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Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
19.25 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: specific (for further details see discussion below)
Overall assessment factor (AF):
5
Modified dose descriptor starting point:
NOAEC
Value:
96.27 mg/m³
Explanation for the modification of the dose descriptor starting point:
The starting point was corrected according to Figure R.8-3 in chapter R.8 in the ECHA guidance document (version 2.1, November 2012).
AF for dose response relationship:
1
Justification:
Default value (ECHA) for NOAEL chosen as starting point
AF for differences in duration of exposure:
1
Justification:
Default value (ECHA) for chronic exposure
AF for interspecies differences (allometric scaling):
1
Justification:
rat versus human: According to table R.8-4 in chapter R.8 of the ECHA guidance document (version 2.1, November 2012) the AF of 4 is already included in the route to route extrapolation.
AF for other interspecies differences:
1
Justification:
Specific assessment factor (for further details see discussion below)
AF for intraspecies differences:
5
Justification:
Default value (ECHA) for workers
AF for the quality of the whole database:
1
Justification:
Default assessment factor for good/standard quality of database as suggested by the ECHA guidance R.8.
AF for remaining uncertainties:
1
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
irritation (respiratory tract)
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
21.84 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: specific (for further details see discussion below)
Overall assessment factor (AF):
5
Modified dose descriptor starting point:
NOAEL
Value:
109.2 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
Deriving the DNEL by means of route-to-route extrapolation from repeated dose toxicity data after chronic oral exposure revealed a stricter DNEL as compared to the first approach, taking the subacute dermal repeated dose toxicity study as a basis. The DNEL derived from the chronic oral study is more reliable, as measured data are available for the route-to-route extrapolation, whereas DNEL derivation from the subacute dermal study necessitates time extrapolation using default values, which is more a rough estimate rather than reflecting realistic conditions. Moreover, no LOAEL could be deduced from the subacute dermal study; the NOAEL deduced was set at the high dose. Therefore, in contrast to the oral study, no real threshold value for systemic toxicity could be identified from the dermal study. Thus, a DNEL of 21.84 mg/kg bw/day derived from the chronic oral OECD 453 study in rats will be used for the following risk assessment.
AF for dose response relationship:
1
Justification:
Default value (ECHA) for NOAEL chosen as starting point
AF for differences in duration of exposure:
1
Justification:
Default value (ECHA) for chronic exposure
AF for interspecies differences (allometric scaling):
1
Justification:
Specific assessment factor (for further details see discussion below)
AF for other interspecies differences:
1
Justification:
Specific assessment factor (for further details see discussion below)
AF for intraspecies differences:
5
Justification:
Default value (ECHA) for workers
AF for the quality of the whole database:
1
Justification:
Default assessment factor for good/standard quality of database as suggested by the ECHA guidance R.8.
AF for remaining uncertainties:
1
Acute/short term exposure
Hazard assessment conclusion:
no DNEL required: short term exposure controlled by conditions for long-term
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium hazard (no threshold derived)

Additional information - workers

Various studies are available for the assessment of long term effects of 2-phenylphenol (OPP): a combined chronic toxicity/carcinogenicity study in the rat (OECD 453), a combined chronic toxicity/carcinogenicity study in the mouse (OECD 453), and a subchronic (1 year) repeated dose toxicity study in the dog (similar to OECD 409) are available. Moreover, a subacute repeated dose toxicity study via the dermal route in the rat (OECD 410) is available.

In the combined chronic toxicity/carcinogenicity study (according to OECD 453 and in compliance with GLP) male and female Fischer 344 rats were fed with OPP at dietary levels of 39, 200, and 402 mg/kg bw/day (males) or 49, 248, and 647 mg/kg bw/day (females), respectively. There was no toxicological effect noted after chronic treatment with OPP in females at any dose level or in males of the low dose group. In males treated with 200 mg/kg bw and above, structural alterations in the urinary bladder and kidney were observed. Thus, a NOAEL of 39 mg/kg bw/day and a LOAEL of 200 mg/kg bw/day were derived from this study (Wahle, B.S. and Christenson, W.R., 1996; Wahle, B.S. and Christenson, W.R., 1999; Wahle, B.S. et al., 1997 and Bomhard, E. M. et al., 2002).

In the second combined chronic toxicity/carcinogenicity study (according to OECD 453 and in compliance with GLP) male and female B6C3F1 mice were fed with OPP at dietary levels of 250, 500 or 1000 mg/kg bw. Systemic toxicity was noted as decreased body weight gain throughout the study and an increase in absolute and relative liver weights at 12 and 24 months in all treated males and females. Additionally, a dose-related increase of microvacuolation in the tubular epithelial cells of the kidney cortex together with an increased incidence and severity of degeneration and decreased regeneration of their tubules was noted at 12 and 24 months in males. Mice did not develop any treatment-related effects in the urinary bladder. An increased incidence of liver adenoma, carcinoma and hepatoblastoma was observed in male mice at 500 mg/kg bw/day and 1000 mg/kg bw/day. The NOAEL for systemic toxicity in mice was <250 mg/kg bw/day, whereas the NOAEL for tumours was 250 mg/kg bw/day (Quast, J.F. and McGuirk, R.J., 1995 and Bomhard, E. M. et al., 2002).

