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Effects on fertility

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 reproductive toxicity, covering effects on fertility, developmental toxicity and teratogenic activity, as stated is a quotation taken from this EU Risk Assessment. The information on effects on fertility of acrolein given in the EU Risk Assessment correspond to the greatest extend to 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 a inhalation study on fertility (Kutzman, 1981 as quoted in US EPA, 2003 and US ATSDR, 2007) and a new in vitro study on mouse ovaries (Desmeules and Devine, 2006) have been considered:

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

Remark: In EU, 2001 studies on effects on fertility and studies on developmental toxicity/teratogenicity are reported together under the heading “Toxicity to reproduction”. For ease of comparability, indications on information on developmental toxicity/teratogenicity have not been withdrawn in quotations of preambles and conclusions.

 “A number of in vitro experiments showed the potency of acrolein to cause growth retardation or embryolethality and malformations. Developmental effects in mammals in vivo were only seen at dose levels that also resulted in maternal toxicity. The overall NOAEL in the oral teratogenicity studies amounted to 2 mg/kg bw or higher for developmental and 0.75 mg/kg bw per day for maternal effects. Except for a slight reduction in F1 pup weights at 6 mg/kg bw, no effects on reproduction parameters were found in the oral 2-generation rat studies. The overall NOAEL amounted to 1 and 3 mg/kg bw per day for parental and developmental effects, respectively.” quotation from EU, 2001, p79

“Only oral studies on reproductive toxicity are available. Developmental effects and effects on reproduction parameters occur only at parental toxic dose levels. The oral NOAELs from reproduction studies are higher than the overall oral NOAEL from the repeated dose studies and therefore, it is concluded that the risk for reproductive effects after oral exposure will be low when other effects due to repeated exposure are avoided. The data available do not allow a definite conclusion on the risk for reproductive effects after inhalation or dermal exposure, because route-specificity cannot be excluded. However, the risk for reproductive effects after these exposure routes is considered to be low because (1) acrolein is very reactive and will bind primarily to the application site, (2) the effects observed in the inhalation studies are primarily limited to local effects, and (3) reproductive/developmental effects in the oral reproduction studies occurred only at clear-cut parentally toxic doses.” quotation from EU, 2001, p87

In Detail:

Toxicity to Reproduction: Oral

“There are two publications of oral studies available: a 2-generation reproduction study and a teratogenicity study, both from Parent et al., (1992c, 1993). Beside these studies, three other unpublished oral reproduction studies are cited in US ATSDR, 1990: an oral 2-generation reproduction study (King, 1984 (Remark: also cited in US ATSDR 2007)), and two teratogenicity studies, one with rabbits (Hoberman, 1987) and the other with rats (King, 1982).”

“In an oral 2-generation reproduction study in male and female rats the only effects observed were a decreased body weight gain in the F0 generation at the highest dose of 7.2 mg per kg bw per day and stomach ulcerations at 5.4 mg/kg bw per day and higher (King, 1984 cited in US ATSDR, 1990 (Remark: also cited in US ATSDR 2007)). From this study a NOAEL of 7.2 mg/kg bw per day (the highest dose tested) for developmental and of 4 mg/kg bw per day for parental toxicity is established.”

“In an adequately performed 2-generation oral gavage study, male and female rats were given daily 0, 1, 3, or 6 mg acrolein/kg bw by stomach tube. Reproductive parameters, including male and female fertility, were not affected by acrolein treatment with the exception of reduced pup weights of the F1- generation pups at the high dose level (6 mg/kg bw per day). Parental toxicity seen as increased mortality, clinical signs, decreased body weight gain and histopathological stomach changes (erosions of glandular stomach and hyperplasia/hyperkeratosis of the forestomach) occurred in the mid and high dose groups (Parent et al., 1992c). From this study a NOAEL of 3 mg/kg bw per day for developmental and of 1 mg/kg bw per day for parental toxicity is established.” quotations from EU, 2001, p77-78 (only studies on fertility quoted in detail)

Toxicity to Reproduction: Dermal:

No data available.

Toxicity to Reproduction: Inhalation:

“There is only one inhalation study (Bouley et al., 1975, 1976) available. In this study groups of 3 male and 21 female rats were exposed continuously for 26 days to 0 or 1.26 mg/m3 (0.55 ppm) acrolein (nature not reported) and allowed to mate on day 4 of the exposure period. No significant differences were observed between control and intoxicated animals with respect to pregnancy rate and number and weight of fetuses. This study is not considered appropriate for evaluation of the reproductive properties of acrolein since the exposure period did not cover the whole spermatogenic cycle, the premating exposure was only 4 days and only a restricted number of parameters was studied  In addition, no details concerning study design and results were presented.” quotation from EU, 2001, p77

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

US-EPA 2003 and US ATSDR 2007: In addition to the study of Bouley et al., 1975, 1976, a further study (Kutzman, 1981) on effects on fertility by inhalation exposures is referred: According to US-EPA 2003: “Kutzman (1981) exposed female and male Fischer 344 rats (8/group) via inhalation to acrolein at 0, 0.4, 1.4, or 4.0 ppm (0, 0.9, 3.2 or 9.2 mg/m³) 6 hr/day, 5 days/week for a total of 62 exposure days. The duration of exposure was 12.4 weeks and the animals were evaluated 13.3 weeks after initiation of exposure. Exposed and control male rats were mated with unexposed females for 6 days and also exposed females were mated with unexposed and exposed males. Parameters evaluated were corpora lutea, viable embryos, early and late deaths, and preimplantation losses. There were no treatment-related effects on reproductive performance.” quotation from US-EPA, 2003, p35. According to US ATSDR 2007 (see pp 40, 27 and 31), the NOAEL for reproductive effects in this study was 4 ppm (highest concentration tested); the LOAEL for bronchiolar epithelial hyperplasia and necrosis was 1.4 ppm.

