Acrylaldehyde

Endpoint summary

Description of key information

Based on repeated dose studies in a range of species, consistent with observations for oral, dermal and inhalation exposure, histopathological effects were solely observed at the portal of entry.
The overall NOAEL for oral toxicity amounted to 0.05 mg/kg bw/day and was found in a 102 weeks rat study. 
Erythema, oedema, and histopathological changes in the skin (hyperkeratosis, acanthosis, parakeratosis) have been observed in male and female New Zealand white rabbits exposed dermally to acrolein (7, 21, or 63 mg/kg body weight; concentrations of 3.5, 10.5, and 31.5 mg/ml) for 6 h/day, 5 days/week, for 3 weeks. 
The results of the repeated-dose inhalation studies referred in the EU Risk Assessment Report 2001 do not permit establishment of a NOAEL. In the meantime since publication of the EU Risk Assessment Report 2001, a further subchronic inhalation study on rats has been performed. The LOAEL for nasal pathology seen in this study was 0.6 ppm acrolein (1.374 mg/m³, DCV (duration corrected value) = 0.245 mg/m³). The NOAEL for nasal pathology seen in this study was 0.2 ppm acrolein (0.458 mg/m³, DCV (duration corrected value) = 0.082 mg/m³). 

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

0.05 mg/kg bw/day

Study duration:

chronic

Species:

rat

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LOAEC

0.9 mg/m³

Study duration:

subchronic

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LOAEC

Study duration:

subchronic

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LOAEL

7 mg/kg bw/day

Study duration:

subacute

Species:

rabbit

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LOAEL

Study duration:

subacute

Species:

rabbit

Additional information

Acrolein has been the subject of a risk assessment carried out under Community Regulation (EEC) No 793/93 (EU, 2001). The key information on repeated dose toxicity 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 subchronic oral studies performed on mice and rats (quoted in US ATSDR, 2007), data on a subacute dermal toxicity study performed on rabbits (quoted in WHO, 2002, US-EPA,2003 and US-EPA, 2008) as well as a recently published study (Dorman et al., 2008) regarding an subchronic rat inhalation study with focus on the respiratory tract toxicity and derivation of a NOAEC have been referred in addition:

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

“The overall NOAEL for oral toxicity amounted to 0.05 mg/kg bw/day and was found in a 102 week rat study. The discriminating effects for establishing NOAELs in the oral studies comprised decreased survival in rats (NOAEL 0.05 mg/kg bw), decreased survival and decreased body weight gain in mice (NOAEL 2 mg/kg bw, study duration 18 months), and an increased incidence of vomiting accompanied by a decrease in total serum protein, calcium and albumin at the highest dose level (1.5-2 mg/kg/bw) in dogs (NOAEL 0.5 mg/kg bw, study duration 53 weeks). Effects at higher dose levels included severe gastric lesions and increased mortality.” quotation from EU, 2001, p82 (remark on quotation: data on duration of mice and dog repeated dose studies have been added from EU, 2001, p66)

“No data on repeated-dose dermal toxicity were available.“ quotation from EU, 2001, p82

“The results of the repeated-dose inhalation studies do not permit establishment of a NOAEL. Intermittent exposure (6-7 hours per day, 5 days per week for a total period of 62 days – 13 weeks) to 0.9 mg/m³ (0.4 ppm, DCV (duration corrected value): 0.16 mg/m³) acrolein vapour (the lowest concentration examined) resulted in slight, but treatment-related changes in rats, but not in hamsters and rabbits. Continuous exposure (24 hours per day, 7 days per week for 90 days) to 0.5 mg/m³ (0.22 ppm) acrolein (the lowest concentration examined) resulted in treatment-related effects in guinea pigs, monkeys, and dogs, but not in rats. The effects found at the lowest-observed adverse effect concentrations, consisted of histopathological changes in the epithelium of the respiratory system and changes in respiratory tract function; they were minimal to slight and were found in one animal or a few animals only. Effects at higher concentrations included signs of chronic inflammatory changes, and epithelial metaplasia and hyperplasia of the respiratory tract, and at even higher concentrations increased mortality.” quotation from EU, 2001, p82

