Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.75 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
10
Dose descriptor starting point:
NOAEC
DNEL value:
15 mg/m³
Modified dose descriptor starting point:
NOAEC
DNEL value:
7.54 mg/m³
Explanation for the modification of the dose descriptor starting point:

Correction for 8h exposure of workers compared to 6h used in the animal experiment

AF for dose response relationship:
1
Justification:
NOAEC identified from an inhalation Study in the rat
AF for differences in duration of exposure:
2
Justification:
Default AF for extrapolation from Subchronic to chronic exposure
AF for interspecies differences (allometric scaling):
1
Justification:
Not needed here, correction already applied for respiratory volume etc.
AF for other interspecies differences:
1
Justification:
Not needed here
AF for intraspecies differences:
5
Justification:
Default AF
AF for the quality of the whole database:
1
Justification:
Guideline studies
AF for remaining uncertainties:
1
Justification:
Not needed here
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.5 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
DNEL derivation method:
other: ECHA guidance and German AGW delineation method as basis for the binding nationel OEL
Overall assessment factor (AF):
6
Dose descriptor:
NOAEC
DNEL value:
3 mg/m³
AF for dose response relationship:
1
Justification:
NOAEC identified
AF for differences in duration of exposure:
2
Justification:
Subchronic to chronic extrapolation standard factor REACH and AGS (2010)
AF for interspecies differences (allometric scaling):
1
Justification:
Assessment factor for allometric scaling is not needed here as the local effects of aerosols rather depend on local deposition than on metabolism.
AF for other interspecies differences:
1
Justification:
No remaining differences are assumed as the effects are solely local effects and the rat is considered a sufficient conservative model.
AF for intraspecies differences:
3
Justification:
Assessment factor for the extrapolation from irritative effects on the respiratory tract according to Brüning, 2014 and Brüning et al., 2014.
AF for the quality of the whole database:
1
Justification:
Guideline studies
AF for remaining uncertainties:
1
Justification:
No remaining differences are assumed as the effects are solely local effects and the rat is considered a sufficient conservative model, espeecialy for local effects.
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.13 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
60
Modified dose descriptor starting point:
LOAEL
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
low hazard (no threshold derived)

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.

 

Kinetics (absorption figures for oral, dermal and inhalation route of exposure)

DEA is well absorbed following oral administration in rats (57%) and to a lower degree after dermal administration (3-16% in rats; 25 – 60% in mice). When applied dermally, DEA appears to facilitate its own absorption, as higher doses were more completely absorbed than lower doses. DEA (20 mg/cm²) applied to skin preparations in vitro showed penetration rates of 6.68% (mouse) > 2.81 % (rabbit) >0.56% (rat) > 0.23% (human). Distribution to the tissues was similar via all routes examined. DEA is cleared from the tissues with a half-life of approximately 6 days. The highest concentrations are observed in liver and kidney. Metabolism after oral administration revealed non-metabolized DEA and smaller proportions of N-methyl-DEA (N-MDEA), N,N-dimethyl-DEA (N’N-DMDEA) and DEA-phosphates co-eluting with phosphatidyl ethanolamine and phosphatidyl choline. After digestion, 30% of the phospholipids were identified as ceramides and the remaining 70% as phosphog1ycerides. DEA is excreted primarily in urine as the parent molecule (25-36%), with lesser amounts of O-phosphorylated and N-methylated metabolites. Accumulation of DEA at high levels in liver and kidney is assumed by a mechanism that normally conserves ethanolamine, a normal constituent of phospholipids. DEA is incorporated as the head group in phospholipids, presumably via the same enzymatic pathways that normally utilize ethanolamine.

 

Acute toxicity

DEA is classified for acute oral toxicity (H302).  However, oral exposure is expressed as amount (per kg bw) per day. Therefore acute oral exposure (peaks; in mg/kg bw) will not be higher than a calculated total exposure per day (chronic; in mg/kg bw). Practically relevant peak exposure therefore does not occur for DEA. Furthermore, DEA does not have to be classified based on the acute inhalation and dermal toxicity data. Therefore, no acute DNEL is needed.

