Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Acute/short term exposure
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
5 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
10 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Acute/short term exposure
DNEL related information

Workers - Hazard for the eyes

Additional information - workers

Rational:

Inhalation exposure is the most relevant route for assessing occupational risk in humans.

The weak irritant capacity of caprolactam to the respiratory tract was described as the dominating toxicological effect in an animal experiment and in human occupational reports. 

No adverse systemic toxicity or evidence of a carcinogenic potential were identified in long term inhalation and oral bioassays in rodents and dogs. Tests assessing the mutagenic potential in vitro and in vivo provide convincing evidence that ε-caprolactam does not possess mutagenic or genotoxic activity.

 

According to the ECHA Guidance on information requirements and chemical safety assessment - chapter R.8 (May 2008), a national occupational exposure limit (OEL) can be used as a surrogate for a DNEL. 

The German Committee on Hazardous Substances (Ausschuss für Gefahrstoffe - AGS) derived an OEL (Arbeitsplatzgrenzwert - AGW) for ε-caprolactam which was substantiated in respective criteria documents (published in German on the website of the Federal Institute for Occupational Safety and Health, BAuA - www.baua.de). According to the German Hazardous Substances Ordinance (Gefahrstoffverordnung) an AGW is a time-weighted average concentration in the workplace air, referring to a given period of time. The AGW states the concentration of a substance below which acute or chronic adverse health effects are not generally expected. AGWs are thus based exclusively on available occupational medical experience and toxicological findings.

 

For ε-caprolactam the AGS established an OEL of 5 mg/m3, referring to an 8-hour exposure period of an inhalable fraction of a dust or aerosol atmosphere. This OEL is used as a surrogate DNEL for long-term exposure.

A ceiling limit value of 10 mg/m3 was given which is used as a surrogate DNEL for short-term exposure.

The justification of the OEL was based on an evaluation of the German MAK Commission (DFG, 1990/2002) and published in criteria documents for ε-caprolactam (issue: 1990, update 2002) with the following statements:

 

The OEL-value was principally determined on the basis of its known irritating effects on skin and mucosa in man. It is relatively well documented for ε-caprolactam that air concentrations of 66 mg/m3 have irritant effects, 56 mg/m3 is the irritation threshold and that concentrations up to 35 mg/m3 don´t cause mucosal irritation (Ferguson & Wheeler, 1973). From the vapour pressure of ε-caprolactam it can be calculated that even at room temperature the saturated vapour concentration is only about 13 mg/m3. At higher concentrations, at least some of the ε-caprolactam must have been present as dust or aerosol. It can be concluded that workers are predominantly exposed to caprolactam dust or aerosol.

ε-caprolactam dust has irritant effects on the skin at 84 mg/m3 and on mucous membranes at 61 mg/m3 (Kelman, 1986).

 

Studies published later than the derivation of the german OEL provide further evidence for the protective nature of the OEL-value:

  • In an exposure chamber study, chemosensory effects of ε-caprolactam were assayed in human volunteers at low concentrations up to 5 mg/m3 (Ziegler et al., 2008). 6h exposures to vaporous ε-caprolactam were associated with a significant unpleasant odor perception but no irritative effects on the conjunctiva or nasal mucosa could be observed. This study is supporting german OEL since no significant local irritation of the upper respiratory tract was identified in human volunteers at 5 mg/m3. 
  •  In a 90-day inhalation study rats were exposed to highly respirable aerosols at concentrations of 0, 23, 66 and 245 mg/ m3 (Reinhold et al., 1997). Transient signs of mild respiratory tract irritation were observed in a dose dependent manner from a dose level of 23 mg/m3. The authors interpreted these effects as local adaptive responses to the minimal irritant effect commonly associated with inhaled particulate material. Keratinisation of the metaplastic epithelium in the larynx (reversible within 4 week recovery) was observed in the highest dose group and was considered to be adverse indicating a NOAEC for local effects in the upper respiratory tract of 66 mg/m3. No signs of systemic toxicity were observed in the highest dose tested (245 mg/m3). The NOAEC of 66 mg/m3 derived from this animal assay is further supporting the german OEL of 5 mg/m3 for local irritant effects on the respiratory tract. 

The German OEL for ε-caprolactam is in agreement with the threshold limit value (TLV-TWA) of 5mg/m3 for an inhalable aerosol and vapor recommended by the American Conference of Governmental Industrial Hygienists (ACGIH, 2003). This value should sufficiently protect against mucous membrane, respiratory tract, and dermal irritation. The TLV justification is taking into account the 90-day inhalation study in rats (Reinhold et al., 1997), although the ACGIH proclaims that there are no specific data on which to base a TLV-STEL. 