In detail:

Repeated dose toxicity: Oral:

“In a subchronic oral study, acrolein was administered daily in gelatin capsules at dose levels of 0.1, 0.5 and 1.5 (increased to 2.0 after four weeks) mg/kg bw to male and female dogs for 53 weeks. The major treatment-related effect noted was frequent vomiting in the high dose group, mainly during the first four weeks, and in the mid dose group occasional vomiting only. Significantly lower levels of serum total protein, calcium and albumin occurred in animals of the high dose group. No other treatment-related effects were found (Parent et al, 1992b). From this study a NOAEL for subchronic toxicity in dogs of 0.5 mg/kg bw/day is concluded.”

“Long-term gavage studies have been performed with rats (102 weeks) and mice (18 months of both sexes. Mortality in rats and mortality and decreased weight gain in mice were the effects noted (Parent et al, 1991, 1992a). From these studies a NOAEL for chronic toxicity in rats of 0.05 mg/kg bw/day and in mice of 2 mg/kg bw/day are established.” quotations from EU, 2001, p66 and p67 (table not included)

Repeated dose toxicity: Dermal:

“No data on repeated-dose dermal toxicity were available.“ quotation from EU, 2001, p82

Repeated dose toxicity: Inhalation:

Only studies suitable for derivation of NOAELs in detail:

“In one study designed to evaluate the effects of exposure to 0.17, 1.07 and 2.98 ppm (0.4, 2.5 and 6.9 mg/m³) of acrolein (nature unknown), 6 h/d, 5 d/w, for three weeks, on immune and host defence functions of male rats the respiratory tract was histologically investigated as well. No effects were seen in the low and mid concentration groups, while in the high concentration group depressed body weights and nasal lesions but no lung lesions were found (Leach et al., 1987). From this three-week rat study a NOAEL for respiratory tract lesions of 1.07 ppm (2.5 mg/m³) can be derived.”

“Lyon et al. (1970) examined the effects of acrolein vapour in rats, guinea pigs, monkeys and dogs exposed to 0.7 and 3.7 ppm (1.6 and 8.5 mg/m³) 8 h/d, 5 d/w, for six weeks. Nasal passages and trachea were not examined. Treatment did not result in mortality, clinical signs or changes in haematological and biochemical parameters. In all species, lung effects (chronic inflammatory changes, emphysema) were seen. From this six-week study the NOAEL is concluded to be 0.7 ppm ( 1.6 mg/m³) for rats, guinea pigs, monkeys and dogs).”

“In the same series of experiments the effects of continuous exposure for 90 days to 0.22, 1.0 and 1.8 ppm (0.5, 2.3 and 4.1 mg/m³; nature of the substance is assumed to be vapour, however this was not explicitly stated in the report) were examined in rats, guinea pigs, dogs and monkeys. The nose was not examined microscopically and no organ weights were recorded. Reduced body weight gain occurred in rats only at the two higher concentration levels. Non-specific inflammations in lung, liver, kidneys, brain and heart were seen in all species (rat: high concentration group; guinea pig, monkey: low, high concentration groups; dogs: all groups). In dogs, there were definite treatment-related pathological changes in the lungs of the animals of the low concentration group. Eye irritation was reported for dogs and monkeys of the two higher concentration groups (Lyon et al., 1970). From this study the NOAEL for continuous subchronic exposure is concluded to be 0.22 ppm (0.5 mg/m³) for dogs, guinea pigs and monkeys; for rats the NOAEL is 0.22 ppm (0.5 mg/m³).”