 

Irritation

DEA is a skin and severe eye irritant in rabbits (H318 + H315).The available data do not allow a quantitative approach. According to the REACH guidance on information requirements and chemical safety assessment, Part E: Risk Characterisation, a qualitative risk characterisation should be performed for this endpoint. In order to guarantee ‘adequately control of risks’, it is necessary to stipulate risk management measures that prevent skin and severe eye irritation.

 

Sensitisation

DEA is not considered a skin sensitiser.

 

Repeated dose toxicity

Nose-only exposure of rats to DEA aerosols for 3 months resulted in systemic effects:

- kidney effects (increased incidences of mild hematuria in both sexes, some increase in renal tubular cells and granular casts in male animals, slight increases in kidney weights, minimal or slight tubular hyperplasia in some female animals and intratubular lithiasis slightly more pronounced than in controls in some male animals);

- adaptive liver effects (mild increases of liver weights and serum alkaline phosphatase serum levels without histopathological findings);

- a mild normochromic microcytic anemia and some influence on the male reproductive system consisting of diffuse testicular atrophy and minimal to slight atrophy of the prostate was present at the high concentration only.

Furthermore, local effects (respiratory tract irritation, squamous metaplasia of the laryngeal epithelium, inflammatory response) were observed. No functional or morphological evidence of neurotoxicity was observed. The NOAEC for systemic effects was 15 mg/m³ and the NOAEC for upper respiratory tract irritation was 3 mg/m³.

 

Repeated unoccluded dermal application of ethanolic DEA solutions in subacute and subchronic studies with rats and mice led to mortality at high dose levels (500 mg/kg bw in rats;1000 mg/kg bw in mice). In rats, systemic signs of toxicity consisted predominantly of anaemia and nephropathy. In addition, liver weights were increased without a histopathological correlate. In mice, systemic effects occurred mainly in the form of liver and kidney damage. In both species, local skin irritation was observed. A NOAEL for systemic effects or local skin irritation could not be achieved (LOAEL 32 mg/kg bw in rats; 80 mg/kg bw in mice).

 

In rats, subchronic oral treatment via the drinking water caused mortality at the high dose in males (5000 ppm). Impaired body weight gains were observed at concentrations equal to or higher than 320 ppm in females and 630 ppm in males. Systemic effects consisted of anaemia, nephrotoxicity, cortical vacuolization of adrenal glands and demyelinization of brain/spinal cord without any neurofunctional finding. In males, damage of reproductive organs in the form of testicular degeneration and associated weight changes and impaired spermatology was observed. Based on the observed anaemia and nephropathy, a LOAEL of 25/14 mg/kg bw (equal to 320/160 ppm) was achieved in males/females.

In the subchronic oral study in mice, mortality was observed in males at5000 ppm and in females at2500 ppm. Body weight gain was decreased in both species at concentrations of 1250 ppm (females) or 2500 ppm (males) and higher. Systemic effects consisted of hepato- and nephrotoxicity and myocardial degeneration. The most sensitive effect was necrotic liver damage at all concentrations. A LOAEL of 104/142 mg/kg bw (equal to 630/630 ppm) was noted in males/females.

 

Mutagenicity and carcinogenicity

DEA is assessed as being non-mutagenic.

DEA formulated in ethanol showed no oncogenic potential in the rat after unoccluded daily dermal exposure for 2 years. In the dermal mouse carcinogenicity study using similar exposure techniques, there was an increased incidence of liver neoplasms in males and females at all doses tested and an increased incidence of renal tubule adenomas in males at the high dose level only. The liver tumours in mice were considered to be directly related to the observed increase in the cellular proliferation rate, which is due to the observed enzyme induction, weak peroxisome proliferation and choline depletion with subsequent disturbance of its metabolism. While nitrosamine formation has been highlighted as a matter of concern for DEA, and for this reason it has been banned for use in cosmetics in the EU, nitrosamine formation was ruled out under the conditions of this study. Benign kidney tumours (adenomas) were only observed in male mice at the high dose level at a low incidence, when using serial sections. Based on the increased S-phase synthesis observed in this organ, it is conceivable that a similar non-genotoxic mode of action involving choline deficiency is responsible for the renal tubular adenomas.

In short term tests on carcinogenicity, DEA was not carcinogenic, when tested in the Tg.Ac transgenic mouse model up to topical dose levels exceeding the MTD. Cell transformation in Syrian hamster embryo cells in vitro was observed predominantly in the range of cytotoxic concentrations but supplementation of choline completely inhibited this effect.