In the subchronic repeated dose toxicity study in dogs (1-year gavage) the NOAEL was set at ≥300 mg/kg bw/day, based on increased emesis with respect to the controls at highest doses. The emesis observed at 300 mg/kg bw/day was categorised as a local transitory response of the upper alimentary duct and no adverse toxicological effects were observed in comprehensive examinations (Cosse, P.F. et al., 1990 and Bomhard, E. M. et al., 2002).

In the subacute dermal repeated dose toxicity study (according to OECD 410 and in compliance with GLP) male and female Fischer 344 rats were treated with the test item OPP at doses of 100, 500 or 1000 mg/kg by dermal application once daily, 5 days per week for a total of 15 applications over 21 days. There were no changes in any parameter evaluated indicative of systemic toxicity associated with the administration of OPP in any of the animals treated. The only toxicological effect noted comprised slight alterations of the skin at the applications site in both males and females at 500 mg/kg bw/day and above. These alterations were consistent with the diagnosis of local irritation (erythema and scaling) of the skin. No dermal alterations were observed in rats administered 100 mg/kg bw/day or the vehicle alone. Thus, a NOAEL of ≥1000 mg/kg bw/day can be deduced for systemic toxicity

 

Repeated-dose toxicity – systemic effects – inhalation route – worker:

The DNEL for systemic effects via inhalation is determined on the basis of route-to-route extrapolation from an oral OECD 453 combined chronic toxicity/carcinogenicity study in rats (Wahle, B.S. and Christenson, W.R., 1996; Wahle, B.S. and Christenson, W.R., 1999; Wahle, B.S. et al., 1997 and Bomhard, E. M. et al., 2002). In contrast to the recommendations of the ECHA Guidance, a factor of 1 (equal absorption of 100% assumed for the oral and the inhalation route for animals and humans) was included for the extrapolation from oral to inhalation absorption based on the available data. As shown by McNett et al. (1997, Section5.1), OPP is rapidly bioavailable after oral dosing. The data obtained from studies with rats and mice indicate a fast and complete absorption of OPP via the gastrointestinal tract as 97 and 105% of the administered radiolabeled OPP were recovered after 24 and 48 h, respectively. Thus, equal absorption of OPP after inhalation and oral ingestion is estimated and using the factor of 1 for route-to-route extrapolation is appropriate.

In this study a NOAEL of 39 mg/kg bw/day was derived.

 

The following correction was made to the NOAEL:

No correction for relative absorption oral vs. inhalation.

Correction for number of exposures per week: 7 days/week in animal study versus 5 days/week for workers

Correction for respiratory volume (rat/worker): 0.38 m³/kg bw (8 h)

Correction for respiratory volume (worker, light physical activity): 6.7 m³/10 m³

 

Therefore, the corrected NOAEC for repeated-dose systemic effects via inhalation is:

39 mg/kg bw/day×(7d/5d) ×1/(0.38 m³/kg bw)×(6.7 m³/10 m³) = 96.27 mg/m³/day

 

The following assessment factors were applied to the corrected NOAEC:

Interspecies differences (toxicodynamics): 1 [specific assessment factor (for details see justification below)]

Intraspecies differences (worker): 5 [default value (ECHA)]

 

Total AF: 1×5 = 5

 

The overall DNEL (repeated-dose – systemic – inhalation – worker) is therefore:

96.27 mg/m³/day / 5 = 19.25 mg/m³/day

 

Remark:
Recently an OEL of 5 mg/m³ was established in Germany by the DFG MAK Commission for OPP. This OEL that is defined by an independent expert committee covers systemic and local effects after inhalation exposure and is used as a representative toxicological threshold for long term local effects. Exposure peaks are limited at the DFG MAK OEL to a factor of 1. Therefore, in line with this assessment the representative toxicological threshold for acute/short term local effects is defined as 5 mg/m³.

 

Repeated-dose toxicity – systemic effects – dermal route – worker:

The DNEL for systemic effects via dermal route can be determined following two different approaches: either by using the available data from a subacute repeated dose toxicity study via the dermal route or by means of route-to-route extrapolation using the available data from a chronic repeated dose toxicity study via the oral route.

