version 2, 2010
	Dose response	1	Standard value for calculation based on NOAEL	ECHA Guidance Doc., R8, version 2, 2010
	Database quality	1	As for DNEL derivation starting from the sub acute repeated dose study, a factor different from 1 is considered unjustified.	ECHA Guidance Doc., R8, version 2, 2010
DNEL calculation		300 / [1 x 4 x 2.5 x 5 x 6 x 1 x 1]
DNEL value		1.00 mg/kg bw/day

Long-term, inhalation, systemic effects, DNEL calculation based on route to route extrapolation starting from reproduction toxicity test (oral)
Description		Value	Remark	Reference
Selected dose descriptor		NOAEL = 300 mg/kg bw/d	OECD 421 screening test.	ECHA Guidance Doc., R8, version 2, 2010
Modification of starting point		1	No default factor for route to route extrapolation	ECHA Guidance Doc., R8, version 2, 2010
		0.38 m3/kg bw	An 8 h respiratory volume of 0.38 m3/kg bw for rat was considered and used for conversion of NOAEL in NOAEC
		6.7 m3 /10 m3	Correction factor for conversion rat to human and activity driven differences of respiratory volumes in workers compared to worker in rest
Modified dose-descriptor		NOAEC = 300 / 0.38 x [6.7 /10] = 529 mg/m3
Assessment factors
	Interspecies	1	No allometric scaling factor needed	ECHA Guidance Doc., R8, version 2, 2010
	Intraspecies	5	Default factor for worker “subpopulation”	ECHA Guidance Doc., R8, version 2, 2010
	Exposure duration	6	Extrapolation factor, from subacute to chronic exposure	ECHA Guidance Doc., R8, version 2, 2010
	Dose response	1	Standard value for calculation based on NOAEL	ECHA Guidance Doc., R8, version 2, 2010
	Database quality	1	As for DNEL derivation starting from the sub acute repeated dose study, a factor different from 1 is considered unjustified.	ECHA Guidance Doc., R8, version 2, 2010
DNEL calculation		529 / [1 x 5 x 6 x 1 x 1]
DNEL value		17.6 mg/m3

CONCLUSION

For both the dermal and inhalation DNEL derivation for worker, the NOAEL of 200 mg/kg bw/d obtained from a subacute oral repeated dose study was found to be the more sensitive value resulting in respective DNELs of 0.67 mg/kg bw/day and 11.75 mg/m3, for the dermal and the inhalation route. These values will be considered for further exposure assessment.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

5.8 mg/m³

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Overall assessment factor (AF):

30

Modified dose descriptor starting point:

NOAEC

Acute/short term exposure

DNEL related information

Local effects

Acute/short term exposure

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.33 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Overall assessment factor (AF):

600

Modified dose descriptor starting point:

NOAEL

Acute/short term exposure

DNEL related information

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.33 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Overall assessment factor (AF):

600

Modified dose descriptor starting point:

NOAEL

Acute/short term exposure

DNEL related information

Additional information - General Population

According to the REACH “Guidance on information requirements and chemical safety assessment”, a leading DN(M)EL needs to be derived for every relevant human population and every relevant route, duration and frequency of exposure, if feasible. Since the substance is intended to be use for colouring paper, the general population will almost come in contact with dyed paper products, and thus, the dermal route of exposure will be the most expected. Nevertheless, DNEL derivation will here be considered for all 3 routes: dermal, inhalation and oral.

OVERVIEW OF DATA

An overview of all relevant available data was already given for the worker discussion (see above).

DERIVATION OF DNELS:

For DNEL derivation, as for the worker, the NOAEL of 200 mg/kg bw/d obtained from the 28 day oral repeated dose study was selected, and route-to-route extrapolation was done where necessary. Thus, the NOAEL was modified accordingly as recommended by the ECHA Guidance Document, Chapter R8 (version 2, 2010) into a corrected dermal NOAEL and a corrected NOAEC for inhalation. The assessment factors were selected as already described above, according to the ECHA Guidance Document, Chapter R8. Since comparison of dermal and inhalation systemic DNEL derivation for worker, starting (1) from the 28 day repeated dose study and (2) from the screening reproduction toxicity study, had shown that the DNELs obtained from the repeated dose NOAEL of 200 mg/kg bw/d were the more sensitive, it was decided to only consider the repeated dose NOAEL of 200 mg/kg bw/d for derivation of systemic DNELs for the general population.

