2,4-di-tert-butylphenol

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

44.1 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):

6

Modified dose descriptor starting point:

NOAEC

Value:

264.5 mg/m³

Explanation for the modification of the dose descriptor starting point:

A repeat dose inhalation toxicity study with 2,4 -di-tert-butyl phenol (2,4 -DTBP) is not required due to the physical nature of the substance and its usage and the toxicological information available via the oral route of administration.

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:

6.25 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):

24

Modified dose descriptor starting point:

NOAEL

Value:

150 mg/kg bw/day

Explanation for the modification of the dose descriptor starting point:

A repeat dose dermal toxicity study with 2,4-di-tert-butyl phenol (2,4-DTBP) is not required due to the chemical properties of the substance and its usage and the toxicological information available via the oral route of administration.

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:

no hazard identified

Additional information - workers

Repeated Dose Studies on 2,4-Di-tert-butylphenol (2,4-DTBP)

Results from a 28 day repeated dose study on 2,4-DTBP are available in the published literature. Hirata-Koizumi, M. et al., published a study `Elevated susceptibility of newborn as compared with young rats to 2-tert-butylphenol and 2,4-di-tert-butylphenol toxicity’ (Congenital Anomalies, 2005,45, 146-153), in which newborn male and female rats were orally dosed with 2,4 DTBP and the findings compared to a 28 day repeat dose study in young rats available in the Toxicity Testing Reports of Environmental Chemicals of the Japanese Government database. Whilst the results of the newborn rat study confirmed the increased susceptibility of newborn animals to xenobiotic agents they are not of use in providing information to define the DNEL for 2,4-DTBP. However, the 28-day repeat dose toxicity study was conducted in compliance with the test guideline in the Japanese Chemical Control Act and although a full study report is not available the summary report has sufficient information to identify target organs and a NOAEL.

2,4-DTBP was administered orally to rats for 28 days at 0, 5, 20, 75 and 300 mg/kg/day. At the end of the treatment period a group of animals dosed at 300 mg/kg/day were allowed 14 day treatment free period prior to sacrifice. In this study the principal findings related to treatment with 2,4-DTBP were hepatic and renal changes at 300 mg/kg/day. The hepatic change related to centrilobular hypertrophy of hepatocytes which resulted in heavier livers in males and females treated at 300 mg/kg/day. A slight increase in liver weight was also present in females treated at 75 mg/kg/day; however this was not accompanied by centrilobular hypertrophy. No changes were noted in liver enzymes, therefore, the increased liver weights and centrilobular hypertrophy may be attributed to an increased work load. As this is a common phenomenon in rats, in order to metabolise a xenobiotic agent, these findings were considered not to be a change of toxicological significance. Findings in the kidney in animals treated at 300 mg/kg/day included tubular basophilia and an increased incidence of proteinaceous and granular casts (graded as slight). Urinary volume accompanied by decreased osmolality and specific gravity, and pale colour was also reported in these animals. Other changes reported in the study were increased cholesterol and phospholipid in females treated at 300 mg/kg/day and to a lesser extent in females treated at 75 mg/kg/day. Whilst these changes were numerically statistically significantly increased they were not of clinical significance and may be secondary to changes in the liver. At the end of the recovery period cholesterol and phospholipid remained increased but there was a reduction in the magnitude or incidence of findings in the liver and kidney which indicated the potential for recovery in 300 mg/kg/day treated animals, however no tables of summarized data for the recovery animals are presented in the report to verify and quantify these statements. It was concluded from this study that 75 mg/kg/day can be considered to be the no observed adverse dose level (NOAEL) for 2,4-DTBP following 28 days treatment.

In addition to the 28 day study, a combined 1-Generation Reproduction Toxicity Study / Repeated Dose Toxicity Study was conducted in rats using 2,4-DTBP. This study was carried out to investigate the oral toxicity of 2,4-DTBP to prenatal animals prior and through mating, gestation and lactation. F1 progeny was maintained on the experimental diet containing DTBP for 13 weeks after weaning. Recovery was investigated in a number of F1 animals throughout an additional subsequent 4 week treatment-free period.