In subchronic feeding studies with rats, kidney toxicity characterized by hyaline-droplet degeneration was identified in male animals (TNO, 1970/1971). The only systemic effect reported for female rats was a mild increase in relative liver weights in the highest tested dose group (14% at the most in female Sprague-Dawley rats at 704 mg/kg bw). Chronic progressive nephropathy can occur in rat strains commonly used in toxicology studies, exhibiting a male predisposition. This rat specific observation is well characterized (Hard and Khan, Tox.Path., 32,171-180, 2004) and for chemicals exacerbating chronic progressive nephropathy the rat is apparently not the ideal animal species to finally address systemic toxicity. Therefore the biological relevance and the adverse character of the mild liver weight increase in females is arguable since additionally no such effect was identified in a subchronic dog study (at albeit lower concentrations of 341 mg/kg bw/day; Hazelton, 1980). (NOEL female rats 342 mg/kg bw, NOAEL dogs 341 mg/kg bw).

No reliable human data is available for the oral exposure route.

 

Details:

The following DNELs / DMELs were not derived:

  • Dermal exposure: Skin and eye irritation is the leading acute effect and no signs of systemic toxicity were observed at the acute limit dose of 2000 mg/kg bw. Since no quantitative dose descriptor can be derived for skin irritation, the risk assessment has to be performed in a qualitative manner. In absence of adverse systemic effects (see below) the derivation of a DNELs for dermal exposure would be misleading. In this context, protection from irritation is protecting from any kind of potential systemic toxicity on the dermal route of exposure.
  • Oral exposure: In an industrial setting, ingestion is not an anticipated route of exposure.
  • Systemic effects – inhalation exposure: Both OEL-values (MAK and TLV) were based on transient signs of respiratory tract irritation observed in humans. Following single or repeated inhalation exposure/s to irritating concentrations of caprolactam, neither from human experience nor in animal studies, signs of adverse systemic toxicity were reported. Inhalative uptake of even higher concentrations is limited by the irritant potential of caprolactam to the eyes and the respiratory tract. Furthermore subchronic and chronic oral animal assays in rodents and dogs did not demonstrate the existence of an adverse systemic effect or a carcinogenic potential of caprolactam.

Acute/short-term exposure – systemic effects – dermal DNEL

Not quantifiable; see above

 

Acute/short-term exposure – systemic effects – inhalation DNEL

Not quantifiable; see above

 

Acute/short-term exposure – local effects – dermal DNEL

Not quantifiable; see above

 

Acute/short-term exposure – local effects – inhalation DNEL

MAK-ceiling limit value 10mg/m3 (for details see rational)

 

Long-term exposure – systemic effects – dermal DNEL

Not quantifiable; see above

 

Long-term exposure – systemic effects – inhalation DNEL

Not quantifiable; see above

 

Long-term exposure – local effects – dermal DNEL

Not quantifiable; see above

 

Long-term exposure – local effects – inhalation DNEL

MAK-value 5 mg/kg bw(for details see rational)

 

General Population - Hazard via inhalation route

Systemic effects

Acute/short term exposure
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.5 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information
Overall assessment factor (AF):
2
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
5 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information
Overall assessment factor (AF):
2

General Population - Hazard via dermal route

Systemic effects

Acute/short term exposure
DNEL related information

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
8.55 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
DNEL related information
Overall assessment factor (AF):
40
Modified dose descriptor starting point:
NOAEL
Acute/short term exposure
DNEL related information

General Population - Hazard for the eyes

Additional information - General Population

Rational:

As for workers inhalation exposure is the most relevant route for assessing risk in the general population. The weak irritant capacity of caprolactam to the respiratory tract was described as the dominating toxicological effect in an animal experiment and in human occupational reports. No adverse systemic toxicity or evidence of a carcinogenic potential were identified in long term inhalation and oral bioassays in rodents and dogs. Tests assessing the mutagenic potential in vitro and in vivo provide convincing evidence that ε-caprolactam does not possess mutagenic or genotoxic activity.

 

According to the ECHA Guidance on information requirements and chemical safety assessment - chapter R.8 (May 2008), a national occupational exposure limit (OEL) can be used as a surrogate for a DNEL. 

