3.3.3. Case study results for NOAEL* urinary mass balance approach

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frequent exceedances of metabolic pathways. This difference in exposure patterns cannot be generally taken into account in advance, but might justify case-specific additional assessment factors.

For the urinary mass balance approach, the preferred DNELoral is multiplied by a urinary excretion factor FUE, which is a steady-state concentration factor for urine measured after 24h or 48h exposure. When the DNELoral is derived for metabolites, it is also multiplied by the ratio of the molecular weights (RM) to the parent substance. This product is then divided by the urine Volume (u) (0.02 L/kg bodyweight/24 h). (Aylward et al., 2015) observed that the urinary flow rates in adults were consistent across the range of ages from 15 to 80, averaging approximately 20 mL/kg bw/day with no consistent differences between men and women. Newer studies indicate (e.g., by Lermen et al., 2019 or Mengelers et al., 2019) 3236% higher urinary flow rates (30 mL/kg bw/day) in men and women compared to historical values. As of yet, no harmonization has been reached for the urinary flow rate values (for details see Apel et al., 2020). We propose to use either of the two, and always indicate which 24-hour urinary flow rate (u) that was used in the derivation equation:

This POBL* will then give an indication of acceptable or unacceptable risks for workers depending on the Risk Characterisation Ratio (RCR) given the current knowledge and data.

Relevance assessment of POD*

The relevance of a POD needs to be evaluated before using a POD* for POBL* derivation. In contrast to the reliability, relevance does not concern the inherent quality of the study but mainly depends on the purpose of the assessment or regulatory framework for which it is evaluated. This assessment is always expert judgement driven, but includes questions such as:

 Are the reported endpoints relevant for humans and appropriate for the regulatory purpose (e.g., leading to adverse effects)?  Are the reported endpoints appropriate for the investigated effects or the mode of action of the test substance and the target human population?  Are the experimental conditions relevant for the tested species and the target human population?  Is the exposure duration relevant and appropriate for the studied endpoints and species?  Is the route of administration relevant for target human population exposure?

If the overall relevance of a POD* is rated relevant without restrictions or relevant with limited restrictions, then the POD* can be used for POBL* derivation. Please note: Exposure of pregnant and breast-feeding women at the workplace can have an effect on developing fetuses and infants, respectively, at lower concentrations.

3.3.3. Case study results for NOAEL* urinary mass balance approach

Two organic (DEHP* & HDI*) and two inorganic (Chromium & Aluminium) substances have been chosen as case study substances because of their different toxicological profiles and wide use in several industry sectors. To compare POBL* derivations with OBL* derivations most of the human toxicity data were excluded with a focus on animal toxicity data, trying to simulate a low human data availability. The primary source for these case studies was data compiled by biomonitoring experts. Dedicated experts added pertinent data at a later stage. Selected PODs* of these data were categorized into three categories of conservatism: “precautionary”, “balanced”, and “relaxed” data selections (with numerically low, medium and high NOAEL*/LOAELs*). The different data selections were used partially as case study scenarios to derive POBL* and to check the variability of method results, depending on the choice of toxicological PODs* (see Tables 8-11).

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To compare the results in terms of toxicity reference values (TRV*), the urinary excretion factors (see Table 7) were kept constant and a urinary flow rate (u) was set equal to 20 ml/kg bw/d

Table 7. For case studies used urinary excretion factors

substance

DEHP* HDI* Aluminium

FUE (urinary excretion factor)

0.4 0.21 0.00145

partially or less soluble Al substances

0.0074

Chromium for soluble Al substances 0.8

Table 8. DEHP* case study scenarios for provisional OBL* derivation

DEHP* scenario NOAEL* /LOAEL*, reference Mode of action relevant endpoint DNEL* oral POBL* Relevance of POD*

precautionary LOAEL = 3 mg/kg bw/d, (Christiansen et al., 2010) dysgenesis of genitalia in rat 0.01 mg/kg/d

0.15 mg/L Yes

5-oxo and 5-OH-MEHP

balanced NOAEL= 4.8 mg/kg bw/d, (German HBM Commission, 2007) reproduction toxicity in rats 0.096 mg/kg/d

1.44 mg/L

5-oxo and 5-OH-MEHP Yes

relaxed NOAEL = 5.8 mg/kg/d,

(David et al., 2010) bilateral aspermatogenesis, reprotoxicity 0.116 mg/kg/d

1.74 mg/L

5-oxo and 5-OH-MEHP Yes

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Table 9. HDI* case study scenarios for provisional OBL* derivation

Table 10. Aluminium case study scenarios for provisional OBL* derivation

HDI* scenario NOAEL* /LOAEL*, reference Mode of action relevant endpoint DNEL* oral POBL* Relevance of POD*

precautionary LOEC*= 0.035 mg/m3

(Mobay, 1989 in German MAK derivation, 1996) hyaline degeneration of the respiratory epithelium in rats in study of 0.0886 µg/kg/d

balanced NOAEL*= 0.005 ml/m3='ppm,' (German MAK derivation, 1996) for HDI 2 years chronic rat study was leading to adaptations in nasal epithelium, because of missing adversity of adaptations this LOAEL* was interpreted as NOAEL* 0.2656 µg/kg/d

relaxed LOEC*='3.5' mg/m3

(German MAK derivation, 1996) for HDI maternal toxicity and fetotoxicity in rats 8.87 µg/kg/d

0.93 µg/L HDA* Yes, sensitisation

2.79 µg/L HDA* Yes, partially

93.14 µg/L HDA* No, not related to sensitisation

Aluminium scenario

NOAEL* /LOAEL* reference

precautionary Chronic NOAEL* =2.5 mg Al/m3 (Piggot et al., 1981) balanced Sub-chronic LOAEC* for local effects= 50 mg/m3 , (Gross et al., 1973) from ECHA* dossier: LOAEC* is based on local effects, such as lipid pneumonitis, granulomatous inflammation; collagenous scars but fibrosis was not evident. Measured in rats exposed to aluminium powders 0.127 mg/kg/d

relaxed Chronic NOAEL* for systemic effects = 158 mg Al/kg bw/day (Alberta Research Council Inc. 2010, as cited in REACH dossier, 2018). used in ECHA* dossier:Chronic systemic effects. Developmental and One-Year Chronic Neurotoxicity Study of Aluminium Citrate in rats (NOAEL*corr = NOAEL * 5.27 = 30 * 5.27 = 158.0 mg Al/kg bw/day) 7.9 mg/kg bw/d

Mode of action relevant endpoint DNEL* oral

inhalation exposure to Al2O3 in a rat study was evaluated by ACGIH*. 0.019 mg/kg/d

POBL* Relevance of POD*

1.38 µg/L Yes

9.2 µg/L Partially, due to local effects

2.92 mg/L No, oral exposure

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