Various mechanistic in vitro and in vivo studies identified that DEA induced choline depletion is the key event in the toxic mode of action. DEA decreased gap junctional intracellular communication in primary cultured mouse and rat hepatocytes, but all these events were prevented with choline supplementation. DNA hypomethylation was observed in mouse hepatocytes as a further epigenetic mechanism involved in liver tumourigenesis.

DEA decreased phosphatidylcholine synthesis by blocking the cellular uptake of choline in vitro, but these events did not occur in the presence of excess choline.

DEA increased S-phase DNA synthesis in mouse hepatocytes but had no effect on apoptosis. No such effects were noted in human hepatocytes in vitro. Apparent differences in the susceptibility of two different mice strains (B6C3F1 > C57BL) were noted. B6C3F1 mice are extremely sensitive to non-genotoxic effects and are known to possess a relatively high incidence of spontaneous liver tumours. Moreover, chronic stimulation and compensatory adaptive changes of hepatocyte hypertrophy and proliferation are able to enhance the incidence of common spontaneous liver tumours in the mouse by mechanisms not relevant to humans. Analysis of gene expressions in animal studies showed an increase in genes associated with cell proliferation, while a decrease in genetic processes relevant for apoptotic mechanisms was observed.

In conclusion, based on the above evaluation, no separate risk characterisation for mutagenicity and carcinogenicity is needed.

The 2 year studies with rats and mice also showed non-carcinogenic effects. The overall dermal LOAEL based on the 13 weeks and 2 years studies is concluded to be 8 mg/kg bw/day. Critical effects appear to be kidney (nephropathy) and liver toxicity, anaemia and dermal hyperkeratosis/acanthosis. Besides anaemia, nephropathy was observed at the lowest tested dose in the 13 weeks dermal toxicity study (32 mg/kg bw/day). After 13 weeks effects on the kidneys are not yet masked by ageing and appear a treatment related adverse effect. Therefore, the observation of nephropathy in females at the lowest tested dermal dose of 8 mg/kg bw/day in the 2 years study, which was somewhat masked by ageing, is also considered adverse. In males this effect was completely masked by the ageing process after 2 years of exposure.

 

Reproduction toxicity

In the developmental toxicity studies with DEA, the substance caused only developmental toxicity in the presence of clear maternal toxicity. Furthermore, maternal toxicity was observed at levels higher/comparable to general toxic effects in the repeated dose toxicity studies.

For DEA CAS 111-42-2, an extended One-Generation Reproductive Toxicity Study (EOGRTS) according to OECD TG 443 has been performed and finalized on January 29th2018.

2,2’-iminodiethanol was administered to groups of 30 male and 30 female healthy young Wistar rats (F0 parental generation) as a solution to the drinking water in different concentrations (0, 100, 300 and 1000 ppm). At least 16 days after the beginning of treatment, F0 animals were mated to produce a litter (F1 generation). Mating pairs were from the same dose group. Pups of the F1 litter were selected (F1 rearing animals) and assigned to 5 different cohorts which were continued in dose groups 10 - 13 in the same fashion as their parents and which were subjected to specific post weaning examinations. The study terminated with the terminal sacrifice of the male and female animals of cohort 1B. Test drinking water containing 2,2’-iminodiethanol were offered continuously throughout the study.

Intake of test substance: the overall mean dose of 2,2’-iminodiethanol throughout all study phase and across all cohorts was approx. 12.75 mg/kg body weight/day (mg/kg bw/d) in the 100 ppm group, approx. 37.68 mg/kg bw/d in the 300 ppm group and approx. 128.35 mg/kg bw/d in the 1000 ppm group.

Under the conditions of the present modified extended 1-generation reproduction toxicity study the NOAEL (no observed adverse effect level) for general toxicity is 100 ppm for the F0 parental animals, based on evidence for distinct kidney toxicity and stomach irritation, as well as corresponding effects on water consumption, food consumption, body weights and clinical pathological parameters, which were observed at the LOAEL (Lowest Observed Adverse Effect Level) of 300 ppm. Similar toxicity was noted in the adolescent F1 animals, which had no stomach irritation but liver toxicity in addition.