Three groups of parental generation rats each comprising 15 males and 15 females were fed diets containing DTBP at concentrations which provided an approximately constant intake of 50, 150 or 300 mg/kg bw/day for 4 weeks before mating and throughout mating, gestation and lactation. Groups of 20 F1 generation progeny of each sex were maintained on the experimental diets for 13 weeks after weaning. Similar groups of animals fed untreated powdered diet for similar periods acted as control group. Five male and 5 female F1 generation progeny from each of the groups were maintained untreated after the 13 week feeding phase, to investigate the nature of any treatment-related changes observed.

One male animal of the parental generation at dose level 300 mg/kg/day was killed and necropsied on day 39, following a generalised deterioration in condition. A cause of clinical deterioration could not be deduced from the findings at necropsy. A pregnant animal at dose level 50 mg/kg/day died after a prolonged gestation period, and at necropsy was noted to have a fetus presented for birth in the breech position. All other parental generation animals survived the scheduled treatment period, and showed no overt signs of toxicity attributable to the ingestion of 2,4-DTBP.

Parental generation animals treated with 2,4-DTBP at 150 mg/kg/day showed retarded body weight gain during the pre-mating period, and those treated at 300 mg/kg/day showed body weight losses during the first 2 weeks of the study. Animals treated at 50 mg/kg/day showed a growth rate similar to that of the controls, as did all 2,4-DTBP -treated pregnant females during gestation and lactation. The food consumption of parental generation animals treated at 150 or 300 mg/kg/day was reduced during the pre-mating period and water consumption was markedly increased. In conjunction with the reduced weight gain, these data are suggestive of a reduction in the palatability of the diets. The food and water consumption of animals treated at 50 mg/kg/day were similar to those of the controls.

Reproductive capability of the parental generation animals was unimpaired by the ingestion of 2,4-DTBP at dose levels of up to 300 mg/kg/day. However, the data suggested that ingestion of 300 mg 2,4-DTBP/kg bw/day elicited a reduction in the mean number of progeny born and reduced the growth rate of the F1 progeny during lactation. The former effect was not apparent at dose levels of 50 and 150 mg/kg/day. Although reduced growth rate was also apparent in the progeny of animals treated at 150 mg/kg/day, it was associated with a higher average number of pups per litter. Post-mortem examination of the parental generation animals and the surplus F1 progeny did not reveal any gross lesions attributable to the ingestion of 2,4-DTBP at any of the dose levels employed. There were no deaths in any of the experimental groups during the F1 generation feeding phase. Daily observations of these animals did not reveal any overt signs of toxicity attributable to the ingestion of 2,4-DTBP.

From the onset of treatment of the F1 generation animals selected for further study, there was a dose-dependent reduction in the food consumption and body weight gain at all dose levels of 2,4-DTBP employed. The effect in the females was less marked than in the males. At dose levels of 50 and 150 mg/kg/day the severity of the effect on food consumption was of a similar magnitude to that of the effect on body weight, and probably indicated reduced diet palatability. However, at the highest dose level employed (300 mg/kg/day) the retardation of body weight gain was disproportionally high in relation to the effect on food consumption. Therefore, a primary toxic effect on growth rate may have been produced by the ingestion of 2,4-DTBP at 300 mg/kg/day. The water consumption of 2,4-DTBP -treated groups of animals was generally lower than that of the controls during the 13 week F1 generation feeding phase. No ocular defects were observed in the F1 generation animals treated with 2,4-DTBP at 300 mg/kg/d which could be related to the ingestion of the test article.