The German Committee on Hazardous Substances (Ausschuss für Gefahrstoffe - AGS) derived an OEL (Arbeitsplatzgrenzwert - AGW) for ε-caprolactam which was substantiated in respective criteria documents (published in German on the website of the Federal Institute for Occupational Safety and Health, BAuA - www.baua.de). According to the German Hazardous Substances Ordinance (Gefahrstoffverordnung) an AGW is a time-weighted average concentration in the workplace air, referring to a given period of time. The AGW states the concentration of a substance below which acute or chronic adverse health effects are not generally expected. AGWs are thus based exclusively on available occupational medical experience and toxicological findings.

 

For ε-caprolactam the AGS established an OEL of 5 mg/m3, referring to an 8-hour exposure period of an inhalable fraction of a dust or aerosol atmosphere. This OEL is used as a surrogate DNEL for long-term exposure.

A ceiling limit value of 10 mg/m3 was given which is used as a surrogate DNEL for short-term exposure.

The justification of the OEL was based on an evaluation of the German MAK Commission (DFG, 1990/2002) and published in criteria documents for ε-caprolactam (issue: 1990, update 2002) with the following statements:

 

The OEL-value was principally determined on the basis of its known irritating effects on skin and mucosa in man. It is relatively well documented for ε-caprolactam that air concentrations of 66 mg/m3 have irritant effects, 56 mg/m3 is the irritation threshold and that concentrations up to 35 mg/m3 don´t cause mucosal irritation (Ferguson & Wheeler, 1973). From the vapour pressure of ε-caprolactam it can be calculated that even at room temperature the saturated vapour concentration is only about 13 mg/m3. At higher concentrations, at least some of the ε-caprolactam must have been present as dust or aerosol. It can be concluded that workers are predominantly exposed to caprolactam dust or aerosol.

ε-caprolactam dust has irritant effects on the skin at 84 mg/m3 and on mucous membranes at 61 mg/m3 (Kelman, 1986).

 

Studies published later than the derivation of the german OEL provide further evidence for the protective nature of the OEL-value:

  •  In an exposure chamber study, chemosensory effects of ε-caprolactam were assayed in human volunteers at low concentrations up to 5 mg/m3 (Ziegler et al., 2008). 6h exposures to vaporous ε-caprolactam were associated with a significant unpleasant odor perception but no irritative effects on the conjunctiva or nasal mucosa could be observed. This study is supporting german OEL since no significant local irritation of the upper respiratory tract was identified in human volunteers at 5 mg/m3. 
  •  In a 90-day inhalation study rats were exposed to highly respirable aerosols at concentrations of 0, 23, 66 and 245 mg/ m3 (Reinhold et al., 1997). Transient signs of mild respiratory tract irritation were observed in a dose dependent manner from a dose level of 23 mg/m3. The authors interpreted these effects as local adaptive responses to the minimal irritant effect commonly associated with inhaled particulate material. Keratinisation of the metaplastic epithelium in the larynx (reversible within 4 week recovery) was observed in the highest dose group and was considered to be adverse, indicating a NOAEC for local effects in the upper respiratory tract of 66 mg/m3. No signs of systemic toxicity were observed in the highest dose tested (245mg/m3). The NOAEC of 66 mg/m3 derived from this animal assay is further supporting the german OEL of 5 mg/m3 for local irritant effects on the respiratory tract. 

 

The German OEL for ε-caprolactam is in agreement with the threshold limit value (TLV-TWA) of 5mg/m3 for an inhalable aerosol and vapor recommended by the American Conference of Governmental Industrial Hygienists (ACGIH, 2003). This value should sufficiently protect against mucous membrane, respiratory tract, and dermal irritation. The TLV justification is taking into account the 90-day inhalation study in rats (Reinhold et al., 1997), although the ACGIH proclaims that there are no specific data on which to base a TLV-STEL. 

 

In subchronic feeding studies with rats, kidney toxicity characterized by hyaline-droplet degeneration was identified in male animals (TNO, 1970/1971). The only systemic effect reported for female rats was a mild increase in relative liver weights in the highest tested dose group (14% at the most in female Sprague-Dawley rats at 704 mg/kg bw). Chronic progressive nephropathy can occur in rat strains commonly used in toxicology studies, exhibiting a male predisposition. This rat specific observation is well characterized (Hard and Khan, Tox.Path., 32,171-180, 2004) and for chemicals exacerbating chronic progressive nephropathy the rat is apparently not the ideal animal species to finally address systemic toxicity. Therefore the biological relevance and the adverse character of the mild liver weight increase in females is arguable since additionally no such effect was identified in a subchronic dog study (at albeit lower concentrations of 341 mg/kg bw/day; Hazelton, 1980). (NOEL female rats 342 mg/kg bw, NOAEL dogs 341 mg/kg bw).