“Feron et al. (1978) examined rats, hamsters and rabbits of both sexes exposed to 0.4, 1.4 and 4.9 ppm (0.9, 3.2 and 11.2 mg acrolein vapour/m³), 6 h/d, 5 d/w, for thirteen weeks; the rat was the most sensitive species. The main findings in rats consisted of a significant mortality (50%) in the high concentration group, a concentration-related decrease in body weight gain (not significant in the low concentration group, statistically significant in both other groups) and concentration related respiratory tract lesions varying from slight squamous cell metaplasia in the nasal cavity of one animal of the low concentration group to severe lesions of several parts of the respiratory tract of the animals of the high concentration group. Rabbits and hamsters did not show treatment-related adverse effects at 0.4 ppm, at 1.4 ppm rabbits showed minimal inflammatory changes in the nasal cavity and in hamster some occasional sneezing and a slightly decreased food consumption and body weight gain were seen, serious respiratory tract lesions in both species occurred at 4.9 ppm (Feron et al., 1978). From these studies it is concluded that the NOAEL for subchronic toxicity in rats is 0.4 ppm (0.9 mg/m³). For rabbits and hamsters the NOAEL is 0.4 ppm (0.9 mg acrolein vapour/m³).”

“In a series of separate experiments two strains of rats were exposed to 0.4, 1.4 and 4.0 ppm (0.9, 3.2 and 9.2 mg acrolein vapour/m³), 6 h/d, 5 d/w, for 62 days. In Fischer rats, no histological changes were seen in the lungs of the animals of the low concentration group, while in Dahl rats - amongst others - hyperplastic/metaplastic terminal bronchiolar epithelial changes were observed. Lung function parameters investigated in the Fischer rats were affected to some extent in the low concentration group (Costa et al., 1986; Kutzman et al., 1984, 1985). From these studies it can be concluded that the NOAEL in both strains of rats was 0.4 ppm (0.9 mg acrolein vapour/m³).” quotations from EU, 2001, p61-65 (tables not included)

Repeated dose toxicity: Humans:

“There are no human data on repeated exposure.” quotation from EU, 2001, p67

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

No substantial deviations in characterisation of these intrinsic properties in the EU Risk Assessment Report 2001 to WHO, 2002; US-EPA, 2003, US ATSDR, 2007 and US-EPA, 2008.

Due to the large number of studies on repeated toxicity of acrolein available, the selection of studies referred slightly deviates within the international reports. Furthermore, the focus of the different international reports are non-identically, therefore the way of data preparation and elaborateness are different, especially in US-EPA, 2003, US ATSDR, 2007, US-EPA, 2008 in comparison to the EU Risk Assessment Report 2001. However, within the individual reports the judgement on repeated dose toxicity does not substantially deviate.

In WHO 2002 the study NTP 2006 (see below) is cited as NTP 1998 with slightly deviating NOAELs. However, the narrationin WHO 2002 is based on just an abstract of the study and a pathology working group review and not the final report referred in US ATSDR, 2007.

4. Additional Aspects in further International Reports

US ATSDR, 2007: Subchronic oral studies performed in the meantime since finalisation of the EU Risk Assessment Report 2001 are referred (NTP 2006): “Groups of 10 rats/sex/dose were administered 0.75, 1.25, 2.5, 5, and 10 mg/kg/day by gavage for 14 weeks, while groups of 10 mice/sex/dose were given 1.25, 2.5, 5, 10, and 20 mg/kg/day for the same duration. Dose volumes were 5 ml/kg for rats and 10 ml/kg for mice. Common high-dose effects were observed for both species, including hemorrhage and necrosis, and forestomach and glandular stomach lesions. Rats receiving 10 mg/kg/day exhibited abnormal breathing, nasal discharge, and death. The lowest LOAEL observed was 2.5 mg/kg/day for forestomach squamous epithelial hyperplasia in male mice and female rats and mice, with an associated NOAEL of 1.25 mg/kg/day. In male rats, the lowest LOAEL observed was 5 mg/kg/day with an associated NOAEL of 2.5 mg/kg/day. Mice exhibited no clinical signs of toxicity. Glandular stomach lesions appeared in rats and mice given 10 and 20 mg/kg/day, respectively. Liver weights were significantly increased in female rats and male mice given 5 and 10 mg/kg/day, respectively. Squamous epithelial hyperplasia of the forestomach was the most sensitive end point observed in both rats and mice.” quotation from US ATSDR, 2007, Appendix A-7