Long-term, dermal, systemic effects, DNEL calculation based on route to route extrapolation, starting from a 28 day oral repeated dose study
Description		Value	Remark	Reference
Selected dose descriptor		NOAEL = 200 mg/kg bw/d	28-day oral repeated dose study	ECHA Guidance Doc., R8, version 2, 2010
Modification of starting point		Factor of 1 used	Assuming that dermal absorption will not be higher than oral absorption, no default factor was considered for the route to route extrapolation	ECHA Guidance Doc., R8, version 2, 2010
Assessment factors
	Interspecies	4	Allometric scaling factor (rat versus human)	ECHA Guidance Doc., R8, version 2, 2010
		2.5	Additional factor for remaining differences
	Intraspecies	10	Default factor for general population	ECHA Guidance Doc., R8, version 2, 2010
	Exposure duration	6	Extrapolation factor, from subacute to chronic exposure	ECHA Guidance Doc., R8, version 2, 2010
	Dose response	1	Standard value for calculation based on NOAEL	ECHA Guidance Doc., R8, version 2, 2010
	Database quality	1	Similar as for the worker, a factor different from 1 is considered unjustified.	ECHA Guidance Doc., R8, version 2, 2010
DNEL calculation		200 / [1 x 4 x 2.5 x 10 x 6 x 1 x 1]
DNEL value		0.33 mg/kg bw/day

Long-term, inhalation, systemic effects, DNEL calculation based on route to route extrapolation, starting from a 28 day oral repeated dose study
Description		Value	Remark	Reference
Selected dose descriptor		NOAEL = 200 mg/kg bw/d	28-day oral repeated dose study	ECHA Guidance Doc., R8, version 2, 2010
Modification of starting point		1	No default factor for route to route extrapolation since 100% absorption is assumed for both routes and species.	ECHA Guidance Doc., R8, version 2, 2010
		1.15 m3/kg bw	A 24 h respiratory volume of 1.15 m3/kg bw for rat was considered and used for conversion of NOAEL in NOAEC	ECHA Guidance Doc., R8, version 2, 2010
Modified dose-descriptor		NOAEC = 200 / 1.15 = 174 mg/m3
Assessment factors
	Interspecies	1	No allometric scaling factor needed	ECHA Guidance Doc., R8, version 2, 2010
	Intraspecies	10	Default factor for general population	ECHA Guidance Doc., R8, version 2, 2010
	Exposure duration	6	Extrapolation factor, from subacute to chronic exposure	ECHA Guidance Doc., R8, version 2, 2010
	Dose response	1	Standard value for calculation based on NOAEL	ECHA Guidance Doc., R8, version 2, 2010
	Database quality	1	Similar as for the worker, a factor different from 1 is considered unjustified.	ECHA Guidance Doc., R8, version 2, 2010
DNEL calculation		174 / [1 x 5 x 6 x 1 x 1]
DNEL value		5.8 mg/m3

Long-term, oral, systemic effects, DNEL calculation starting from a 28 day oral repeated dose study
Description		Value	Remark	Reference
Selected dose descriptor		NOAEL = 200 mg/kg bw/d	28-day oral repeated dose study	ECHA Guidance Doc., R8, version 2, 2010
Modification of starting point		Factor of 1 used	No modification	ECHA Guidance Doc., R8, version 2, 2010
Assessment factors
	Interspecies	4	Allometric scaling factor (rat versus human)	ECHA Guidance Doc., R8, version 2, 2010
		2.5	Additional factor for remaining differences
	Intraspecies	10	Default factor for general population	ECHA Guidance Doc., R8, version 2, 2010
	Exposure duration	6	Extrapolation factor, from subacute to chronic exposure	ECHA Guidance Doc., R8, version 2, 2010
	Dose response	1	Standard value for calculation based on NOAEL	ECHA Guidance Doc., R8, version 2, 2010
	Database quality	1	Similar as for the worker, a factor different from 1 is considered unjustified.	ECHA Guidance Doc., R8, version 2, 2010
DNEL calculation		200 / [1 x 4 x 2.5 x 10 x 6 x 1 x 1]
DNEL value		0.33 mg/kg bw/day

CONCLUSION

Direct Yellow 166 is intended to be use for colouring paper, the general population will almost come in contact with dyed paper products, and thus, the dermal route of exposure will be the most expected.Nevertheless, systemic DNEL derivation was done for all 3 routes, the dermal, the inhalation and the oral one. For the systemic DNEL derivation for the general population, the NOAEL of 200 mg/kg bw/d obtained from a subacute oral repeated dose study was used as dose descriptor and resulted in respective DNELs of 0.33 mg/kg bw/day, 5.8 mg/m3 and 0.33 mg/kg bw/day, for the dermal, the inhalation and the oral route of exposure. These values will be considered for further exposure assessment.