Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
23 mg/m³
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
70 mg/m³
DNEL related information

Local effects

Acute/short term exposure
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
5 mg/kg bw/day
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
15 mg/kg bw/day
DNEL related information

Workers - Hazard for the eyes

Additional information - workers

INTRODUCTORY NOTE

Monochlorobenzene is a colourless liquid with a mild aromatic odour. It has a MP of -45°C. BP of 132°C and a vapour pressure of 1.14 kPa at 20°C. The odour threshold is about 0.21 ppm (0.98 mg/m³, SCOEL 2001).

Oral ingested or inhaled monochlorobenzene cause mainly adverse effects on liver and kidneys. Male and female Fisher 344 rats or male and female B6C1F3 mice received by gavage 0, 60, 125, 250, 500 or 750 mg/kg bw/d diluted in corn oil 5 days a week over a period of 90 days resulting in a NOAEL for both species of ca 125 mg/kg bw/d. Prolongation of oral treatment up to 2 years resulted in an overall NOAEL(systemic) of 60 mg/kg bw (NTP 1985, SCOEL 2001).

With respect to the inhalation exposure route no reliable subchronic or chronic study in rats according to the respective guidelines are available. Therefore, a 2-generation reproductive study was taken as surrogate based on the exposure period comparable to subchronic studies In this study male and female CD rats were exposed 0, 50, 150 and 450 ppm (0, 234, 702 or 2106 mg/m³) 6 hours a day, 7 days a week until weaning of F2 pups resulting in a LOAEC (systemic) of 50 ppm due to significantly elevated absolute and relative liver weights in F0 and F1 male and female rats at 150 and 450 ppm and at 50 ppm in F1 males accompanied by hepatocellular hypertrophy in F0 and F1 males exposed to 150 and 450 ppm (Nair 1987)

WORKER

For workers the oral DNEL is not relevant and is therefore not applicable for monochlorobenzene. Only the dermal and inhalation route are regarded to be relevant in the case of monochlorobenzene and therefore the respective DNELs are derived

DNEL (systemic, long-term, inhalation)

LOAEC: 50 ppm (234 mg/m³) 6 hours a day and 7 days a week is taken as starting point

LOAEC 175.5 mg/m³/8h on 7 days

LOAEC 245.7 mg/m³/8h on 5 days

LOAEC to NOAEC 1

This factor was chosen because the LOAEC of 234 mg/m³ is based only on impaired relative liver weight in F1 male rats without histopathological correlate. No systemic effect at this concentration was reported in the P-Generation.

Subchronic to chronic: 2

NOAEC 122,85 mg/m³

Standard respiratory volume rat vs. worker respiratory volume: 6.7 m3/10m3= 0.67

NOAEC 82.31 mg/m³

For intraspecies differences in worker: 3*

For reliability of dose-response: 1

For quality of whole database: 1

Overall factor: 3

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ECETOC TR 110, 2010:Guidance on assessment factors to derive a DNEL

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calculated DNEL: 27.44 mg/m³/8h

Monochlorobenzene was evaluated by SCOEL (SCOEL/SUM/42; 2001). Based on all available data SCOEL selected the same point of departure (LOAEC 50 ppm) obtained in the previously discussed 2 -generation rat inhalation study and applied an uncertainity factor of 10 to allow for intra- and interspecies variation and for the absence of a NOAEL. Based on these considerations the committee recommended an indicative occupational exposure limit value (IOELV) of 5 ppm (23 mg/m³).

Since the calculated DNEL(systemic, long term, inhalation) is very close to the recently derived OEL by SCOEL, the SCOEL value of 23 mg/m³ (5 ppm) as 8 hour TWA is taken as DNEL (systemic, long term, inhalation).

