Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
5.88 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
Overall assessment factor (AF):
15
Modified dose descriptor starting point:
NOAEC
DNEL value:
88.2 mg/m³
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:
3.33 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Dermal
DNEL related information
Overall assessment factor (AF):
60
Modified dose descriptor starting point:
NOAEL
DNEL value:
200 mg/kg bw/day
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

Selection of the relevant dose descriptor (starting point): 

The basis of the derived systemic inhalative DNELs for 4-methoxybenzaldehyde formed the available key study for repeated dose toxicity, i.e. a subchronic repeated dose toxicity study in rats (OECD TG 408, GLP, BASF 2018; 50C0538/11S273).

Adverse and test substance related effects consisted of a decrease in absolute and relative eosinophil counts and lower total protein values in rats of both sexes of the 500 mg/kg bw/d dose group and additionally higher glucose levels in males are due to a chronic stress situation among these individuals. A drop in the mean urine pH values (from pH 6.0 to pH 5.6 in males and from pH 5.9 to pH 5.5 in females) potentially causing precipitation of crystals was observed. This finding supports the disproportionate increase of endogenous anisic acid due to overwhelmed elimination pathways.

In high dose males (500 mg/kg bw/d), sperm parameters (motility of the sperms, sperm head counts, incidence of abnormal sperms in the cauda epididymidis) were adversely affected, epididymides weights were decreased and histopathology of the epididymis revealed a ductal atrophy at the distal corpus and proximal cauda, associated with oligospermia.

Under the conditions of this study the oral administration of 4-methoxybenzaldehyde by gavage to Wistar rats over a period of 3 months revealed adverse signs of toxicity at a dose level of 500 mg/kg bw/d in male and female animals taking clinical pathology and pathology findings into account. Thus, the no observed adverse effect level (NOAEL) for was set to 100 mg/kg bw/d in male and female Wistar rats.

 

In a combined repeat dose and reproductive/developmental toxicity screening test (OECD TG 422, GLP, Japan Chemicals Investigation Promoting Council, 2001), 4-methoxybenzaldehyde, was administered orally (gavage) to male and female Sprague-Dawley rats at doses of 0 (vehicle), 20, 100 and 500 mg/kg bw/d in corn oil. Local irritating test substance related effects were transient salivation at 500 mg/kg bw/d, increases in food consumption in males and females at 500 mg/kg bw/d, increases in body weights in females at 100 mg/kg bw/d during lactation and at 500 mg/kg bw/d during gestation and lactation and hyperplasia of squamous epithelium in the forestomach at 100 and 500 mg/kg bw/d.

Substance related systemic effects were increased A/G ratio, GOT activity and inorganic phosphorus concentration in males, whereas increased glucose levels and decreased calcium levels have been observed in females at 500 mg/kg bw/d. Increased absolute/relative liver weights and centrilobular hypertrophy of hepatocytes has been observed for both sexes at 500 mg/kg bw/d. Overall, these findings indicate a test substance related effect on the liver.

Concerning reproduction toxicity effects, the number of pregnant dams and the respective fertility index was significantly decreased and the number of pups born, liveborns and live pups at day 4 of lactation per litter was affected at 500 mg/kg bw/d.

From these test results, under the conditions of this study, the no observed effect level (NOEL) for parental toxicity is set at 20 mg/kg/day and the stomach (local irritative effects at 100 mg/kg bw/d) and the liver (systemic effects at 500 mg/kg bw/d) represent target organs after oral (gavage) administration of 4-methoxybenzaldehyde. The no observed effect level (NOEL) for fertility and/or developmental toxicity is to be set at 100 mg/kg/day.

 

As a support for the derivation of the systemic dermal DNELs for 4-methoxybenzaldehyde, a 14-day percutaneous study in rats (with a gavage study extension, including an evaluation of the toxicokinetics the test substance, RIFM, 2011) has been used. At 1000 mg/kg/day, body weight gains in male rats were reduced. Apart from this, only adverse skin reactions were observed at the test side after substance application. From these test results, the systemic no observed adverse effect level (NOAEL) for dermal subacute repeated dose toxicity was set at 500 mg/kg/day. The NOAEL for local effects (i.e. skin irritation) was set at 100 mg/kg bw/d.

 

Route to route extrapolation:

No experimental data on absorption of 4-methoxybenzaldehyde are available. Based on the physicochemical properties, 4-methoxybenzaldehyde is considered to become readily bioavailable via the dermal and oral route. However, in a comparative toxicokinetic study, plasma levels of the metabolite anisic acid was found to be 10-100 fold lower after dermal application compared to oral application at comparable doses. Levels of anisic acid glycine conjugates (i.e. a saturable metabolisation process) were comparable. Although no full balancing (by determining all elimination routes of the parent compound /metabolites) was performed to quantitatively compare the uptake of the test substance between the oral and the dermal route, the difference in the key metabolite anisic acid indicates higher uptake via the oral route.

