Acrylaldehyde

Endpoint summary

Description of key information

Text was truncated. The full text is available in the migration report.

Additional information

Short descriprion of key information

Humans may be exposed to acrolein via man-made sources. However, acrolein is not a xenobiotic chemical. Small amounts of acrolein are produced endogenously during the normal intermediary catabolism of various amino acids and polyamines and during the peroxidation of membrane lipids. Acrolein is very reactive and conjugates easily with glutathione or other thiol-containing molecules, with protein sulfhydryl groups as well as primary and secondary amine groups. As a consequence of its high reactivity the acrolein molecule will bind primarily at the application site. The retention of acrolein in the respiratory tract of dogs exposed to acrolein vapour amounted to 81-84%. In mice absorption rate in the upper respiratory tract was 92 %. Absorption in the upper respiratory tract of rats was found to be dose- and breathing-rate related and reaches nearly 100 % in rats exposed to 0.6 ppm at a 100/min air flow rate. A statistically significant decline in uptake efficiency occurred during the exposures. Preexposed rats having higher uptake efficiency than their naive counterparts but also higher glutathione concentrations in the respiratory epithelium. Acrolein mercapturic acid derivatives recovered in the urine upon oral, subcutaneous or intraperitoneal administration to rats amounted to 70-80%, 10-18%, and 29.1±6.5% of the administered dose, respectively. Upon inhalation exposure 11-22% of the estimated absorbed dose was found in the urine. After oral administration of ¹⁴C-acrolein to rats, radioactivity is found in urine, exhaled air and faeces.

The main metabolic pathway of acrolein in vivo presumably includes conjugation with glutathione. An adaptive response of respiratory glutathione levels to repeated acrolein exposures was seen in rats.

The in vitro metabolites acrylic acid, glycidaldehyde and glyceraldehyde have not been demonstrated in vivo.

Toxicokinetic data on absorption, distribution, metabolism and excretion for the dermal route are lacking. The available acute dermal toxicity data do not allow the assessment of dermal absorption due to the irritant and corrosive properties of acrolein. Although experimental data on dermal absorption of acrolein are lacking, a prediction of the dermal absorption can be inferred from the general knowledge on the toxicodynamik of acrolein and inhalative metabolism studies performed on this substance: Acrolein is very reactive and conjugates easily with glutathione or other thiol-containing molecules, with protein sulfhydryl groups as well as primary and secondary amine groups. Due to this highly reactive nature, acrolein can bind rapidly (both enzymatically and non-enzymatically) with cellular components. .As a consequence of this rapid binding with cellular components, the acrolein molecule will bind primarily at the application site as seen in several studies on inhalative retention. Therefore, a binding of acrolein to epidermal and dermal cellular components is very likely after dermal exposure and a passage of acrolein through the subcutis and systemic uptake after dermal exposure is expected to be low.

Discussion

Acrolein has been the subject of a risk assessment carried out under Community Regulation (EEC) No 793/93 (EU, 2001). The key information on toxicokinetik, metabolism and distribution of acrolein as stated above correspond to the greatest extend to this assessment and further assessments carried out under other international and national programmes published after finalisation of the EU Risk Assessment Report 2001 (World Health Organization, International Programme on Chemical Safety (IPCS), Concise International Chemical Assessment Document of Acrolein, CICADS 43 (WHO, 2002); United States Environmental Protection Agency, Toxicological Review of Acrolein (US-EPA, 2003); United States Agency for Toxic Substances and Desease Registry, Toxicological Profile for Acrolein (US ATSDR, 2007); United States Environmental Protection Agency, HED Risk Assessment for Reregistration Eligibility Decision (RED) Document for Acrolein (US-EPA, 2008). Supplementary information to EU, 2001 regarding endogenous acrolein (quoted in WHO, 2002, US-EPA, 2003 and US ATSDR, 2007) and information on retention of acrolein in the respiratory tract of mice (quoted in US ATSDR, 2007) as well as a recently published study (Struwe et al., 2008) regarding retention of acrolein in the respiratory tract of rats have been referred in addition. Moreover, since experimental data on dermal absorption are lacking, a prediction of the dermal absorption has been inferred from the general knowledge on the toxicodynamik of acrolein and inhalative metabolism studies performed on this substance:

1. European Union Risk Assessment Report of Acrolein (EU, 2001)

"Acrolein is very reactive and conjugates easily with glutathione or other thiol-containing molecules, with protein sulfhydryl groups and primary and secondary amine groups. As a consequence of its high reactivity the acrolein molecule will bind primarily at the application site. The retention of acrolein in the respiratory tract of dogs exposed to acrolein vapour (172-258 ppm) amounted to 81-84%. Acrolein mercapturic acid derivatives recovered in the urine upon oral, subcutaneous or intraperitoneal administration to rats amounted to 70-80%, 10-18%, and 29.1±6.5% of the administered dose, respectively. Upon inhalation exposure 11-22% of the estimated absorbed dose is found in the urine. After oral administration of ¹⁴C-acrolein to rats, radioactivity is found in urine, exhaled air and faeces."

"The main metabolic pathway of acrolein in vivo presumably includes conjugation with glutathione."

For figure on proposed metabolism of acrolein, see EU, 2001, p 54 (comment: copy paste not possible)

"The in vitro metabolites acrylic acid, glycidaldehyde and glyceraldehyde have not been demonstrated in vivo.

Toxicokinetic data on absorption, distribution, metabolism and excretion for the dermal route are lacking. The available acute dermal toxicity data do not allow the assessment of dermal absorption due to the irritant and corrosive properties of acrolein." quotations from EU, 2001, p55

2. Agreement with further International Reports and Studies Published after Finalisation of the EU Risk Assessment Report 2001

Yes

3. Substantial Disagreements in Comparison to further International Reports to European Union Risk Assessment Report 2001

None

4. Additional Aspects in further International Reports

WHO, 2002, US-EPA, 2003, US ATSDR, 2007: "Small amounts of acrolein are produced endogenously during the normal intermediary catabolism of various amino acids and polyamines and during the peroxidation of membrane lipids." quotation from WHO, 2002, p22; analogous information in US-EPA, 2003, p6 and US ATSDR, 2007, p9

US ATSDR, 2007: The high retention of acrolein in the respiratory tract of dogs exposed to acrolein vapour reported in the European Union Risk Assessment Report 2001, has been confirmed for mice and rats. As cited in US ATSDR, 2007: "Morris (1996) and Morris et al. (2003) exposed mice to 1.1 ppm and rats to 0.9–9.1 ppm acrolein. In both species, most of the inhaled acrolein was absorbed entirely into the upper respiratory tract. Mice absorbed 92% of 1.1 ppm over 10 minutes. Absorption in the upper respiratory tract of rats was found to be dose- and breathing-rate related. At a breathing rate of 50 ml/minute, absorption ranged from >90% to approximately 70% for 0.9–9.1 ppm, while approximately 50–30% was absorbed when breathing 300 ml/minute of the same concentrations for 40 minutes." quotation from US ATSDR, 2007, p64 -65

5. Additional Information in Newer Studies, not Included in the European Union Risk Assessment Report 2001 or further Cited International Reports