Overall DNEL (systemic, long term, inhalation):= 23 mg/m³(5 ppm)

DNEL (systemic, long term, dermal application)

There is no repeated dose toxicity study available using the dermal route which could be taken into account. In such cases the Technical Guidance Document R8 (2008) proposes to consider a reliable oral study as surrogate, because it can be assumed that dermal absorption is not higher than oral absorption. Furthermore, this is the reason why it is not necessary to introduce a factor for the route to route extrapolation

The NOAEL of 60 mg/kg bw/day (NTP) derived from the 2 year oral repeated dose toxicity study in rats and mice was taken as a point of departure for the dermal DNEL calculation

For extrapolation from oral exposure to dermal exposure: 1

For interspecies differences rat vs. human: 4

For intraspecies differences in worker: 3*

For reliability of dose-response: 1

For quality of whole database: 1

Overall factor: 12

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*ECETOC TR 110, 2010:Guidance on assessment factors to derive a DNEL

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DNEL(systemic, long term, dermal). 5 mg/kg bw/day

DNEL (reproductive toxicity, fertility assessment)

In a two generation reproductive toxicity study, male and female CD rats were exposed 0, 50, 150 and 450 ppm (0, 234, 702 or 2106 mg/m³) 6 hours a day, 7 days a week. resulting in a LOAEL of 50 ppm due to impaired relative liver weight in F1 animals but no effect at this dose in the P-generation. Fertility was not affected by treatment with monochlorobenzene neither in P- nor in F1 generation. Thus the NOAEC (fertility) is 450 ppm = 2106 mg/m³.

As this NOAEC is higher than the LOAEC (systemic) of 50 ppm it can be assumed that the derived DNEL (systemic, long term, inhalation) covers also reproductive toxicity (fertility assessment)

DNEL (reproductive toxicity, developmental toxicity)

There are developmental toxicity studies in rats and rabbits similar to OECD TG 414 available in which animals were exposed up to 560 ppm (approximately 2761 mg/m³) 6 hours a day during the period of major organogenesis. Slight maternal toxicity (increased liver weights) in both species at the highest exposure level did not lead to developmental toxicity. Thus the NOAEL(developmental) in these studies is considered to be 560 ppm (2761 mg/m³).

As this NOAEC is higher than the LOAEC (systemic) of 50 ppm it can be assumed that the derived DNEL (systemic, long term, inhalation) covers also reproductive toxicity (fertility assessment)

DNEL (systemic, short term, inhalation or dermal)

DNEL (short term) should be derived if peak exposure can occur. Chlorobenzene is a liquid with a rather low vapour pressure of 1.14 kPa at 20 °C and it is explosive in the range 1.3 -7.1% in air (SCOEL 2001) Therefore DNEL (short term) has to be considered. For estimation purposes SCOEL(2001) proposes of short term peak exposure (STEL[15min]) an exceeding factor of 3.

Thus, the the respective values are

DNEL (systemic, short term, inhalation): 70 mg/m³ (15 ppm)

DNEL (systemic, short term, dermal): 15 mg/kg bw/day

Summary:

The Critical DNELs are

DNEL (systemic, inhalation, long term): 5 ppm (23 mg/m³)

DNEL (systemic, inhalation, short term): 15 ppm (70 mg/m³)

DNEL (systemic, dermal, long term): 5 mg/kg bw/day

DNEL (systemic dermal short term): 15 mg/kg bw

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1 mg/m³
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1 mg/m³
DNEL related information

Local effects

Acute/short term exposure
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
3 mg/kg bw/day
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
3 mg/kg bw/day
DNEL related information

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
3 mg/kg bw/day
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
3 mg/kg bw/day
DNEL related information

General Population - Hazard for the eyes

Additional information - General Population

INTRODUCTORY NOTE

Monochlorobenzene is a colourless liquid with a mild aromatic odour. It has a MP of -45°C.; BP of 132°C and a vapour pressure of 1.14 kPa at 20°C. The odour threshold is about 0.21 ppm (0.98 mg/m³, SCOEL 2001).

Oral ingested or inhaled monochlorobenzene cause mainly adverse effects on liver and kidneys. Male and female Fisher 344 rats or male and female B6C1F3 mice received by gavage 0, 60, 125, 250, 500 or 750 mg/kg bw/d diluted in corn oil 5 days a week over a period of 90 days resulting in a NOAEL for both species of ca 125 mg/kg bw/d. Prolongation of oral treatment up to 2 years resulted in an overall NOAEL(systemic) of 60 mg/kg bw (NTP 1985, SCOEL 2001).