1. The DNEL for systemic effects via dermal route is determined on the basis of the subacute dermal OECD 410 repeated dose toxicity study in rats:

 

No corrections were made to the NOAEL of ≥1000 mg/kg bw/day.

 

The following assessment factors were applied to the systemic NOAEL:

Exposure duration (subacute to chronic): 6 [default value (ECHA)]

Interspecies differences (toxicodynamics): 1 [specific assessment factor (for details see justification below)]

Interspecies differences (toxicokinetics, rat/human): 1 [specific assessment factor (for details see justification below)]

Intraspecies differences (worker): 5 [default value (ECHA)]

 

Total AF: 6×5 = 30

 

The overall DNEL (repeated-dose – systemic – dermal – worker) is therefore:

1000 mg/kg bw/day / 30 = 33.3 mg/kg bw/day.

 

2. The DNEL for systemic effects via dermal route is determined by means of route-to-route extrapolation using the available data from a chronic oral OECD 453 combined repeated dose toxicity / carcinogenicity study in rats. The NOAEL derived from this study is 39 mg/kg bw/day.

Data are available on dermal absorption in man, indicating that approximately 50% of the applied dose is rapidly absorbed via human skin.

 

The following correction was made to the NOAEL:

Correction of absorption rates: dermal absorption ≈ 50%, oral absorption ≈ 100%

Correction for number of exposures per week: 7 days/week in animal study versus 5 days/week for workers

 

Therefore, the corrected NOAEL for repeated-dose systemic effects via dermal exposure is:

39 mg/kg bw/day×(7d/5d)×(100%/50%) = 109.2 mg/kg bw/day

 

The following assessment factors were applied to the corrected NOAEL:

Interspecies differences (toxicodynamics): 1 [specific assessment factor (for details see justification below)]

Interspecies differences (toxicokinetics, rat/human): 1 [specific assessment factor (for details see justification below)]

Intraspecies differences (worker): 5 [default value (ECHA)]

 

Total AF: 1×1×5 = 5

 

The overall DNEL (repeated-dose – systemic – dermal – worker) is therefore:

109.2 mg/kg bw/day / 5 = 21.84 mg/kg bw/day

 

The second approach, deriving the DNEL by means of route-to-route extrapolation from repeated dose toxicity data after chronic oral exposure revealed a stricter DNEL as compared to the first approach, taking the subacute dermal repeated dose toxicity study as a basis. The DNEL derived from the chronic oral study is more reliable, as measured data are available for the route-to-route extrapolation, whereas DNEL derivation from the subacute dermal study necessitates time extrapolation using default values, which is more a rough estimate rather than reflecting realistic conditions. Moreover, no LOAEL could be deduced from the subacute dermal study; the NOAEL deduced was set at the high dose. Therefore, in contrast to the oral study, no real threshold value for systemic toxicity could be identified from the dermal study. Thus, a DNEL of 21.84 mg/kg bw/day derived from the chronic oral OECD 453 study in rats will be used for risk assessment.

 

Justification for application of specific assessment factors:

An assessment factor of 1 for interspecies differences (toxicokinetics, rat/human) was applied, because there are high quality data available investigating the toxicokinetic behaviour of OPP in both rodents and man (Bartels, M. J. et al., 1997; Selim, S., 1996 and Bomhard, E. M. et al., 2002). These data indicate that toxicokinetics of OPP are comparable in rats, mice and human volunteers: independent on the species tested, OPP was rapidly taken up, metabolised, and eliminated via the renal pathway. Metabolism of OPP at concentrations relevant for human exposure followed the same principles in both rodents and man, comprising above all of sulfation, followed by glucoronidation, conjugation of PHQ, and sulphate conjugation of DHB. Thus, due to comparable metabolism and formation of the same breakdown products, elimination of these metabolites is comparable in rats, mice, and humans, too. Renal elimination was rapid in all species tested, and the bioaccumulation potential of OPP is even less in man as compared to rodents. Thus, it can be concluded that application of an assessment factor of 1 for interspecies differences (toxicokinetics, rat/human) is appropriate, as there is a comparable toxicokinetic behaviour of OPP in rats, mice and man.

An assessment factor of 1 for interspecies differences (toxicodynamics) was applied, because there are high quality data available for three different species, including two rodent species (rat, mouse) and one non-rodent species (dog). Out of all these data, the effect level deduced from the study with the most severe outcome and, thus, the species with the highest sensitivity was used to derive the DNELs. Thus, interspecies differences were already taken into account when selecting the starting point for DNEL derivation.