Struve et al. (2008): The high retention of acrolein in the upper respiratory tract of rats as reported in US ATSDR, 2007, has been confirmed by Struve et al. (2008), who observed in addition an adaptive response of respiratory glutathione levels to repeated acrolein exposures. In detail, "the uptake efficiency of 0.6, 1.8, or 3.6 ppm acrolein was measured in the isolated upper respiratory tract of anesthetized naive rats under constant-velocity unidirectional inspiratory flow rates of 100 or 300 ml/min for up to 80 min. An additional group of animals was exposed to 0.6 or 1.8 ppm acrolein, 6 h/day, 5 days/wk, for 14 days prior to performing nasal uptake studies (with 1.8 or 3.6 ppm acrolein) at a 100 ml/min airflow rate. Olfactory and respiratory glutathione (GSH) concentrations were also evaluated in naive and acrolein-preexposed rats. Acrolein uptake efficiency in naïve animals was dependent on the concentration of inspired acrolein, airflow rate, and duration of exposure, with increased uptake efficiency occurring with lower acrolein exposure concentrations. A statistically significant decline in uptake efficiency occurred during the exposures. (Remark: The highest upper respiratory tract uptake efficiency of acrolein was seen in rats exposed to 0.6 ppm at a 100/min air flow rate and was 97.8 ± 1.5%.) Exposure to acrolein vapour resulted in reduced respiratory epithelial GSH concentrations. In acrolein-preexposed animals, upper respiratory tract acrolein uptake efficiency was also dependent on the acrolein concentration used prior to the uptake exposure, with preexposed rats having higher uptake efficiency than their naïve counterparts. Despite having increased acrolein uptake efficiency, GSH concentrations in the respiratory epithelium of acrolein preexposed rats were higher at the end of the 80 min acrolein uptake experiment than their in naïve  rat counterparts, suggesting that an adaptive response in GSH metabolism occurred following acrolein preexposure." quotation from Struve et at., 2008, study abstract (remark: remark on highest upper respiratory tract uptake efficiency taken from p 220 of publication; abbrevations UE and URT replaced by whole phrases)

6. Prediction of the Dermal Absorption Inferred from the General Knowledge on the Toxicodynamik of Acrolein and Inhalative Metabolism Studies Performed on this Substance

Although experimental data on dermal absorption of acrolein are lacking, a prediction of the dermal absorption can be inferred from the general knowledge on the toxicodynamik of acrolein and inhalative metabolism studies performed on this substance (see 7.1): Acrolein is very reactive and conjugates easily with glutathione or other thiol-containing molecules, with protein sulfhydryl groups as well as primary and secondary amine groups. Due to this highly reactive nature, acrolein can bind rapidly (both enzymatically and non-enzymatically) with cellular components. As a consequence of this rapid binding with cellular components, the acrolein molecule will bind primarily at the application site as seen in several studies on inhalative retention. Therefore, a binding of acrolein to epidermal and dermal cellular components is very likely after dermal exposure and a passage of acrolein through the subcutis and systemic uptake after dermal exposure is expected to be low.

Discussion on bioaccumulation potential result:

Acrolein has been the subject of a risk assessment carried out under Community Regulation (EEC) No 793/93 (EU, 2001). The key information on toxicokinetik, metabolism and distribution of acrolein as stated above correspond to the greatest extend to this assessment and further assessments carried out under other international and national programmes published after finalisation of the EU Risk Assessment Report 2001 (World Health Organization, International Programme on Chemical Safety (IPCS), Concise International Chemical Assessment Document of Acrolein, CICADS 43 (WHO, 2002); United States Environmental Protection Agency, Toxicological Review of Acrolein (US-EPA, 2003); United States Agency for Toxic Substances and Desease Registry, Toxicological Profile for Acrolein (US ATSDR, 2007); United States Environmental Protection Agency, HED Risk Assessment for Reregistration Eligibility Decision (RED) Document for Acrolein (US-EPA, 2008). Supplementary information to EU, 2001 regarding endogenous acrolein (quoted in WHO, 2002, US-EPA, 2003 and US ATSDR, 2007) and information on retention of acrolein in the respiratory tract of mice (quoted in US ATSDR, 2007) as well as a recently published study (Struwe et al., 2008) regarding retention of acrolein in the respiratory tract of rats have been referred in addition:

1. European Union Risk Assessment Report of Acrolein (EU, 2001)

"Acrolein is very reactive and conjugates easily with glutathione or other thiol-containing molecules, with protein sulfhydryl groups and primary and secondary amine groups. As a consequence of its high reactivity the acrolein molecule will bind primarily at the application site. The retention of acrolein in the respiratory tract of dogs exposed to acrolein vapour (172-258 ppm) amounted to 81-84%. Acrolein mercapturic acid derivatives recovered in the urine upon oral, subcutaneous or intraperitoneal administration to rats amounted to 70-80%, 10-18%, and 29.1±6.5% of the administered dose, respectively. Upon inhalation exposure 11-22% of the estimated absorbed dose is found in the urine. After oral administration of ¹⁴C-acrolein to rats, radioactivity is found in urine, exhaled air and faeces."