At the start of the F1 generation treatment period, animals treated with 300 mg/kg 2,4-DTBP showed reduced haemoglobin, packed cell volume, mean cell volume and white blood cell counts. These effects were considered to reflect the degree of growth retardation observed during the lactation period. Investigation of the blood chemistry and urine constituents in animals treated at 300 mg/kg/day did not reveal any consistent evidence of an effect of 2,4-DTBP ingestion. The relative liver weight of male and female animals at 300 mg/kg/day was significantly higher than that of the controls. A similar but less marked effect was also apparent in female animals treated at 150 mg/kg/day. After 4 weeks without 2,4-DTBP ingestion, relative liver weights had returned to normal values in animals treated at 300 mg/kg/day. These observations are indicative of a physiological (adaptive) response to the ingestion of 2,4-DTBP. The relative weight of the kidney of males treated at 150 and 300 mg/kg/day, and the relative spleen weight of males treated at 300 mg/kg/day were high in relation to those of the controls. The biological significance of these observations is questionable in the absence of microscopic changes in the architecture of these organs.

Post-mortem examination of the parental generation animals treated with 2,4-DTBP at dose levels of up to 300 mg/kg/day did not reveal any treatment related gross lesions. Post-mortem and microscopic examination of the tissues and organs of F1 generation animals treated with 2,4-DTBP at 300 mg/kg/day for 13 weeks did not reveal any gross or microscopic lesions which could be attributed to the ingestion of 2,4-DTBP.Dietary administration of 2,4-DTBP at a dose level of 300 mg/kg daily for 13 weeks to the F1 generation rats probably elicited a primary toxic effect on growth rate, and at dose level of 150 mg/kg/day, elicited growth retardation which was secondary to reduced diet palatability.

With the exception of adaptive, hepatic changes and palatability effects, the "no adverse effect" level established in this study was 150 mg 2,4-DTBP/kg/day. This value will be used to determine the inhalation and dermal DNEL for the human health risk assessment.

The NOAEL determined from the combined 1 generation repeated dose study is supported from data on the read across substance 2,6-di-tert-butylphenol. 2,4-DTBP is structurally similar to 2,6-di-tert-butylphenol (2,6-DTBP) and has a log Kow close in value to 2,6-DTBP with slightly higher water solubility. Both compounds are not classified for acute toxicity or mutagenicity, but have been shown to be irritating to the skin (R38). Whilst 2,6-DTBP is not classified with respect to the eye, 2,4-DTBP is irritant to the eye and is classified as R41.

2,6- DTBP		2,4 DTBP
Log Kow 4.5	Log Kow 4.8
Water solubility 4.11 mg/L	Water Solubility 33 mg/L
Acute oral LD50> 5000 mg/kg	Acute oral LD50> 2000 mg/kg

Repeated Dose Studies on 2,6-Di-tert-butylphenol (2,6-DTBP)

Two studies have been identified that may be used to provide information regarding the toxicity of 2,6 DTBP in rats following repeated dosing. These are a 28 day oral (gavage) toxicity study in rats and a preliminary reproduction toxicity screening toxicity (oral gavage dosing) study in rats.

Subacute 28 Day Oral Toxicity Study with 2,6-bis (1,1 dimethylethyl) -phenol by daily gavage in the rat, RCC Notox project 057454, Reijnders, J. B. J., 1992.

Dose levels were 0, 15, 100 and 600 mg/kg/day. Treatment related changes in the blood, liver and kidney were observed at 100 and 600 mg/kg/day. At 600 mg/kg/day male and females had around 30 to 40% heavier livers than control animals and these weight increases were accompanied by very slight centrilobular hepatocellular hypertrophy. Although relative liver weight (% of bodyweight) in males at 100 mg/kg/day was approximately 20% heavier than controls this was not accompanied by microscopic changes and liver weight in females was comparable to controls. The increased liver weight at 100 (males only) and 600 mg/kg/day accompanied by slight centrilobular hypertrophy at 600 mg/kg/day was considered to be an adaptive change and of no toxicological significance. Reduced serum urea (17%) was present in females at 100 mg/kg/day and also noted in females at 600 mg/kg/day (33%). This is not considered a toxicologically relevant finding as a pathological change is normally reflected by an increase in serum urea levels.