There is further evidence that association between intra- and interspecies assessment factors is conservative and that the inclusion of a remaining difference factor is only necessary under rare circumstances. ECETOC (2003) analyzed the available data of Freireich, E. et al. (1966), Schein, P. et al. (1979), and Watanabe, K. et al. (1992) and concluded that apart from allometric scaling there is the likelihood of additional variability around the extrapolated dose or predicted NOAEL in humans. However, this additional variability is probably due not only to possible differences in biological sensitivity between species, but also to intraspecies differences. Apart from these aspects, one also has to consider the different endpoints (maximum tolerated dose – MTD - versus toxic dose low - TDL) used for the evaluation of human and animal data. Thus, it is evident that the comparison of ‘toxic doses’ across species is actually a comparison between doses that cause ‘dose-limiting’ toxicity (MTDH) in a sensitive subpopulation of humans (health-compromised, cancer patients) at one extreme and lethality in 10% of the population of otherwise assumed healthy animals (lethal dose - LD10) at the other. This will overestimate the sensitivity of humans in relation to other species, but to an extent which is unquantifiable. As a consequence, the adjustment of interspecies AF to account for the differences noted in such analyses is scientifically questionable. Therefore, although residual interspecies variability may remain following allometric scaling, this is largely accounted for in the default assessment factor proposed for intraspecies variability reflecting the inherent interdependency of inter- and intraspecies factors (ECETOC, 2003). Therefore, a separate residual AF for interspecies is unnecessary because it is already accounted for by the intraspecies assessment factor (Calabrese, E.J., 1985; Hattis, D. et al, 1987).

The assumption is further supported by a publication of the Fraunhofer Institute for Toxicology and Experimental Medicine in cooperation with BASF Personal Care and Nutrition GmbH. Within this publication large datasets of repeated dose toxicity studies were evaluated to derive a scientifically sound assessment factor for interspecies extrapolation. It was shown that, despite the factor for allometric scaling, no additional factor for interspecies differences is required (Escher, S.E. et al., 2013). Based on this newly available scientific evaluation of repeated dose toxicity studies the used interspecies factor of 1 is further supported.

 

References:

Calabrese, E.J. (1985). Uncertainty factors and interindividual variation. Regul Toxicol Pharmacol 5:190-196

ECETOC (2003). Guidance on Assessment Factors to Derive a DNEL. Technical Report No. 110. Brussels, October 2010

Escher, S.E. et al.(2013). Interspecies extrapolation based on the RepDose database - A probabilistic approach. Toxicology Letters 218(2):159-165.

Freireich, E. et al. (1996). Quantitative comparison of toxicity of anticancer agents in mose, rat, hamster, dog, monkey, and man. Canc Chemotherap Res 50:219-245.

Hattis, D. et al. (1987). Human variability in susceptibility to toxic chemicals: a preliminary analysis of pharmacokinetic data from normal volunteers. Risk Anal 7:415-426.

Schein, P. et al. (1979). The evaluation of anticancer drugs in dogs and monkeys for the prediction of qualitative toxicities in humans. Clin Pharmacol Therap 11:3-40.

Watanabe, K. et al. (1992). Interspezies extrapolation: a re-examination of acute toxicity data. Risk Anal 12:301-310.

 

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
other toxicological threshold
Value:
1.2 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
irritation (respiratory tract)
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
other toxicological threshold
Value:
0.4 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
Acute/short term exposure
Hazard assessment conclusion:
no DNEL required: short term exposure controlled by conditions for long-term
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
other toxicological threshold
Value:
0.4 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium hazard (no threshold derived)

Additional information - General Population

Based on the chronic oral OECD 453 study with 2-phenylphenol (OPP) various regulatory bodies [e.g. FAO/WHO (1999), EFSA (2008) and US EPA (2006)] have proposed an acceptable daily intake (ADI) of 0.4 mg/kg bw/day.

This ADI is taken forward as a "toxicological threshold” for system long-term oral exposure for the general population.

 

The oral ADI of 0.4 mg/kg bw/day is also taken forward as a conservative toxicological threshold for system long-term dermal exposure for the general population. This toxicological threshold is considered conservative, because compound specific data discussed in the worker section for DNEL derivation are not taken into account (e.g. dermal/oral absorption; toxicokinetic aspects, ...).

 

A conservative toxicological threshold for system long-term inhalation exposure for the general population can be derived taking into account the oral ADI of 0.4 mg/kg bw/day as a starting point, a body weight of 60 kg and a respiratory volume of 20 m3/day.

The calculated toxicological threshold for system long-term inhalation exposure is:

0.4 mg/kg bw/day × 60 kg bw / 20 m3/day = 1.2 mg/m3.

 

Overall:

The available oral ADI for 2-phenylphenol (OPP) is taken as a conservative starting point for the derivation of a toxicological threshold for system long-term dermal and inhalation exposure for the general population. Compound specific data discussed in the worker section are not taken into account (e.g. dermal/oral absorption; toxicokinetic aspects, …) leading to very conservative toxicological thresholds.