The NOAEL for fertility and reproductive performance for the F0 and F1 rats is 300 ppm, based on a lower number of implants, prolonged/irregular estrous cycles as well as pathological changes in sexual organs, pituitary and mammary glands of both genders at the LOAEL (Lowest Observed Adverse Effect Level) of 1000 ppm. However, eosinophilic cysts in the pituitary gland were present in the F1 animals of cohort 1A down to the 100 ppm dose level, but no assessment on adversity of this finding is possible at present. Therefore, no NOEL can be established for this particular effect.

The NOAEL for developmental toxicity in the F1 progeny is 100 ppm, based on impaired pup survival at 1000 ppm as well as reduced pup body weights in the F1 offspring, which were observed at the LOAEL (Lowest Observed Adverse Effect Level) of 300 ppm. As these weight reductions were only observed in the presence of maternal toxicity, including lower weight gain during pregnancy, they are not regarded as independent effect of the treatment.

The NOAEL for developmental neurotoxicity for the F1 progeny is 300 ppm, based on adverse clinical observations, impaired auditory startle response and corresponding neuropathological findings at the LOAEL (Lowest Observed Adverse Effect Level) of 1000 ppm. In addition, increased T4 values were noted in adult and adolescent males at 1000 ppm as well as newborn and weanling females at 100 and 300 ppm.

The NOAEL for developmental immunotoxicity for the F1 progeny is 300 ppm, based on effects on the T-helper cells and cytotoxic T-cells in the spleen in the F1 females at the LOAEL (Lowest Observed Adverse Effect Level) of 1000 ppm. Lower mean and median anti-SRBC IgM antibody titers of the positive control group (4.5 mg/kg bw/d cyclophosphamide, oral) demonstrated that the test system worked properly.

In addition to the EOGRST / OECD 443 that is available for DEA, there is a 3-month inhalation study in rats reporting an influence on the male reproductive system at the high concentration. The NOAEC for male fertility parameters was 0.15 mg/l. When DEA was orally administered to rats via the drinking water for 13 weeks, decreases in testis and epididymis weights, testicular degeneration, atrophy of the seminal vesicles and prostate glands and associated effects on spermatology were observed. The NOAEL for fertility effects in males was 48 mg/kg bw. In all of these studies no histopathological effects were observed in female reproductive organs.

 

 

In conclusion, the long-term DNELs derived using the repeated dose toxicity studies are also considered sufficient for reproduction toxicity (effects on fertility and developmental toxicity).

 

Worker DNELs

Long-term – inhalation, local effects

For DEA a national “occupational exposure limit” OEL = MAK value of 1 mg/m³ was established in Germany based on the critical NOAEC of 3 mg/m³ air (male/female) (BASF AG, 2002). At the next higher level, respiratory tract irritation, squamous metaplasia of the laryngeal epithelium and an inflammatory response in the respiratory tract were observed.

In 2016, this national OEL has been re-evaluated by the German “Auschuss für Gefahrstoffe” (AGS). The outcome is that the national OEL (i.e. AGW) is now at 0.5 mg/m³ inconsistency with the most recent delineation for related Ethanolamines (such as Monoethanolamine Cas No. 141-43-5 and Triethanolamine CAS No. 102-71-6). The scientific documentation is currently only available in German language, the justification of the selection of assessment factors within the AGS-delineation hast been translated and can be found in the table given below:

 

 Description

 

Value

Remark

Step 1) Relevant dose-descriptor

 

NOAEC (local effects) = 3 mg/m³

 

In a subchronic aerosol study according to OECD 413 DEA has been tested mainly as aerosol (MMAD 0.6 – 0.7 µm). The calculated saturated vapor pressure at RT is > 0.9 mg/m³. At 3 mg/m³ squamous-cell metaplasia was observed in males in the larynx level 1. The evaluation of the findings for humans is considered not adverse (Osimitz et la., 2007; Kaufmann et al., 2009), The concentration has therefore been considered the NOAEC with 8 mg/m³ being the LOAEC.

Step 2) Modification of starting point

 

/

 

No correction for 8h exposure of workers compared to 6h used in the animal experiment applicable as the effect on the respiratory tract underlies deposition of aerosol in the larynx. Therefore, no correction of the starting point has been applied.