The NOEL in this study was determined to be 15 mg/kg/day. However, it may be considered that the findings at 100 mg/kg/day were not adverse in that they would not be considered to affect the performance of the whole organism or the ability of the organism to respond to an additional environmental challenge. The NOAEL in this study was therefore, 100 mg/kg/day. Definitions on NOAEL and adverse effects are extracted from the Ecetoc technical report No 85, Recognition of, and Differentiation between, Adverse and Non-adverse Effects in Toxicology Studies. [i]This conclusion is supported by the results of the reproduction toxicity screening test discussed below.

Preliminary reproduction toxicity screening test with 2,6-bis(1,1-dimethylethyl) -phenol, Becker H., Biedermann K. (1992), RCC, Research and Consulting Company Ltd. and RCC Umweltchemie AG, Itingen, Switzerland, SI Group, Report No. 321794)

In this study male and female rats were dosed during a preparing and pairing period and until the day before sacrifice (around 43 days) at 0, 30, 150 and 750 mg/kg/day in order to investigate the effects on male and female reproductive performance. Marked toxicity as manifested by clinical signs of sedation, ataxia, lateral/ventral recumbancy, tremors, clonic spasms and hunched posture were recorded in both sexes at 750 mg/kg/day. There were no effects on general tolerability (clinical signs, bodyweight change, food intake), reproduction parameters or pup viability at 150 mg/kg/day.

Therefore, the findings from these studies add weight to the definition of a NOAEL of 150 mg/kg/day.

ASSESSMENT FACTORS

Study duration: The combined 1 generation reproduction/90 day repeated dose study is considered a sub-chronic study and a duration extrapolation factor of 2 was used to convert the value from a sub-chronic study to a chronic study (R8.4.3, Table R8-5, Chapter R.8).

Oral absorption: Absorption of a chemical from the GI tract depends on its physical properties, including lipid solubility and the dissociation rate. 2,4 -DTBP has water solubility of 33 mg/L and Log Kow of 4.8 indicating the substance is lipophilic and can diffuse across the lipid domain of cellular membranes. Generally, Log Kow values between 0 and 4 are optimal for absorption. 2,4 -DTBP also has a molecular weight of 206.33 indicating that it is small enough to diffuse across the lipid domain of the membrane. Generally, molecular weights < 500 are optimal for absorption. Facilitated transportation across the cell membrane is not likely to occurviaformation of a complex with carrier proteins because 2,4 -DTBP is not expected to bind to a protein (OECD Toolbox v.1.1). Therefore, absorption in the GI tract is expected to occur predominantly via simple diffusion. Additionally, Tebufelone, a member of the chemical class of DTBP antirheumatic agents, has been shown to have complete absorption and bioavailability following oral (bolus) administration of the drug (Sietsema W. K. et al. 1993). Therefore, significant first pass effects are not expected for 2,4 -DTBP either. For the conversion of an oral NOAEL to an inhalation DNEL the correction factor for systemic availability will be 1 as there is sufficient evidence that the absorbed oral dose is greater than 80% (SANCO 7531, 2006)

Interspecies Assessment factors: In addition to the allometric scaling factor of 4 a further interspecies assessment factor of 2.5 (remaining difference) is proposed in REACH Guidance R8, section R8.4.3.3, Table R.8-6, however no scientific basis for this is reported. In Ecetoc Technical Report No 86 (ECETOC 2003), a conclusion was reached that in the absence of a substance specific mode of action, allometric scaling based on metabolic rate is considered to provide an appropriate default assessment factor. As a specific mode of action has not been identified for 2,4 -DTBP it has not been considered necessary to apply this factor.