On the basis of the low vapour pressure, the exposure with 4-methoxybenzaldehyde via inhalation as a vapour is low. According to Chapter R.8 of REACH Guidance on information requirements and chemical safety assessment, it is proposed in the absence of route-specific information to include a default factor in the case of inhalation-to-oral extrapolation, assuming 50% oral and 100% inhalation absorption. Based on the indications given by experimental data a default factor of 2 for oral-to-dermal extrapolation, assuming 100% oral and 50% dermal absorption is used for the DNEL derivation.

 

Workers – Hazard via inhalation route

Long term, systemic inhalation DNEL

For derivation of the long-term systemic inhalative DNEL for 4-methoxybenzaldehyde, the oral systemic no adverse effect level of the subchronic repeated dose toxicity study (100 mg/kg bw/d) was taken as a basis and converted into a corrected inhalative NOAEC of 88.2 mg/m3 according to the procedure, recommended in the current guidance document (R8, ECHA 2008). Applying all assessment factors, the inhalative long-term systemic DNEL was set at 5.88 mg/m3 for the worker.

 

Long-term – inhalation, systemic effects

Description

Value

Remark

Step 1) Relevant dose-descriptor

NOAEL: 100 mg/kg bw/day

Subchronic repeated dose toxicity study in rats, oral (OECD 408)

Step 2) Modification of starting point

50%/100%

 

0.38 m3/kg bw

 

6.7 m3/10 m3

 

Ratio of oral (rat) to inhalation (human) absorption (default value, as proposed in the REACH guidance (R.8.4.2)

 

Standard respiratory volume of a rat, corrected for 8 h exposure, as proposed in the REACH Guidance (R.8.4.2)

 

Correction for activity driven differences of respiratory volumes in workers compared to workers in rest (6.7 m3/10 m3).

Modified dose-descriptor

NOAEC corrected inhalative = 100 * (50/100) * (1/0.38) * (6.7/10) = 88.2 mg/m3

Step 3) Assessment factors

 

 

Allometric scaling

1

No allometric scaling has to be applied in case of oral to inhalation route to route extrapolation according to R8 ECHA 2008.

Remaining differences

2.5

No evident differences in the formation of the metabolite anisic acid was observed in rat or human hepatocytes, which is considered as possible mode of action of the adverse systemic effects observed in the reproductive screening study. Therefore, additional toxicokinetic differences besides allometry between rats and humans are not expected.

Within the ERASM project, using repeated dose toxicity studies from a large database (RepDose database) to determine interspecies differences for rats and mice, it was found, that species are on average equally sensitive to equipotent doses, if doses are related to energy turnover. An animal to human interspecies extrapolation distribution with a geometric mean identical to the allometric scaling factor (e.g. 4 rat/human, 7 mouse/human) for body doses (e.g. gavage studies) was identified and a factor of 1 for doses in ppm or mg/m3 (e.g. uptake via food, drinking water or inhalation), without an additional factor of 2.5 for putative toxicodynamic differences was proposed (Escher et al., 2013, Toxicology Letters 218; 159-165). 

In case of any ‘residual’ interspecies variability that may theoretically remain following allometric scaling, this is largely accounted for in the assessment factors proposed for intraspecies variability, i.e. reflecting the interdependency of inter- and intraspecies assessment factors (see also Calabrese et al., 1993, Regul. Toxicol. Pharmacol. 17: 44-51).  

However, the default assessment factor for remaining differenes (acc. to ECHA GD R8) will be been applied until additional substance specific data are available to better assess a potential higher toxicodynamic sensitivity of humans. Further mechanistic studies are initiated in order to elucidate the mode of action and the human relevance of the sperm and epididymides effects observed in the rat (see Chapter "Reproductive Toxicity").

Intraspecies

3

An AF of 3/5 has been included to cover for remaining uncertainties of putative subpopulations, based on the following assessment.