"The main metabolic pathway of acrolein in vivo presumably includes conjugation with glutathione."

For figure on proposed metabolism of acrolein, see EU, 2001, p 54 (comment: copy paste not possible)

"The in vitro metabolites acrylic acid, glycidaldehyde and glyceraldehyde have not been demonstrated in vivo.

Toxicokinetic data on absorption, distribution, metabolism and excretion for the dermal route are lacking. The available acute dermal toxicity data do not allow the assessment of dermal absorption due to the irritant and corrosive properties of acrolein." quotations from EU, 2001, p55

2. Agreement with further International Reports and Studies Published after Finalisation of the EU Risk Assessment Report 2001

Yes

3. Substantial Disagreements in Comparison to further International Reports to European Union Risk Assessment Report 2001

None

4. Additional Aspects in further International Reports

WHO, 2002, US-EPA, 2003, US ATSDR, 2007: "Small amounts of acrolein are produced endogenously during the normal intermediary catabolism of various amino acids and polyamines and during the peroxidation of membrane lipids." quotation from WHO, 2002, p22; analogous information in US-EPA, 2003, p6 and US ATSDR, 2007, p9

US ATSDR, 2007: The high retention of acrolein in the respiratory tract of dogs exposed to acrolein vapour reported in the European Union Risk Assessment Report 2001, has been confirmed for mice and rats. As cited in US ATSDR, 2007: "Morris (1996) and Morris et al. (2003) exposed mice to 1.1 ppm and rats to 0.9–9.1 ppm acrolein. In both species, most of the inhaled acrolein was absorbed entirely into the upper respiratory tract. Mice absorbed 92% of 1.1 ppm over 10 minutes. Absorption in the upper respiratory tract of rats was found to be dose- and breathing-rate related. At a breathing rate of 50 ml/minute, absorption ranged from >90% to approximately 70% for 0.9–9.1 ppm, while approximately 50–30% was absorbed when breathing 300 ml/minute of the same concentrations for 40 minutes." quotation from US ATSDR, 2007, p64 -65

5. Additional Information in Newer Studies, not Included in the European Union Risk Assessment Report 2001 or further Cited International Reports

Struve et al. (2008): The high retention of acrolein in the upper respiratory tract of rats as reported in US ATSDR, 2007, has been confirmed by Struve et al. (2008), who observed in addition an adaptive response of respiratory glutathione levels to repeated acrolein exposures. In detail, "the uptake efficiency of 0.6, 1.8, or 3.6 ppm acrolein was measured in the isolated upper respiratory tract of anesthetized naive rats under constant-velocity unidirectional inspiratory flow rates of 100 or 300 ml/min for up to 80 min. An additional group of animals was exposed to 0.6 or 1.8 ppm acrolein, 6 h/day, 5 days/wk, for 14 days prior to performing nasal uptake studies (with 1.8 or 3.6 ppm acrolein) at a 100 ml/min airflow rate. Olfactory and respiratory glutathione (GSH) concentrations were also evaluated in naive and acrolein-preexposed rats. Acrolein uptake efficiency in naïve animals was dependent on the concentration of inspired acrolein, airflow rate, and duration of exposure, with increased uptake efficiency occurring with lower acrolein exposure concentrations. A statistically significant decline in uptake efficiency occurred during the exposures. (Remark: The highest upper respiratory tract uptake efficiency of acrolein was seen in rats exposed to 0.6 ppm at a 100/min air flow rate and was 97.8 ± 1.5%.) Exposure to acrolein vapour resulted in reduced respiratory epithelial GSH concentrations. In acrolein-preexposed animals, upper respiratory tract acrolein uptake efficiency was also dependent on the acrolein concentration used prior to the uptake exposure, with preexposed rats having higher uptake efficiency than their naïve counterparts. Despite having increased acrolein uptake efficiency, GSH concentrations in the respiratory epithelium of acrolein preexposed rats were higher at the end of the 80 min acrolein uptake experiment than their in naïve  rat counterparts, suggesting that an adaptive response in GSH metabolism occurred following acrolein preexposure." quotation from Struve et at., 2008, study abstract (remark: remark on highest upper respiratory tract uptake efficiency taken from p 220 of publication; abbrevations UE and URT replaced by whole phrases)