Step 3) Assessment factors

 

 

 

Remaining differences

 

1

No remaining differences are assumed as the effects are solely local effects and the rat is considered a sufficient conservative model.

Interspecies

 

1

Assessment factor for allometric scaling is not needed here as the local effects of aerosols rather depend on local deposition than on metabolism.

Intraspecies

 

3

Assessment factor for the extrapolation from irritative effects on the respiratory tract according to Brüning, 2014 and Brüning et al., 2014.

Exposure duration

 

2

Subchronic to chronic extrapolation standard factor REACH and AGS (2010)

Dose response

 

1

NOAEC available

Quality of the database

 

1

Actual guideline study and GLP-conform

DNEL

 

Value

 

3 / (1 x 3 x 2 x 1 x 1) = 0.5 mg/m³

 

 

Long-term – inhalation, systemic effects

Within the above described AGW delineation by the German AGS the following two DNELs / AGW for long-term systemic effects (OPTIONs 1+2) have been derived in comparison with the DNEL for long-term and local effects as a plausibility check. OPTION 3 has been derived based on the NOAELs obtained from the most recent OECD443 Extended-one-generation reproductive toxicity study.

The following 3 possibilities have been taken into consideration (please compare with the following 3 tables).

Overall, the DNELs long-term for systemic effects ranged from 0.74 to 0.81 mg/m³ and were above the DNEL for long-term local effects. Therefore, the DNEL = AGW covering local effects on the respiratory tract is thought to protect from systemic effects.

 

OPTION 1 - Long-term – inhalation, systemic effects

 Description

 

Value

Remark

Step 1) Relevant dose-descriptor

 

NOAEC (systemic effects) = 15mg/m³

 

NOAEC form 3-months inhalation study in Wistar rats. Effects were anemia, liver effects, kidney toxicity testis/prostate atrophy and erosion of the glandular stomach.

Step 2) Modification of starting point

 

x 6h/d / 8h/d

x 6.7 m³ (8h) / 10 m³ (8h)

 

corrected NOAEC = 7.54 mg/m³

 

Correction for 8h exposure of workers compared to 6h used in the animal experiment

 

Step 3) Assessment factors

 

 

 

Remaining differences

 

1

No remaining differences are assumed as the effects are solely local effects and the rat is a sufficient conservative model.

 

Interspecies

 

1

Assessment factor for allometric scaling is not needed here as the local and systemic effects of aerosols rather depend on local deposition than on metabolism.

 

Intraspecies

 

5

Default assessment factor

Exposure duration

 

2

Subchronic to chronic

Dose response

 

1

Starting point was NOAEC

Quality of the database

 

1

Actual guideline study and GLP-conform

DNEL

 

Value

 

7.5 / (1 x 5 x 2 x 1 x 1) = 0.75 mg/m³

 

 

OPTION 2 - Long-term – inhalation, systemic effects

 Description

 

Value

Remark

Step 1) Relevant dose-descriptor

 

LOAEC (systemic effects effects) = 14 mg/kg BW/day

 

Systemic LOAEL from the 3-months drinking water study in rats. Effects were anemia, liver effects, kidney toxicity, degeneration of testis/seminiferous tubules and effects on sperm. No NOAEL could be identified.

Step 2) Modification of starting point

 

0.29 m³/kg BW

 

6h/d / 8h/d

x 6.7 m³ (8h) / 10 m³ (8h)

 

corrected NOAEC = 24.25 mg/m³

 

Respiratory volume rat (6h exposure)

 

Extrapolation from oral exposure to inhalation (NOAEL to NOAEC conversion)

 

Step 3) Assessment factors

 

 

 

Remaining differences

 

1

No remaining differences are assumed here. The underlying mode-of-action has been well characterized (i.e. effects on choline-homeostasis).

 

Interspecies

 

1

Assessment factor for allometric scaling is not needed here as the extrapolation is already corrected form oral to inhalative exposure.