In an attempt to evaluate the intraspecies variability within the human population, the distribution of human data for various toxicokinetic and toxicodynamic parameters were examined (Hattis et al. 1987, 1999; Hattis and Silver 1994; Renwick and Lazarus, 1998; see ECETOC TR No.86, 2003). These evaluations included data from ‘healthy adults’ of both sexes, as well as limited data from the young and elderly, mixed races and patients with various medical conditions such as cancer and hypertension. The data of Renwick and Lazarus (1998) and Hattis et al. (1999) were based exclusively on human data and similar values were obtained within each percentile. Considering that the data analysed by these authors included both sexes, a variety of disease states and ages, the use of the 95thpercentile is considered sufficiently conservative to account for intraspecies variability in the general population. Thus, a default assessment factor of 5 was taken for the general population with a lower factor of 3 (i.e. closer to the 90thpercentile) for the more homogenous worker population.

Exposure duration

2

Use of a subchronic study as starting point for long-term systemic DNEL derivation (default assessment factor according to R8 ECHA 2008)

Dose response

1

according to R8 ECHA 2008

Quality of database

1

according to R8 ECHA 2008 (GLP guideline Study)

DNEL

Value

 

88.2 / (1 x 2.5 x 3 x 2 x 1 x 1) = 5.88 mg/m3

 

Acute/short term, systemic and acute/short term and long term, local inhalation DNEL

The substance 4-methoxybenzaldehydeis not classified and labelled for acute systemic toxicity, according to Regulation (EC) No 1272/2008 (CLP), based on the test data for acute oral and dermal toxicity. Thus, no DNEL for systemic effects after acute inhalation exposure is required. Furthermore, the DNEL derived for systemic effects after long term inhalation exposure is considered sufficiently conservative to cover potential acute systemic and general local inhalation effects.

 

 

Workers - Hazard via dermal route

Long term, systemic dermal DNEL

For derivation of the long-term systemic dermal DNEL for 4-methoxybenzaldehyde, the oral systemic no adverse effect level of the subchronic repeated dose toxicity study (100 mg/kg bw/d) was taken as a basis and converted into a corrected dermal NOAEL of 200 mg/kg bw/d according to the procedure, recommended in the current guidance document (R8, ECHA 2008). This point of departure is supported by the dermal systemic no adverse effect level of 500 mg/kg bw/d derived from a subacute dermal repeated dose toxicity study in rats.

Applying all assessment factors, the dermal long-term systemic DNEL derived was 3.33 mg/kg bw/d for the worker.

Long-term – dermal, systemic effects 

Description

Value

Remark

Step 1) Relevant dose-descriptor

NOAEL: 100 mg/kg bw/day

Subchronic repeated dose toxicity study in rats, oral (OECD 408)

Step 2) Modification of starting point

Oral absorption rat = 100%           

Dermal absorption human = 50%

Modified Dose descriptor

 

Step 3) Assessment factors

NOAEL: 200 mg/kg bw/day

NOAEL corrected dermal = 100 * (100/50) = 200 mg/kg bw/d

Allometric scaling

4

Assessment factor for allometric scaling according to R8 ECHA 2008

Remaining differences

2.5

No evident differences in the formation of the metabolite anisic acid was observed in rat or human hepatocytes, which is considered as possible mode of action of the adverse systemic effects observed in the reproductive screening study. Therefore, additional toxicokinetic differences besides allometry between rats and humans are not expected.

Within the ERASM project, using repeated dose toxicity studies from a large database (RepDose database) to determine interspecies differences for rats and mice, it was found, that species are on average equally sensitive to equipotent doses, if doses are related to energy turnover. An animal to human interspecies extrapolation distribution with a geometric mean identical to the allometric scaling factor (e.g. 4 rat/human, 7 mouse/human) for body doses (e.g. gavage studies) was identified and a factor of 1 for doses in ppm or mg/m3(e.g. uptake via food, drinking water or inhalation), without an additional factor of 2.5 for putative toxicodynamic differences was proposed (Escher et al., 2013, Toxicology Letters 218; 159-165). 

In case of any ‘residual’ interspecies variability that may theoretically remain following allometric scaling, this is largely accounted for in the assessment factors proposed for intraspecies variability, i.e. reflecting the interdependency of inter- and intraspecies assessment factors (see also Calabrese et al., 1993, Regul. Toxicol. Pharmacol. 17: 44-51).  

However, the default assessment factor for remaining differenes (acc. to ECHA GD R8) will be been applied until additional substance specific data are available to better assess a potential higher toxicodynamic sensitivity of humans. Further mechanistic studies are initiated in order to elucidate the mode of action and the human relevance of the sperm and epididymides effects observed in the rat (see Chapter "Reproductive Toxicity").

Intraspecies

3

An AF of 3/5 has been included to cover for remaining uncertainties of putative subpopulations, based on the following assessment.