No reliable human data is available for the oral exposure route.

 

  

Details:

The following DNELs / DMELs were not derived:

  • Dermal exposure: Skin and eye irritation is the leading acute effect and no signs of systemic toxicity were observed at the acute limit dose of 2000 mg/kg bw. Since no quantitative dose descriptor can be derived for skin irritation, the risk assessment has to be performed in a qualitative manner. In absence of adverse systemic effects (see below) the derivation of a DNELs for dermal exposure would be misleading. In this context, protection from irritation is protecting from any kind of potential systemic toxicity on the dermal route of exposure.
  • Systemic effects – inhalation exposure: Both OEL-values (MAK and TLV) were based on transient signs of respiratory tract irritation observed in humans. Following single or repeated inhalation exposure/s to irritating concentrations of caprolactam, neither from human experience nor in animal studies, signs of adverse systemic toxicity were reported. Inhalative uptake of even higher concentrations is limited by the irritant potential of caprolactam to the eyes and the respiratory tract. Furthermore subchronic and chronic oral animal assays in rodents and dogs did not demonstrate the existence of an adverse systemic effect or a carcinogenic potential of caprolactam.

Acute/short-term exposure – systemic effects – dermal DNEL

Not quantifiable; see above

 

Acute/short-term exposure – systemic effects – inhalation DNEL

Not quantifiable; see above

 

Acute/short-term exposure – systemic effects – oral DNEL

Not quantifiable; see above

 

Acute/short-term exposure – local effects – dermal DNEL

Not quantifiable; see above

 

Acute/short-term exposure – local effects – inhalation DNEL

Extrapolating from worker to general population:

MAK-value 10mg/m3

/ 2       (for a higher intraspecies varioation in the general population,

ECHA Guidance - chapter R.8).

                         5mg/m3 

 

Long-term exposure – systemic effects – dermal DNEL

Not quantifiable; see above

 

Long-term exposure – systemic effects – inhalation DNEL

Not quantifiable; see above

 

Long-term exposure – systemic effects – oral DNEL

Intentional oral exposure of consumers is not a relevant route of exposure supported in this CSR. Since caprolactam is not classified for systemic toxicity and no adverse signs of systemic toxicity were observed in subchronic and chronic animal assays, there is generally no concern for a potential risk by theoretical background exposures. Nevertheless, to further substantiate, that exposure of consumers to traces, or of the population via the environment can be deemed to be considered as insignificant an oral DNEL was derived. 

A mild increase (14%) in the relative weights of the liver in females was identified at 704 mg/kg bw in a subchronic feeding study in rats (NOEL 342 mg/kg bw). The adverse character and the biological relevance of this observation is highly questionable since, (1) no liver effects were seen in chronic studies and (2) no systemic toxicity was observed in dogs up to the highest dose tested (341 mg/kg bw ). Therefore is should be emphasized, that the starting point of this DNEL derivation was a NOEL based on a non-adverse mild unspecific increase of liver weight. 

The assessment factor is the product of: 

Subchronic → chronic:                     1 (since mild increase in liver weight in females as the basis for the NOEL was not observed in                                                        chronic studies)

rat → human (allometric scaling):       4 (since no effects were observed in dogs)

remaining differences:                        1 (since there is no indication e.g. for a specific receptor mediated mode of action,

species differences in sensitivity not covered by allometric scaling are unlikely)

General population:                           10

Quality of whole database:                1

Dose-response:                                 1

DNELoral, systemic, chronic:          8.55 mg/kg bw day

 

Long-term exposure – local effects – dermal DNEL

Not quantifiable; see above

 

Long-term exposure – local effects – inhalation DNEL

The MAK-value of 5 mg/m3 was derived for workers, repeatedly exposedfor 8 hours to an inhalable fraction of a caprolactam- dust or -aerosol atmosphere.The value was derived from human data and apart of the leading health effect (respiratory tract irritation) no signs of systemic toxicity were described at this dose level.

 

Extrapolating from worker to general population:

MAK-value 5mg/m3

/ 2       (for a higher intraspecies variation in the general population,

ECHA Guidance - chapter R.8).

                         2.5mg/m3

 

It should be emphasized that this DNEL is protecting from adverselocal irritation of the respiratory tract but not fromannoyance causedbyodor perception which was not considered to be adverse. In a study with human volunteers no signs of irritation but significant odor perception were observed in a dose dependent manner at vapor concentrations between 0.15 - 5 mg/m3 (Ziegler et al., 2008).