US ATSDR 2007: Furthermore, the absence of gross or histopathological changes seen in previous studies (Parent et al. 1991a, 1992a, 1992b) in relation to the effects seen in the study NTP 2006 is discussed in US ATSDR 2007: “Chronic gavage studies in which rats were dosed with up to 2.5 mg/kg/day for 24 months (Parent et al. 1992a), mice were gavage dosed with up to 4.5 mg/kg/day for 18 months (Parent et al. 1991a), and dogs were gavage dosed with up to 2 mg/kg/day for 12 months (Parent et al. 1992b) all failed to produce significant gross or histopathological changes as have been observed in other studies of the same species at lower dose levels (NTP 2006). One possible explanation for discrepancies in effects observed by Parent et al. (1991a, 1992a, 1992b) and NTP (2006) is the use of a thickening agent” (remark: methylcellulose as cited in WHO 2002) “in the dosing vehicle of the NTP (2006) study, which may have increased the gastrointestinal residence time compared to doses in the Parent et al. (1991a, 1992a, 1992b) studies, which administered acrolein in a deionized water vehicle.” quotation from US ATSDR, 2007, p17

WHO 2002, US-EPA 2003 and US-EPA 2008 refers one repeated dermal dose study not included in the EU Risk Assessment Report 2001 (MRID 00141030. Muni, LA. (1982) 21-Day dermal test of Acrolein in rabbits. Bioassay Systems

Corporation, Woburn, MA. Project No.: 10258, July 28, 1982): “In a 21-day dennal toxicity study (MRID 00141030), Acrolein (>96% a.i) in ethanol:deionized water (50:50 v/v) was applied (2 mL/kg) to the shaved skin of 10 New Zealand White rabbits/sex/dose at dose levels of 0, 7,21, or 63 mg/kg/day, 6 hours/day, 5 days/week for 3 weeks (total of 15 applications). The skin of the treatment site was abraded in 5 animals/sex/dose and unabraded in the other 5 animals/sex/dose. Dermal irritation was evaluated daily using the Draize method.

No compound-related effects on body weight, organ weights, hematology, or clinical chemistry parameters were observed.

At >=7 mg/kg/day, body weights were slightly decreased in the males (10-15%, NS) compared to controls on Day 20, and overall body weight gain was decreased (p<0.05) by 28-91% in both sexes. Food consumption was decreased (p<0.05) throughout the majority of the study by 5-38% in both sexes. Dermal irritation characterized by slight to severe reddening with swelling and firmness of the test site, and scab fonnation with cracking and peeling was observed in all animals. The severity of both the erythema and edema increased with time and dose. Increased incidence (# affected/l0 vs 0 controls; unless otherwise stated) of the following histopathological effects were noted at all doses (unless otherwise indicated): (i) treated skin, minimal to severe necrosis (5-10 males and 7-10 females) and minimal to marked hyperkeratosis, parakeratosis, and acanthosis (7-10 males and 9-10 females); (ii) lungs, minimal to severe multifocal interstitial pneumonia (6-8 males at >=21 mg/kglday vs 6 controls and 6-8 treated females vs 1 control); and (iii) kidneys, minimal to severe bilateral interstitial nephritis (3-5 males at >=21 mglkglday vs 1 control and 2-4 treated females vs 1 control). The effects mentioned above occurred with similar frequency in the abraded and unabraded animals.

Additionally, one female each from the 21 and 63 mg/kg/day groups was found dead on Days 4 and 5, respectively. In addition, one female each from the 7 and 63 mg/kg/day groups was sacrificed in extremis on Day 5. It was detennined that the animals sacrificed in extremis had broken backs attributable to hyperactive behavior following dosing. The cause of death in the animals found dead was not detennined.