In an attempt to evaluate the intraspecies variability within the human population, the distribution of human data for various toxicokinetic and toxicodynamic parameters were examined (Hattis et al. 1987, 1999; Hattis and Silver 1994; Renwick and Lazarus, 1998; see ECETOC TR No.86, 2003). These evaluations included data from ‘healthy adults’ of both sexes, as well as limited data from the young and elderly, mixed races and patients with various medical conditions such as cancer and hypertension. The data of Renwick and Lazarus (1998) and Hattis et al. (1999) were based exclusively on human data and similar values were obtained within each percentile. Considering that the data analysed by these authors included both sexes, a variety of disease states and ages, the use of the 95thpercentile is considered sufficiently conservative to account for intraspecies variability in the general population. Thus, a default assessment factor of 5 was taken for the general population with a lower factor of 3 (i.e. closer to the 90thpercentile) for the more homogenous worker population.

Exposure duration

2

Use of a subchronic study as starting point for long-term systemic DNEL derivation (default assessment factor according to R8 ECHA 2008)

Dose response

1

according to R8 ECHA 2008

Quality of database

1

according to R8 ECHA 2008

DNEL

Value

 

200 / (4 x 2.5 x 3 x 2 x 1 x 1) = 3.33 mg/kg bw/day

 

 

Acute/short-term systemic dermal DNEL 

The substance 4-methoxybenzaldehydeis not classified and labelled for acute systemic toxicity, according to Regulation (EC) No 1272/2008 (CLP), based on the test data for acute oral and dermal toxicity. Thus, no DNEL for sytemic effects after acute dermal exposure is required. Furthermore, the DNEL derived for systemic effects after long term dermal exposure is considered sufficiently conservative to cover potential acute systemic dermal effects.

Acute/short-term and Long term local dermal DNEL

The substance 4-methoxybenzaldehydeis not classified and labelled for skin/ eye irritation or skin sensitization, according to Regulation (EC) No 1272/2008 (CLP), based on the test data available. Thus, a derivation of a DNEL for local effects after acute/long-term dermal exposure is not indicated. Furthermore, the DNEL derived for systemic effects after long term dermal exposure is considered sufficiently conservative to cover potential local dermal effects. The local NOAEL (100 mg/kg bw/d) of the subacute dermal toxicity study in rats confirms the point of departure chosen for the respective DNEL.

 

Worker - Hazard for the eyes

The substance 4-methoxybenzaldehydeis not classified and labelled for eye irritation according to Regulation (EC) No 1272/2008 (CLP), based on the test data available. Thus, no hazard for the eyes was identified.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.74 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
Overall assessment factor (AF):
25
Modified dose descriptor starting point:
NOAEC
DNEL value:
43.5 mg/m³
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:
DNEL (Derived No Effect Level)
Value:
2 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
Overall assessment factor (AF):
100
Modified dose descriptor starting point:
NOAEL
DNEL value:
200 mg/kg bw/day
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:
1 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
Overall assessment factor (AF):
100
Modified dose descriptor starting point:
NOAEL
DNEL value:
100 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

Selection of the relevant dose descriptor (starting point): 

The basis of the derived systemic inhalative DNELs for 4-methoxybenzaldehyde formed the available key study for repeated dose toxicity, i.e. a subchronic repeated dose toxicity study in rats (OECD TG 408, GLP, BASF 2018; 50C0538/11S273).

Adverse and test substance related effects consisted of a decrease in absolute and relative eosinophil counts and lower total protein values in rats of both sexes of the 500 mg/kg bw/d dose group and additionally higher glucose levels in males are due to a chronic stress situation among these individuals. A drop in the mean urine pH values (from pH 6.0 to pH 5.6 in males and from pH 5.9 to pH 5.5 in females) potentially causing precipitation of crystals was observed. This finding supports the disproportionate increase of endogenous anisic acid due to overwhelmed elimination pathways.

In high dose males (500 mg/kg bw/d), sperm parameters (motility of the sperms, sperm head counts, incidence of abnormal sperms in the cauda epididymidis) were adversely affected, epididymides weights were decreased and histopathology of the epididymis revealed a ductal atrophy at the distal corpus and proximal cauda, associated with oligospermia.

Under the conditions of this study the oral administration of 4-methoxybenzaldehyde by gavage to Wistar rats over a period of 3 months revealed adverse signs of toxicity at a dose level of 500 mg/kg bw/d in male and female animals taking clinical pathology and pathology findings into account. Thus, the no observed adverse effect level (NOAEL) for was set to 100 mg/kg bw/d in male and female Wistar rats.