Intraspecies assessment factors: A factor for workers of 5 and for the general population of 10 has been suggested by the REACH guidance (8.4.3.1), however, based on several analyses of large data sets and in accordance with many workplace OEL setting practices an intraspecies factor for workers of 3 is considered appropriate for the worker population (ECETOC, 2003). Additionally following a review of human data which included both sexes and a variety of disease states and ages, the use of the 95^thpercentile is considered sufficiently conservative to account for intraspecies variability in the general population and thus a default assessment factor of 5 is recommended (ECETOC, 2003).

 

Conversion of oral NOAEL to inhalation DNEL, Workers.

REACH ECHA guidance Chapter R. 8: Characterisation of dose [concentration]-response for human health, R8.4.2, Figure R. 8-3 Modification of a starting point.

For workers (in case of 8h exposure/d):

Corrected inhalatory N(L) OAEC

          =oral NOAEL * 1/sRV_rat* ABS_oral-rat/ABS_inh-human* sRV_human/wRV

          =oral NOAEL * 1/0.38 m³/kg/dt* ABS_oral-rat/ABS_inh-human* 6.7 m³(8h) /10 m³(8h)

ABS: absorption; sRV: standard respiratory volume; wRV: worker respiratory volume

Using 150 mg/kg/day NOAEL, a factor of 1 is used for oral to inhalation absorption extrapolation based on the assumption of >80% oral absorption

          =150 *1/0.38 m³/kg/d * 1 * 6.7 m3 (8h) /10 m³(8h)

          = 264.5 mg/m³

For interspecies difference no additional interspecies allometric factor is applied at this stage as allometric scaling has already been considered in the route to route extrapolation step above with the respiratory volume adjustments (REACH ECHA guidance Chapter R. 8, Appendix *.8-2, Example B.3). An intraspecies assessment factor of 3 is applied.

          = 264.5 mg/m³/ 3

          = 88.2 mg/m³

Conversion from sub-chronic to chronic DNEL

          = 88.2 mg/m³/ 2

          = 44.1 mg/m³

Inhalation DNEL_long-term(workers) = 44.1 mg/m³

 

Conversion of oral NOAEL to dermal DNEL, Workers.

REACH ECHA guidance Chapter R. 8: Characterisation of dose [concentration]-response for human health, Appendix R8-2, route to route extrapolation and allometric scaling, Part 2, Modification of starting point, Example B. 5.

Correct oral NOAEL rat (in mg/kg bw/d) into dermal NOAEL rat (in mg/kg bw/d) by correcting for differences in absorption between routes (if the case) as well as for differences in dermal absorption between rats and humans (if the case):

Corrected dermal NOAEL = oral NOAEL * ABS_oral-rat/ABS_dermal-rat* ABS_dermal-rat/ ABS_derm-human

          = oral NOAEL * ABS_oral-rat/ ABS_derm-human

(note - on the assumption that, in general, dermal absorption will not be higher than oral absorption, no default factor (i. e. factor 1) should be introduced when performing oral-to-dermal extrapolation (chapter R8.4.2).

For interspecies differences, apply factor for allometric scaling (4 for rat).

          = 150/4

          =37.5

For intraspecies differences apply factor of 3.

= 37.5 mg/kg bw/day / 3

          = 12.5 mg/kg bw/day

Conversion from sub-chronic to chronic DNEL

          = 12.5 mg/kg bw/d / 2

          = 6.25 mg/kg bw/d

Dermal DNEL_long-term(workers) = 6.25 mg/kg bw/day

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

13 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):

10

Modified dose descriptor starting point:

NOAEC

Value:

264.5 mg/m³

Explanation for the modification of the dose descriptor starting point:

A repeat dose inhalation toxicity study with 2,4-di-tert-butyl phenol (2,4-DTBP) is not required due to the physical nature of the substance and its usage and the toxicological information available via the oral route of administration.