 

Intraspecies

 

5

Default assessment factor worker

Exposure duration

 

2

Subchronic to chronic

Dose response

 

3

A factor of 3 is considered sufficient for extrapolation from a LOAEL to a NOAEL

Quality of the database

 

1

Actual guideline study and GLP-conform

DNEL

 

Value

 

24.25 / (1 x 5 x 2 x 3 x 1) = 0.81 mg/m³

 

 

 

 

 

 

 

 

 

OPTION 3 - Long-term – inhalation, systemic effects

 Description

 

Value

Remark

Step 1) Relevant dose-descriptor

 

LOAEC (systemic effects effects) = 12.75 mg/kg BW/day

 

The overall mean doses of DEA throughout all study sections and across all

cohorts were 12.75 mg/kg body weight/day (mg/kg bw/d) in the 100 ppm group. Under the conditions of the present modified extended 1-generation reproduction toxicity study

the NOAEL (no observed adverse effect level) for general toxicity is 100 ppm for the F0 parental animals, based on evidence for distinct kidney toxicity and stomach irritation, as well

as corresponding effects on water consumption, food consumption, body weights and clinicalpathological

parameters, which were observed at the LOAEL (Lowest Observed Adverse Effect Level) of 300 ppm. Similar toxicity was noted in the adolescent F1 animals, which had no

stomach irritation but liver toxicity in addition.

However, due to certain findings in all dose levels in the offspring (i.e. increase in t4 levels and eosinophilic cysts in the pituitary gland, a LOAEL = 100 ppm is assumed for this plausibility check.

 

Step 2) Modification of starting point

 

0.29 m³/kg BW

 

6h/d / 8h/d

x 6.7 m³ (8h) / 10 m³ (8h)

 

corrected NOAEC = 22,1 mg/m³

 

Respiratory volume rat (6h exposure)

 

Extrapolation from oral exposure to inhalation (NOAEL to NOAEC conversion)

 

Step 3) Assessment factors

 

 

 

Remaining differences

 

1

A worst case approach is already used here as the adversity of the findings is not clear.

 

Interspecies

 

1

Assessment factor for allometric scaling is not needed here as the extrapolation is already corrected form oral to inhalative exposure.

 

Intraspecies

 

5

Default assessment factor worker

Exposure duration

 

2

Subchronic to chronic

Dose response

 

3

A factor of 3 is considered sufficient for extrapolation from a LOAEL to a NOAEL

Quality of the database

 

1

Actual guideline study and GLP-conform

DNEL

 

Value

 

22,1 / (1 x 5 x 2 x 3 x 1) = 0.74 mg/m³

 

 

 

 

Long-term – dermal, systemic effects

 

 Description

 

Value

Remark

Step 1) Relevant dose-descriptor

 

LOAEC (local effects) = 8 mg/kgbw/day

 

The overall LOAEL based on the sub- and chronic dermal studies with rats and mice is 8 mg/kg bw/day. The critical systemic effects appear to be kidney and liver toxicity and anaemia. Besides anaemia, nephropathy was observed at the lowest tested dose in the 13 weeks dermal toxicity study (32 mg/kg bw/day in rats). After 13 weeks kidney effects are not yet masked by ageing. Therefore, the observation of nephropathy in female rats at the lowest tested dermal dose of 8 mg/kg bw/day in the 2-year study, which was somewhat masked by ageing, is also considered adverse.

Step 2) Modification of starting point

 

/

 

Not applicable here

Step 3) Assessment factors

 

 

 

Interspecies

 

4

Assessment factor for allometric scaling.

Intraspecies

 

5

Default assessment factor Worker.

Remaining differences

 

1

No remaining differences are assumed as the effects are solely local effects and the rat is a sufficient conservative model.

 

Exposure duration

 

1

The key study is a 2-year study.

Dose response

 

3

A factor of 3 is considered sufficient for extrapolation from a LOAEL to a NAEL

Quality of the database

 

1

Actual guideline study and GLP-conform

DNEL

 

Value

 

8 / (4 x 5 x 1 x 3 x 1) = 0.13 mg/kgbw/day

 

 

References

 

Brüning T, Bartsch R, Bolt HM, Desel H, Drexler H, Gundert-Remy U, Hartwig A, Jackh R, Leibold E, Pallapies D, Rettenmeier AW, Schluter G, Stropp G, Sucker K, Triebig G, Westphal G, van Thriel C (2014) „Sensory irritation as a basis for setting occupational exposure limits, Arch.Toxicol., 88, 1855-1879.