 

In a combined repeat dose and reproductive/developmental toxicity screening test (OECD TG 422, GLP, Japan Chemicals Investigation Promoting Council, 2001), 4-methoxybenzaldehyde, was administered orally (gavage) to male and female Sprague-Dawley rats at doses of 0 (vehicle), 20, 100 and 500 mg/kg bw/d in corn oil. Local irritating test substance related effects were transient salivation at 500 mg/kg bw/d, increases in food consumption in males and females at 500 mg/kg bw/d, increases in body weights in females at 100 mg/kg bw/d during lactation and at 500 mg/kg bw/d during gestation and lactation and hyperplasia of squamous epithelium in the forestomach at 100 and 500 mg/kg bw/d.

Substance related systemic effects were increased A/G ratio, GOT activity and inorganic phosphorus concentration in males, whereas increased glucose levels and decreased calcium levels have been observed in females at 500 mg/kg bw/d. Increased absolute/relative liver weights and centrilobular hypertrophy of hepatocytes has been observed for both sexes at 500 mg/kg bw/d. Overall, these findings indicate a test substance related effect on the liver.

Concerning reproduction toxicity effects, the number of pregnant dams and the respective fertility index was significantly decreased and the number of pups born, liveborns and live pups at day 4 of lactation per litter was affected at 500 mg/kg bw/d.

From these test results, under the conditions of this study, the no observed effect level (NOEL) for parental toxicity is set at 20 mg/kg/day and the stomach (local irritative effects at 100 mg/kg bw/d) and the liver (systemic effects at 500 mg/kg bw/d) represent target organs after oral (gavage) administration of 4-methoxybenzaldehyde. The no observed effect level (NOEL) for fertility and/or developmental toxicity is to be set at 100 mg/kg/day.

 

As a support for the derivation of the systemic dermal DNELs for 4-methoxybenzaldehyde, a 14-day percutaneous study in rats (with a gavage study extension, including an evaluation of the toxicokinetics the test substance, RIFM, 2011) has been used. At 1000 mg/kg/day, body weight gains in male rats were reduced. Apart from this, only adverse skin reactions were observed at the test side after substance application. From these test results, the systemic no observed adverse effect level (NOAEL) for dermal subacute repeated dose toxicity was set at 500 mg/kg/day. The NOAEL for local effects (i.e. skin irritation) was set at 100 mg/kg bw/d.

 

Route to route extrapolation:

 

No experimental data on absorption of 4-methoxybenzaldehyde are available. Based on the physicochemical properties, 4-methoxybenzaldehyde is considered to become readily bioavailable via the dermal and oral route. However, in a comparative toxicokinetic study, plasma levels of the metabolite anisic acid was found to be 10-100 fold lower after dermal application compared to oral application at comparable doses. Levels of anisic acid glycine conjugates (i.e. a saturable metabolisation process) were comparable. Although no full balancing (by determining all elimination routes of the parent compound /metabolites) was performed to quantitatively compare the uptake of the test substance between the oral and the dermal route, the difference in the key metabolite anisic acid indicates higher uptake via the oral route.

On the basis of the low vapour pressure, the exposure with 4-methoxybenzaldehyde via inhalation as a vapour is low. According to Chapter R.8 of REACH Guidance on information requirements and chemical safety assessment, it is proposed in the absence of route-specific information to include a default factor in the case of inhalation-to-oral extrapolation, assuming 50% oral and 100% inhalation absorption. Based on the indications given by experimental data a default factor of 2 for oral-to-dermal extrapolation, assuming 100% oral and 50% dermal absorption is used for the DNEL derivation.

  

 

General population – Hazard via inhalation route

Long term, systemic inhalation DNEL 

For derivation of the long-term systemic inhalative DNEL for 4-methoxybenzaldehyde, the oral systemic no adverse effect level of the subchronic repeated dose toxicity study (100 mg/kg bw/d) was taken as a basis and converted into a corrected inhalative NOAEC of 43.5 mg/m3 according to the procedure, recommended in the current guidance document (R8, ECHA 2008). Applying all assessment factors, the inhalative long-term systemic DNEL was set at 1.74 mg/m3 for the general population.

 

Long-term – inhalation, systemic effects

Description

Value

Remark

Step 1) Relevant dose-descriptor

NOAEL: 100 mg/kg bw/day

Subchronic repeated dose toxicity study in rats, oral (OECD 408)

Step 2) Modification of starting point

50%/100%

 

 

1.15 m3/kg bw

 

Ratio of oral (rat) to inhalation (human) absorption (default value, as proposed in the REACH guidance (R.8.4.2)

 

Standard respiratory volume of a rat, corrected for 24 h exposure, as proposed in the REACH Guidance (R.8.4.2)

Modified dose-descriptor

NOEC corrected inhalative = 100 * (50/100) * (1/1.15) = 43.5 mg/m3

Step 3) Assessment factors

 

 

Allometric scaling

1

No allometric scaling has to be applied in case of oral to inhalation route to route extrapolation according to R8 ECHA 2008.