Treatment-related clinical signs of toxicity were limited to increased incidence of slight to moderate lethargy noted in the 63 mglkglday males (4/10 treated vs 0/10 controls).

The systemic LOAEL was 7 mg/kg/day based on decreased body weight gain, and food consumption in both sexes, and minimal to moderate multifocal interstitial pneumonia and moderate bilateral interstitial nephritis in the females. The systemic NOAEL was not

established.

The dermal LOAEL was 7 mg/kg/day based on dermal irritation characterized by slight tomoderate reddening with swelling and firmness of the test site, and scab formation with peeling and microscopic f'mdings in the treated skin (minimal to marked necrosis,

hyperkeratosis, parakeratosis, and acanthosis). The dermal NOAEL was not established." quotation from US-EPA, 2008, p47-48

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

Dorman et al. (2008): "The goal of this study was to characterize the respiratory tract toxicity of acrolein, including nasal and pulmonary effects, in adult male F344 rats. Animals underwent whole-body exposure to 0, 0.02, 0.06, 0.2, 0.6, or 1.8 ppm acrolein for 6 hr/day, five days/week for up to 65 exposure days (13 exposure weeks). Respiratory tract histopathology was evaluated after 4, 14, 30, and 65 exposure days, as well as 60 days after the end of the 13 week exposure. Acrolein exposure was associated with reduced body weight gain. Rats exposed to >/= 0.06 ppm acrolein had depressed terminal body weights when compared with air-exposed controls. Histologic evaluation of the nasal cavity showed olfactory epithelial inflammation and olfactory neuronal loss following exposure to 1.8 ppm acrolein. Moderately severe (remark: = grade 4 in a scale of 1-5 (1= minimal, 2= slight or mild, 3 = moderate, 4 = moderate severe, 5 = severe/high)) olfactory neuronal loss  in the dorsal meatus and ethmoid turbinates occurred within four days while septal involvement developed with ongoing exposure. A rostral-caudal gradient in lesion severity was noted, with the anterior portion of the nasal cavity being more severely affected. Acrolein exposure was associated with inflammation, hyperplasia, and squamous metaplasia of the respiratory epithelium. The lateral wall was amongst the most sensitive locations for these responses and increased respiratory epithelial cell proliferation occurred at this site following 4 to 30 days of exposure to >/= 0.6 ppm acrolein." Less severe lesions were also observed in the larynx and trachea. "Mild laryngeal inflammation was seen in rats exposed to 1.8 ppm acrolein. Mild squamous metaplasia at the base of the epiglottis was evident in rats exposed to acrolein at 1.8 ppm. This lesion did not fully resolve during the 60 day post-exposure hold. Mild squamous metaplasia of the tracheal epithelium was also evident in rats exposed for 4 or 14 days to 1.8 ppm acrolein. Minimal squamous metaplasia of the nasopharyngeal duct was also present in rats exposed for 4, 14, or 30 days to 1.8 ppm acrolein. No apparent treatment related effects were observed in the lung." The LOAEL for nasal pathology seen in this study was 0.6 ppm acrolein (remark: 1.374 mg/m³, DCV (duration corrected value) = 0.245 mg/m³). "The NOAEL for nasal pathology seen in this study was 0.2 ppm acrolein" (remark: 0.458 mg/m³, DCV (duration corrected value) = 0.082 mg/m³). quotation from Dorman et al., 2008, abstract and p212 (remarks: remark on scaling from p207 of publication; allocation of phrase LOAEL to the 0.6 ppm dose level by referee; conversion of LOAEL and NOAEL in DCV in analogy to EU, 2001 by referee)

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

Based on repeated dose studies in a range of species, consistent with observations for oral, dermal and inhalation exposure, histopathological effects were solely observed at the portal of entry (i. e., severe stomach respectively forestomach lesions in oral studies, skin hyperkeratosis, acanthosis and parakeratosis in a dermal study, severe histopathological alterations of the respiratory tract, especially the upper respiratory tract, with inflammatory changes, epithelial olfactory neuronal loss and hyperplasia, and squamous metaplasia of the respiratory epithelium in inhalative studies.