 

Brüning T (2014) Ableitung von Grenzwerten für Stoffe mit sensorisch irritativer Wirkung, Verfahrensvorschlag der ad hoc Arbeitsgruppe“ Grenzwertableitung bei lokalen Effekten“, IPA Journal 03/2014, 12-17.

 

Kaufmann W, Bader R, Ernst H, Harada T, Hardisty J, Kittel B, Kolling A, Pino M, Renne R, Rittinghausen S , Schulte A, Woehrmann T, Rosenbruch M (2009) 1st International ESTP Expert Workshop:‘‘Larynx squamous metaplasia’’.A reconsideration of morphology and diagnostic capproaches in rodent studies and its relevance for human risk assessment, Experiment. Toxicologic Pathology, 61, 591–603.

 

Osimitz TG, Droegge W, Finch JM (2007)Toxicologic significance of histologic change in the larynx of the rat following inhalation exposure: A critical review, Toxicol. Appl. Pharmacol., 225, 229–237.

 

 

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.125 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
By inhalation
DNEL related information
DNEL derivation method:
other: REACH guidance and AGW
Overall assessment factor (AF):
4
Explanation for the modification of the dose descriptor starting point:

Long-term – inhalation, local/systemic effects

Using the German AGW value of 0.5 mg/m3 as starting point, the following DNEL is calculated:

 

0.5 mg/m3 * 10/20 (a) * 5/10 (b) = 0.125 mg/m3

(a) modification based on differences in exposure duration and activity (10 m3 in 8 h for workers, 20 m3 in 24 h for the general population)

(b) correction for intraspecies differences: workers default factor: 5, general population default factor: 10

Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.125 mg/m³
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
DNEL derivation method:
other: REACH Guidance and AGW
Overall assessment factor (AF):
4
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.07 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
120
Modified dose descriptor starting point:
LOAEL
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.06 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
240
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
low hazard (no threshold derived)

Additional information - General Population

General population DNELs

 

Long-term – inhalation, local/systemic effects

Using the German AGW value of 0.5 mg/m3 as starting point, the following DNEL is calculated:

 

0.5 mg/m3 * 10/20 (a) * 5/10 (b) = 0.125 mg/m3

(a) modification based on differences in exposure duration and activity (10 m3 in 8 h for workers, 20 m3 in 24 h for the general population)

(b) correction for intraspecies differences: workers default factor: 5, general population default factor: 10

Long-term – dermal, systemic effects

Description

Value

Remark

Step 1) Relevant dose-descriptor

LOAEL: 8 mg/kg bw/day

The overall LOAEL based on the sub- and chronic dermal studies with rats and mice is 8 mg/kg bw/day. The critical systemic effects appear to be kidney and liver toxicity and anaemia. Besides anaemia, nephropathy was observed at the lowest tested dose in the 13 weeks dermal toxicity study (32 mg/kg bw/day in rats). After 13 weeks kidney effects are not yet masked by ageing. Therefore, the observation of nephropathy in female rats at the lowest tested dermal dose of 8 mg/kg bw/day in the 2 year study, which was somewhat masked by ageing, is also considered adverse.

Step 2) Modification of starting point

-

-

Step 3) Assessment factors

 

 

Interspecies

4

Assessment factor for allometric scaling.

Intraspecies

10

Default assessment factor

Exposure duration

1

The key study is a 2 year study.

Dose response

3

A factor of 3 is considered sufficient for extrapolation from a LOAEL to a NAEL

Quality of database

1

 

DNEL

Value

 

8 / (4 x 10 x 1 x 3 x 1) =0.07 mg/kg bw/day

Long-term – oral, systemic effects

Description

Value

Remark

Step 1) Relevant dose-descriptor

LOAEL: 14 mg/kg bw/day

Based on anaemia, nephrotoxicity, increased kidney weight (rats)

Step 2) Modification of starting point

-

 

Step 3) Assessment factors

 

 

Interspecies

4

Assessment factor for allometric scaling.

Intraspecies

10

Default assessment factor

Exposure duration

2

Extrapolation to chronic exposure based on a sub-chronic toxicity study

Dose response

3

Extrapolation from LOAEL to NAEL

Quality of database

1

 

DNEL

Value

 

14 / (4 x 10 x 2 x 3 x 1) =0.06 mg/kg bw/day