Remaining differences

2.5

 No evident differences in the formation of the metabolite anisic acid was observed in rat or human hepatocytes, which is considered as possible mode of action of the adverse systemic effects observed in the reproductive screening study. Therefore, additional toxicokinetic differences besides allometry between rats and humans are not expected.

Within the ERASM project, using repeated dose toxicity studies from a large database (RepDose database) to determine interspecies differences for rats and mice, it was found, that species are on average equally sensitive to equipotent doses, if doses are related to energy turnover. An animal to human interspecies extrapolation distribution with a geometric mean identical to the allometric scaling factor (e.g. 4 rat/human, 7 mouse/human) for body doses (e.g. gavage studies) was identified and a factor of 1 for doses in ppm or mg/m3(e.g. uptake via food, drinking water or inhalation), without an additional factor of 2.5 for putative toxicodynamic differences was proposed (Escher et al., 2013, Toxicology Letters 218; 159-165). 

In case of any ‘residual’ interspecies variability that may theoretically remain following allometric scaling, this is largely accounted for in the assessment factors proposed for intraspecies variability, i.e. reflecting the interdependency of inter- and intraspecies assessment factors (see also Calabrese et al., 1993, Regul. Toxicol. Pharmacol. 17: 44-51).  

However, the default assessment factor for remaining differenes (acc. to ECHA GD R8) will be been applied until additional substance specific data are available to better assess a potential higher toxicodynamic sensitivity of humans. Further mechanistic studies are initiated in order to elucidate the mode of action and the human relevance of the sperm and epididymides effects observed in the rat (see Chapter "Reproductive Toxicity").

Intraspecies

5

An AF of 3/5 has been included to cover for remaining uncertainties of putative subpopulations, based on the following assessment.

In an attempt to evaluate the intraspecies variability within the human population, the distribution of human data for various toxicokinetic and toxicodynamic parameters were examined (Hattis et al. 1987, 1999; Hattis and Silver 1994; Renwick and Lazarus, 1998; see ECETOC TR No.86, 2003). These evaluations included data from ‘healthy adults’ of both sexes, as well as limited data from the young and elderly, mixed races and patients with various medical conditions such as cancer and hypertension. The data of Renwick and Lazarus (1998) and Hattis et al. (1999) were based exclusively on human data and similar values were obtained within each percentile. Considering that the data analysed by these authors included both sexes, a variety of disease states and ages, the use of the 95thpercentile is considered sufficiently conservative to account for intraspecies variability in the general population. Thus, a default assessment factor of 5 was taken for the general population with a lower factor of 3 (i.e. closer to the 90thpercentile) for the more homogenous worker population.

Exposure duration

2

Use of a subchronic study as starting point for long-term systemic DNEL derivation (default assessment factor according to R8 ECHA 2008)

Dose response

1

according to R8 ECHA 2008

Quality of database

1

according to R8 ECHA 2008 (GLP guideline Study)

DNEL

Value

 

43.5 / (1 x 2.5 x 5 x 2 x 1 x 1) = 1.74 mg/m3

 

Acute/short term, systemic and acute/short term and long term, local inhalation DNEL

The substance 4-methoxybenzaldehyde is not classified and labelled for acute systemic toxicity, according to Regulation (EC) No 1272/2008 (CLP), based on the test data for acute oral and dermal toxicity. Thus, no DNEL for systemic effects after acute inhalation exposure is required. Furthermore, the DNEL derived for systemic effects after long term inhalation exposure is considered sufficiently conservative to cover potential acute systemic and general local inhalation effects.

General population - Hazard via dermal route

Long term, systemic dermal DNEL

For derivation of the long-term systemic dermal DNEL for 4-methoxybenzaldehyde, the oral systemic no adverse effect level of the subchronic repeated dose toxicity study (100 mg/kg bw/d) was taken as a basis and converted into a corrected dermal NOAEL of 200 mg/kg bw/d according to the procedure, recommended in the current guidance document (R8, ECHA 2008). This point of departure is supported by the dermal systemic no adverse effect level of 500 mg/kg bw/d derived from a subacute dermal repeated dose toxicity study in rats.

Applying all assessment factors, the dermal long-term systemic DNEL derived was 2.0 mg/kg bw/d for the general population.