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:

no hazard identified

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

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

3.75 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):

40

Modified dose descriptor starting point:

NOAEL

Value:

150 mg/kg bw/day

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

Derivation of DNELS for the general population.

For 2,4-DTBP a general population DNEL for the inhalation route of exposure is required to enable the assessment of risk to consumers by the this route whilst an oral DNEL is also required to enable the assessment of risk to man exposed via the environment.

ASSESSMENT FACTORS

Study duration: Note that as the DNEL for general population (chronic exposure) should be derived from a chronic toxicity study, the duration extrapolation factor of 2 was be used to convert the experimental value from a sub-chronic study to a chronic study (R8.4.3, Table R8-5, Chapter R.8).

Interspecies Assessment factors: In addition to the allometric scaling factor of 4 a further interspecies assessment factor of 2.5 (remaining difference) is proposed in REACH Guidance R8, section R8.4.3.3, Table R.8-6, however no scientific basis for this is reported. In Ecetoc Technical Report No 86 (ECETOC 2003), a conclusion was reached that in the absence of a substance specific mode of action, allometric scaling based on metabolic rate is considered to provide an appropriate default assessment factor. As a specific mode of action has not been identified for 2,4 -DTBP it has not been considered necessary to apply this factor.

Intraspecies assessment factors: A factor for workers of 5 and for the general population of 10 has been suggested by the REACH Guidance R8, section 8.4.3.1, however, based on several analyses of large data sets and in accordance with many workplace OEL setting practices an intraspecies factor for workers of 3 is considered appropriate for the worker population (ECETOC, 2003). Additionally following a review of human data which included both sexes and a variety of disease states and ages, the use of the 95th percentile is considered sufficiently conservative to account for intraspecies variability in the general population and thus a default assessment factor of 5 is recommended (ECETOC, 2003).

The oral DNEL_long-term(general population) is required in order to assess the risk to manviathe environment and the derviation of this DNEL is shown below:

Using 150 mg/kg/day NOAEL from the combined 1 generation reproduction/90 day repeated oral toxicity study in rats. No modification of the starting point is required.

For interspecies differences, apply factor for allometric scaling (4 for rat)

                               = 150 mg/kg bw/day /4
                               =37.5

For intraspecies differences, apply factor of 5

                               =37.5 mg/kg bw/day /5
                               =7.5

Conversion from sub-chronic to chronic DNEL, apply a factor of 2

                              = 7.5 mg/kg bw/day / 2
                               =3.75

Oral DNEL_long-term(general population) = 3.75 mg/kg bw/day

General population DNELs for inhalation exposure are based on consumers being exposed to 2,4-DTBP for 24h exposure per day. Following the guidance in REACH Guidance R8, section R.8.4.2, Table R.8-2, the sRV_ratfor 24 hour exposure is calculated to be 1.15 m³/kg bw.

Corrected inhalatory N(L)OAEC

           =oral NOAEL * 1/sRV_rat* ABS_oral-rat/ABS_inh-rat* ABS_inh-rat/ABS_inh-human

           =oral NOAEL * 1/1.15 m³/kg/d* ABS_oral-rat/ABS_inh-human 

ABS: absorption; sRV: standard respiratory volume;

Using 150 mg/kg/d NOAEL, a factor of 1 is used for oral to inhalation extrapolation based on the assumption of >80% oral absorption

           = 150*1/1.15 m³/kg/day*1

           =150*0.87

           =130.5 mg/m³

Intraspecies Assessment factors; a factor of 5 is used

           = 130.5 mg/m³/ 5

           = 26.1 mg/m³

Conversion from sub-chronic to chronic DNEL

           = 26.1 mg/m³/ 2

           = 13.0 mg/m³

Inhalation DNEL_long-term(general population) = 13.0 mg/m³ (24h exposure/d)

1)       ECETOC, 2003, Technical Report No. 86, derivation of Assessment Factors for Human Health Risk Assessment.