The overall NOAEL for oral toxicity amounted to 0.05 mg/kg bw/day and was found in a 102 weeks rat study. The

discriminating effects for establishing NOAELs in the oral studies comprised decreased survival in rats (NOAEL 0.05 mg/kg bw), decreased survival and decreased body weight gain in mice (NOAEL 2 mg/kg bw, study duration 18 months), and an increased incidence of vomiting accompanied by a decrease in total serum protein, calcium and albumin at the highest dose level (1.5-2 mg/kg/bw) in dogs (NOAEL 0.5 mg/kg bw, study duration 53 weeks). Effects at higher dose levels included severe gastric lesions and increased mortality. In subchronic oral studies performed in the meantime since finalisation of the EU Risk Assessment Report 2001 within the US NTP program, rats were administered 0.75, 1.25, 2.5, 5, and 10 mg/kg/day by gavage for 14 weeks, while mice were given 1.25, 2.5, 5, 10, and 20 mg/kg/day for the same duration. Common high-dose effects were observed for both species, including hemorrhage and necrosis, and forestomach and glandular stomach lesions. Rats receiving 10 mg/kg/day exhibited abnormal breathing, nasal discharge, and death. The lowest LOAEL observed was 2.5 mg/kg/day for forestomach squamous epithelial hyperplasia in male mice and female rats and mice, with an associated NOAEL of 1.25 mg/kg/day. In male rats, the lowest LOAEL observed was 5 mg/kg/day with an associated NOAEL of 2.5 mg/kg/day. Mice exhibited no clinical signs of toxicity. Glandular stomach lesions appeared in rats and mice given 10 and 20 mg/kg/day, respectively. Liver weights were significantly increased in female rats and male mice given 5 and 10 mg/kg/day, respectively. Squamous epithelial hyperplasia of the forestomach was the most sensitive end point observed in both rats and mice.

Erythema, oedema, and histopathological changes in the skin (hyperkeratosis, acanthosis, parakeratosis) have been observed in male and female New Zealand white rabbits exposed dermally to acrolein (7, 21, or 63 mg/kg body weight; concentrations of 3.5, 10.5, and 31.5 mg/ml) for 6 h/day, 5 days/week, for 3 weeks.