 

Long-term – dermal, systemic effects 

Description

Value

Remark

Step 1) Relevant dose-descriptor

NOAEL: 100 mg/kg bw/day

Subchronic repeated dose toxicity study in rats, oral (OECD 408)

Step 2) Modification of starting point

Oral absorption rat = 100%           

Dermal absorption human = 50%

Modified dose descriptor

Step 3) Assessment factors

NOAEL: 200 mg/kg bw/day

NOAEL corrected dermal = 100 * (100/50) = 200 mg/kg bw/d

Allometric scaling

4

Assessment factor for allometric scaling according to R8 ECHA 2008

Remaining differences

2.5

 

No evident differences in the formation of the metabolite anisic acid was observed in rat or human hepatocytes, which is considered as possible mode of action of the adverse systemic effects observed in the reproductive screening study. Therefore, additional toxicokinetic differences besides allometry between rats and humans are not expected.

Within the ERASM project, using repeated dose toxicity studies from a large database (RepDose database) to determine interspecies differences for rats and mice, it was found, that species are on average equally sensitive to equipotent doses, if doses are related to energy turnover. An animal to human interspecies extrapolation distribution with a geometric mean identical to the allometric scaling factor (e.g. 4 rat/human, 7 mouse/human) for body doses (e.g. gavage studies) was identified and a factor of 1 for doses in ppm or mg/m3(e.g. uptake via food, drinking water or inhalation), without an additional factor of 2.5 for putative toxicodynamic differences was proposed (Escher et al., 2013, Toxicology Letters 218; 159-165). 

In case of any ‘residual’ interspecies variability that may theoretically remain following allometric scaling, this is largely accounted for in the assessment factors proposed for intraspecies variability, i.e. reflecting the interdependency of inter- and intraspecies assessment factors (see also Calabrese et al., 1993, Regul. Toxicol. Pharmacol. 17: 44-51).  

However, the default assessment factor for remaining differenes (acc. to ECHA GD R8) will be been applied until additional substance specific data are available to better assess a potential higher toxicodynamic sensitivity of humans. Further mechanistic studies are initiated in order to elucidate the mode of action and the human relevance of the sperm and epididymides effects observed in the rat (see Chapter "Reproductive Toxicity").

Intraspecies

5

An AF of 3/5 has been included to cover for remaining uncertainties of putative subpopulations, based on the following assessment.

In an attempt to evaluate the intraspecies variability within the human population, the distribution of human data for various toxicokinetic and toxicodynamic parameters were examined (Hattis et al. 1987, 1999; Hattis and Silver 1994; Renwick and Lazarus, 1998; see ECETOC TR No.86, 2003). These evaluations included data from ‘healthy adults’ of both sexes, as well as limited data from the young and elderly, mixed races and patients with various medical conditions such as cancer and hypertension. The data of Renwick and Lazarus (1998) and Hattis et al. (1999) were based exclusively on human data and similar values were obtained within each percentile. Considering that the data analysed by these authors included both sexes, a variety of disease states and ages, the use of the 95thpercentile is considered sufficiently conservative to account for intraspecies variability in the general population. Thus, a default assessment factor of 5 was taken for the general population with a lower factor of 3 (i.e. closer to the 90thpercentile) for the more homogenous worker population.

Exposure duration

2

Use of a subchronic study as starting point for long-term systemic DNEL derivation (default assessment factor according to R8 ECHA 2008)

Dose response

1

according to R8 ECHA 2008

Quality of database

1

according to R8 ECHA 2008 (GLP guideline Study)

DNEL

Value

 

200 / (4 x 2.5 x 5 x 2 x 1 x 1) = 2.0 mg/kg bw/day

 

Acute/short-term systemic dermal DNEL 

The substance 4-methoxybenzaldehyde is not classified and labelled for acute systemic toxicity, according to Regulation (EC) No 1272/2008 (CLP), based on the test data for acute oral and dermal toxicity. Thus, no DNEL for sytemic effects after acute dermal exposure is required. Furthermore, the DNEL derived for systemic effects after long term dermal exposure is considered sufficiently conservative to cover potential acute systemic dermal effects.

Acute/short-term and Long term local dermal DNEL

The substance 4-methoxybenzaldehyde is not classified and labelled for skin/ eye irritation or skin sensitization, according to Regulation (EC) No 1272/2008 (CLP), based on the test data available. Thus, a derivation of a DNEL for local effects after acute/long-term dermal exposure is not indicated. Furthermore, the DNEL derived for systemic effects after long term dermal exposure is considered sufficiently conservative to cover potential local dermal effects. The local NOAEL (100 mg/kg bw/d) of the subacute dermal toxicity study in rats confirms the point of departure chosen for the respective DNEL.