With respect to the inhalation exposure route no reliable subchronic or chronic study in rats according to the respective guidelines are available. Therefore, a 2-generation reproductive study was taken as surrogate based on the exposure period comparable to subchronic studies In this study male and female CD rats were exposed 0, 50, 150 and 450 ppm (0, 234, 702 or 2106 mg/m³) 6 hours a day, 7 days a week until weaning of F2 pups resulting in a LOAEC (systemic) of 50 ppm due to significantly elevated absolute and relative liver weights in F0 and F1 male and female rats at 150 and 450 ppm and at 50 ppm in F1 males accompanied by hepatocellular hypertrophy in F0 and F1 males exposed to 150 and 450 ppm (Nair 1987)

DNEL DERIVATION (GENERAL PUBLIC)

DNEL (systemic, long term, oral route)

NOAEL 60 mg/kg bw/day

For interspecies differences rat vs human: 4

Additional uncertainty 1*

For intraspecies differences: 5**

For reliability of dose response: 1

For quality of the whole data base: 1

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* (no species difference was observed in comprehensive studies in rats and mice)

**ECETOC TR110, 2010: Guidance on Assessment Factors to derive DNELs

________________________________

Overall factor 20

Thus, the DNEL (systemic, long term, oral route): 3 mg/kg bw/day

DNEL (systemic, long term, dermal route)

There is no repeated dose toxicity study available using the dermal route which could be taken into account. In such cases the Technical Guidance Document R8 (2008) proposes to consider a reliable oral study as surrogate, because it can be assumed that dermal absorption is not higher than oral absorption. Furthermore, this is the reason why it is not necessary to introduce a factor for the route to route extrapolation

The NOAEL of 60 mg/kg bw/day (NTP) derived from the 2 year oral repeated dose toxicity study in rats and mice was taken as a point of departure for the dermal DNEL calculation

For extrapolation from oral exposure to dermal exposure: 1

Additional uncertainty 1*

For interspecies differences rat vs. human: 4

For intraspecies differences                5**

For reliability of dose-response: 1

For quality of whole database: 1

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* no species difference was observed in comprehensive studies in rats and mice

**ECETOC TR110, 2010: Guidance on Assessment Factors to derive DNELs

-------------------------------------------

Overall factor: 20

Thus, the DNEL (systemic, long term, dermal route): 3 mg/kg bw/day

DNEL (systemic, long term, inhalation route)

The California OEHHA (Office of Environmental Health Hazard Assessment) established a Reference Exposure Level (REL) for chronic inhalative exposure of chlorobenzene.

Definition of REL by OEHHA:

“A Chronic REL is an airborne level that would pose no significant health risk to individuals indefinitely eeexposed to that level. RESs are based solely onhealth considerations, and ared developed from the best available data in the scientific literature”

The REL for Chlorobenzene was established with 1 mg/m³ or 300 ppb

This REL is based on the lowest inhalative NOAEC in animal studies with chlorobenzene (50 ml/m³), taking into consideration exposure conversion factors, human equivalent concentration calculation, and a cumulative uncertainty factor of 100 (extrapolation from subchronic to chronic exposure 3, interspecies uncertainty factor 3 and intraspecies uncertainty factor 10)

Therefore, the proposed DNEL (systemic, long term, inhalation route) is 1 mg/m³

DNEL (systemic, short term)

DNEL (short term) should be derived if peak exposure can occur. Chlorobenzene is a liquid with a rather low vapour pressure of 1.14 kPa at 20 °C and it is explosive in the range 1.3 -7.1% in air (SCOEL 2001). Therefore DNEL (short term) has to be considered.

However, using the LC50- or LD50-value from the acute toxicity studies ignore the sublethal or even well tolerated concentration level and is therefore considered to involve too large uncertainties, especially when additionally route to route extrapolation has to be considered. For these cases the ECHA Guidance document R8, 2008 proposes to modify the long-term DNELs by multiplying with a factor.

For estimation purposes it is proposed to take into account an exceeding factor of 1.

Thus, the the respective values are

DNEL (systemic, short term, oral): 3 mg/kg bw

DNEL (systemic, short term, dermal): 3 mg/kg bw

DNEL (systemic, short term, inhalation): 1 mg/m³

SUMMARY

The Critical DNELs are

DNEL (systemic, inhalation, long term): 1 mg/m³

DNEL (systemic, inhalation, short term): 1 mg/m³

DNEL (systemic, dermal, long term): 3 mg/kg bw/day

DNEL (systemic dermal short term): 3 mg/kg bw

DNEL (systemic, oral, long term): 3 mg/kg bw/day