The results of the repeated-dose inhalation studies referred in the EU Risk Assessment Report 2001 do not permit establishment of a NOAEL. Intermittent exposure (6-7 hours per day, 5 days per week for a total period of 62 days – 13 weeks) to 0.9 mg/m³ (0.4 ppm, DCV (duration corrected value): 0.16 mg/m³) acrolein vapour (the lowest concentration examined) resulted in slight, but treatment-related changes in rats, but not in hamsters and rabbits. Continuous exposure (24 hours per day, 7 days per week for 90 days) to 0.5 mg/m³ (0.22 ppm) acrolein (the lowest concentration examined) resulted in treatment-related effects in guinea pigs, monkeys, and dogs, but not in rats. The effects found at the lowest-observed adverse effect concentrations, consisted of histopathological changes in the epithelium of the respiratory system and changes in respiratory tract function; they were minimal to slight and were found in one animal or a few animals only. Effects at higher concentrations included signs of chronic inflammatory changes, and epithelial metaplasia and hyperplasia of the respiratory tract, and at even higher concentrations increased mortality. In the meantime since publication of the EU Risk Assessment Report 2001, a further subchronic inhalation study on rats has been performed. The goal of this study was to characterize the respiratory tract toxicity of acrolein, including nasal and pulmonary effects, in adult male F344 rats. However, since in former performed studies it has been shown that the solely target organ of an inhalation exposure to acrolein is the respiratory tract, this study permits establishment of a NOAEL. Animals underwent whole-body exposure to 0, 0.02, 0.06, 0.2, 0.6, or 1.8 ppm acrolein for 6 hr/day, five days/week for up to 65 exposure days (13 exposure weeks). Respiratory tract histopathology was evaluated after 4, 14, 30, and 65 exposure days, as well as 60 days after the end of the 13 week exposure. Acrolein exposure was associated with reduced body weight gain. Rats exposed to >/= 0.06 ppm acrolein had depressed terminal body weights when compared with air-exposed controls. Histologic evaluation of the nasal cavity showed olfactory epithelial inflammation and olfactory neuronal loss following exposure to 1.8 ppm acrolein. Moderately severe (= grade 4 in a scale of 1-5) olfactory neuronal loss in the dorsal meatus and ethmoid turbinates occurred within four days while septal involvement developed with ongoing exposure. A rostral-caudal gradient in lesion severity was noted, with the anterior portion of the nasal cavity being more severely affected. Acrolein exposure was associated with inflammation, hyperplasia, and squamous metaplasia of the respiratory epithelium. The lateral wall was amongst the most sensitive locations for these responses and increased respiratory epithelial cell proliferation occurred at this site following 4 to 30 days of exposure to >/= 0.6 ppm acrolein. Less severe lesions were also observed in the larynx and trachea. Mild laryngeal inflammation was seen in rats exposed to 1.8 ppm acrolein. Mild squamous metaplasia at the base of the epiglottis was evident in rats exposed to acrolein at 1.8 ppm. This lesion did not fully resolve during the 60 day post-exposure hold. Mild squamous metaplasia of the tracheal epithelium was also evident in rats exposed for 4 or 14 days to 1.8 ppm acrolein. Minimal squamous metaplasia of the nasopharyngeal duct was also present in rats exposed for 4, 14, or 30 days to 1.8 ppm acrolein. No apparent treatment related effects were observed in the lung. The LOAEL for nasal pathology seen in this study was 0.6 ppm acrolein (1.374 mg/m³, DCV (duration corrected value) = 0.245 mg/m³). The NOAEL for nasal pathology seen in this study was 0.2 ppm acrolein (0.458 mg/m³, DCV (duration corrected value) = 0.082 mg/m³).

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
see European Union Risk Assessment Report of Acrolein (EU, 2001)

Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:
Sub-chronic study in rats, rabbits and hamsters, as cited on BAuA (2007)

Justification for selection of repeated dose toxicity inhalation - local effects endpoint:
Sub-chronic study in rats, rabbits and hamsters, as cited on BAuA (2007)

Justification for selection of repeated dose toxicity dermal - systemic effects endpoint:
see United States Environmental Protection Agency, HED Risk Assessment for Reregistration Eligibility Decision (RED) Document for Acrolein (US-EPA,2008)

Justification for selection of repeated dose toxicity dermal - local effects endpoint:
see United States Environmental Protection Agency, HED Risk Assessment for Reregistration Eligibility Decision (RED) Document for Acrolein (US-EPA,2008)

Repeated dose toxicity: via oral route - systemic effects (target organ) digestive: stomach

Repeated dose toxicity: inhalation - systemic effects (target organ) respiratory: nose

Justification for classification or non-classification

Reliable data on repeated oral and inhalative dose toxicity studies are available. Acute lethality appears to be the critical adverse health effect of acrolein. Based on repeated dose studies in a range of species, consistent with observations for oral, dermal and inhalation exposure, histopathological effects were solely observed at the portal of entry (i.e., severe stomach respectively forestomach lesions in oral studies, skin hyperkeratosis, acanthosis and parakeratosis in a dermal study, severe histopathological alterations of the respiratory tract, especially the upper respiratory tract, with inflammatory changes, epithelial olfactory neuronal loss and hyperplasia, and squamous metaplasia of the respiratory epithelium in inhalative studies. Apart of this toxicity at the portal of entry, there is no evidence on a specific target organ toxicity.

Thus acrolein does not comply with the classification requirements regarding specific target organ toxicity — repeated exposure outlined in regulation (EC) 1272/2008 or the former Directive on classification and labelling 67/548/EEC.