General population - Hazard via oral route

Long term, systemic oral DNEL

For derivation of the long-term systemic oral DNEL of 4-methoxybenzaldehyde, the oral systemic no adverse effect level of the subchronic repeated dose toxicity study (100 mg/kg bw/d) was used. After applying the assessment factors, the oral long-term systemic DNEL was set at 1 mg/ kg bw/day for the general population.

 

Long-term – oral, systemic effects

Description

Value

Remark

Step 1) Relevant dose-descriptor

NOAEL: 100 mg/kg bw/day

Subchronic repeated dose toxicity study in rats, oral (OECD 408)

Step 2) Modification of starting point

-

-

Step 3) Assessment factors

 

 

Allometric scaling

4

Assessment factor for allometric scaling according to R8 ECHA 2008

Remaining differences

2.5

No evident differences in the formation of the metabolite anisic acid was observed in rat or human hepatocytes, which is considered as possible mode of action of the adverse systemic effects observed in the reproductive screening study. Therefore, additional toxicokinetic differences besides allometry between rats and humans are not expected.

Within the ERASM project, using repeated dose toxicity studies from a large database (RepDose database) to determine interspecies differences for rats and mice, it was found, that species are on average equally sensitive to equipotent doses, if doses are related to energy turnover. An animal to human interspecies extrapolation distribution with a geometric mean identical to the allometric scaling factor (e.g. 4 rat/human, 7 mouse/human) for body doses (e.g. gavage studies) was identified and a factor of 1 for doses in ppm or mg/m3(e.g. uptake via food, drinking water or inhalation), without an additional factor of 2.5 for putative toxicodynamic differences was proposed (Escher et al., 2013, Toxicology Letters 218; 159-165). 

In case of any ‘residual’ interspecies variability that may theoretically remain following allometric scaling, this is largely accounted for in the assessment factors proposed for intraspecies variability, i.e. reflecting the interdependency of inter- and intraspecies assessment factors (see also Calabrese et al., 1993, Regul. Toxicol. Pharmacol. 17: 44-51).  

However, the default assessment factor for remaining differenes (acc. to ECHA GD R8) will be been applied until additional substance specific data are available to better assess a potential higher toxicodynamic sensitivity of humans. Further mechanistic studies are initiated in order to elucidate the mode of action and the human relevance of the sperm and epididymides effects observed in the rat (see Chapter "Reproductive Toxicity").

Intraspecies

5

An AF of 3/5 has been included to cover for remaining uncertainties of putative subpopulations, based on the following assessment.

In an attempt to evaluate the intraspecies variability within the human population, the distribution of human data for various toxicokinetic and toxicodynamic parameters were examined (Hattis et al. 1987, 1999; Hattis and Silver 1994; Renwick and Lazarus, 1998; see ECETOC TR No.86, 2003). These evaluations included data from ‘healthy adults’ of both sexes, as well as limited data from the young and elderly, mixed races and patients with various medical conditions such as cancer and hypertension. The data of Renwick and Lazarus (1998) and Hattis et al. (1999) were based exclusively on human data and similar values were obtained within each percentile. Considering that the data analysed by these authors included both sexes, a variety of disease states and ages, the use of the 95thpercentile is considered sufficiently conservative to account for intraspecies variability in the general population. Thus, a default assessment factor of 5 was taken for the general population with a lower factor of 3 (i.e. closer to the 90thpercentile) for the more homogenous worker population.

Exposure duration

2

Use of a subchronic study as starting point for long-term systemic DNEL derivation (default assessment factor according to R8 ECHA 2008)

Dose response

1

according to R8 ECHA 2008

Quality of database

1

according to R8 ECHA 2008 (GLP guideline Study)

DNEL

Value

 

100 / (4 x 2.5 x 5 x 2 x 1 x 1) = 1 mg/kg bw/day

 

Acute/short-term systemic oral DNEL 

The substance 4-methoxybenzaldehyde is not classified and labelled for acute systemic toxicity, according to Regulation (EC) No 1272/2008 (CLP), based on the test data for acute oral and dermal toxicity. Thus, no DNEL for systemic effects after acute oral exposure is required. Furthermore, the DNEL derived for systemic effects after long term oral exposure is considered sufficiently conservative to cover potential acute systemic oral effects.

General population - Hazard for the eyes

The substance 4-methoxybenzaldehydeis not classified and labelled for eye irritation according to Regulation (EC) No 1272/2008 (CLP), based on the test data available. Thus, no hazard for the eyes was identified.