Discussion on absorption rate:

Acrolein has been the subject of a risk assessment carried out under Community Regulation (EEC) No 793/93 (EU, 2001). The key information on dermal absorption of acrolein as stated correspond to this assessment and further assessments carried out under other international and national programmes published after finalisation of the EU Risk Assessment Report 2001 (World Health Organization, International Programme on Chemical Safety (IPCS), Concise International Chemical Assessment Document of Acrolein, CICADS 43 (WHO, 2002); United States Environmental Protection Agency, Toxicological Review of Acrolein (US-EPA, 2003); United States Agency for Toxic Substances and Desease Registry, Toxicological Profile for Acrolein (US ATSDR, 2007); United States Environmental Protection Agency, HED Risk Assessment for Reregistration Eligibility Decision (RED) Document for Acrolein (US-EPA, 2008)). However, experimental data on dermal absorption in these assessment reports are lacking. Therefore, a prediction of the dermal absorption has been inferred from the general knowledge on the toxicodynamics of acrolein and inhalative metabolism studies performed on this substance, in addition.

Compilation of Information Given in these Assessment Reports

1. European Union Risk Assessment Report of Acrolein (EU, 2001)

"Toxicokinetic data on absorption, distribution, metabolism and excretion for the dermal exposure route are lacking. The available acute dermal toxicity data do not allow the assessment of dermal absorption due to the irritant and corrosive properties of acrolein and the limited reporting of these studies." quotation from EU, 2001, p53

2. Agreement with further International Reports and Studies Published after Finalisation of the EU Risk Assessment Report 2001

Yes

3. Substantial Disagreements in Comparison to further International Reports to European Union Risk Assessment Report 2001

None

4. Additional Aspects in further International Reports

None

5. Additional Information in newer Studies, not Included in the European Union Risk Assessment Report 2001 or further Cited International Reports

None

6. Prediction of the Dermal Absorption Inferred from the General Knowledge on the Toxicodynamik of Acrolein and Inhalative Metabolism Studies Performed on this Substance

Although experimental data on dermal absorption of acrolein are lacking, a prediction of the dermal absorption can be inferred from the general knowledge on the toxicodynamics of acrolein and inhalative metabolism studies performed on this substance (see 7.1): Acrolein is very reactive and conjugates easily with glutathione or other thiol-containing molecules, with protein sulfhydryl groups as well as primary and secondary amine groups. Due to this highly reactive nature, acrolein can bind rapidly (both enzymatically and non-enzymatically) with cellular components. As a consequence of this rapid binding with cellular components, the acrolein molecule will bind primarily at the application site as seen in several studies on inhalative retention. Therefore, a binding of acrolein to epidermal and dermal cellular components is very likely after dermal exposure and a passage of acrolein through the subcutis and systemic uptake after dermal exposure is expected to be low.

The following information is taken into account for hazard / risk assessment:

Toxicokinetic data on absorption, distribution, metabolism and excretion for the dermal exposure route are lacking. The available acute dermal toxicity data do not allow the assessment of dermal absorption due to the irritant and corrosive properties of acrolein and the limited reporting of these studies.

Although experimental data on dermal absorption of acrolein are lacking, a prediction of the dermal absorption can be inferred from the general knowledge on the toxicodynamics of acrolein and inhalative metabolism studies performed on this substance: Acrolein is very reactive and conjugates easily with glutathione or other thiol-containing molecules, with protein sulfhydryl groups as well as primary and secondary amine groups. Due to this highly reactive nature, acrolein can bind rapidly (both enzymatically and non-enzymatically) with cellular components. As a consequence of this rapid binding with cellular components, the acrolein molecule will bind primarily at the application site as seen in several studies on inhalative retention. Therefore, a binding of acrolein to epidermal and dermal cellular components is very likely after dermal exposure and a passage of acrolein through the subcutis and systemic uptake after dermal exposure is expected to be low.