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

Desmeules and Devine (2006): Intact mouse ovaries (postnatal-day-4) were cultured in vitro and exposed to acrolein on day 0 (d0). Tissues were cultured up to d8, and then follicle counts and immunohistochemistry were performed. Acrolein had no effect on follicle numbers at the concentrations tested (1-100 µM) following single exposures. Under continuous exposures to 30-100 µM acrolein, there were significant decreases in the numbers of primordial follicles, but there was also nonspecifie toxicity in the cortical region of exposed tissues at >/= 60 µM, seen as pyknotic cells. The reported decrease in the number of primordial follicles occurred together with nonspecific toxicity in the cortical region. Therefore, it is not possible to distinguish ovary specific effects from nonspecific toxicity and this study gives no indication on ovary specific effects of acrolein.


Short description of key information:
“Developmental effects, and effects on reproduction parameters occur only at parental toxic dose levels. The oral NOAELs from reproduction studies are higher than the overall oral NOAEL from the repeated dose studies and therefore it is concluded that the risk for reproductive effects after oral exposure will be low when other effects due to repeated exposure are avoided. The data available do not allow a definite conclusion on the risk for reproductive effects after inhalation or dermal exposure, because route-specificity cannot be excluded. However, the risk for reproductive effects after these exposure routes is considered to be low because (1) acrolein is very reactive and will bind primarily to the application site, (2) the effects observed in the inhalation studies are primarily limited to local effects, and (3) eproductive/developmental effects in the oral reproduction studies occurred only at clear-cut parentally toxic doses.” quotation from European Union Risk Assessment Report Acrylaldehyde (EU, 2001)
The theoretocal considerations on missing effects on fertility after inhalative exposure as given in EU, 2001, is affirmed by an inhalative study (Kutzman, 1981) not quoted in in EU, 2001 but in US assessment reports (US-EPA, 2003, US ATSDR , 2007, US-EPA, 2008). "Kutzman (1981) exposed female and male Fischer 344 rats (8/group) via inhalation to acrolein at 0, 0.4, 1.4, or 4.0 ppm (0, 0.9, 3.2 or 9.2 mg/m³) 6 hr/day, 5 days/week for a total of 62 exposure days. The duration of exposure was 12.4 weeks and the animals were evaluated 13.3 weeks after initiation of exposure. Exposed and control male rats were mated with unexposed females for 6 days and also exposed females were mated with unexposed and exposed males. Parameters evaluated were corpora lutea, viable embryos, early and late deaths, and preimplantation losses. There were no treatment-related effects on reproductive performance." quotation from United States Environmental Protection Agency, Toxi...

Effects on developmental toxicity

Description of key information
“Developmental effects, and effects on reproduction parameters occur only at parental toxic dose levels. The oral NOAELs from reproduction studies are higher than the overall oral NOAEL from the repeated dose studies and therefore it is concluded that the risk for reproductive effects after oral exposure will be low when other effects due to repeated exposure are avoided. The data available do not allow a definite conclusion on the risk for reproductive effects after inhalation or dermal exposure, because route-specificity cannot be excluded. However, the risk for reproductive effects after these exposure routes is considered to be low because (1) acrolein is very reactive and will bind primarily to the application site, (2) the effects observed in the inhalation studies are primarily limited to local effects, and (3) eproductive/developmental effects in the oral reproduction studies occurred only at clear-cut parentally toxic doses.” quotation from European Union Risk Assessment Report Acrylaldehyde (EU, 2001)
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 reproductive toxicity, covering effects on fertility, developmental toxicity and teratogenic activity, as stated is a quotation taken from this EU Risk Assessment. The information on developmental toxicity/teratogenicity of acrolein given in the EU Risk Assessment correspond to the greatest extend to 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 two further developmental toxicity studies on rats and on mice (BSC, 1982c,d, as quoted in WHO, 2002 and MRID 00156438. King, M. (1982) Teratology study of acrolein in rats. Bioassay Systems

Corporation, Woburn, MA. Laboratory Project No.: 10258, November 12,1982, as quoted in US-EPA, 2008) and more detailed information in US-EPA, 2003 on the rabbit i.v. study of Claussen et al. (1980) already cited in EU, 2001 have been considered:

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

Remark: In EU, 2001 studies on effects on fertility and studies on developmental toxicity/teratogenicity are reported together under the heading “Toxicity to reproduction”. For ease of comparability, indications on information on fertility have not been withdrawn in quotations of preambles and conclusions.

“A number of in vitro experiments showed the potency of acrolein to cause growth retardation or embryolethality and malformations. Developmental effects in mammals in vivo were only seen at dose levels that also resulted in maternal toxicity. The overall NOAEL in the oral teratogenicity studies amounted to 2 mg/kg bw or higher for developmental and 0.75 mg/kg bw per day for maternal effects. Except for a slight reduction in F1 pup weights at 6 mg/kg bw, no effects on reproduction parameters were found in the oral 2-generation rat studies. The overall NOAEL amounted to 1 and 3 mg/kg bw per day for parental and developmental effects, respectively.” quotation from EU, 2001, p79

“Only oral studies on reproductive toxicity are available. Developmental effects and effects on reproduction parameters occur only at parental toxic dose levels. The oral NOAELs from reproduction studies are higher than the overall oral NOAEL from the repeated dose studies and therefore, it is concluded that the risk for reproductive effects after oral exposure will be low when other effects due to repeated exposure are avoided. The data available do not allow a definite conclusion on the risk for reproductive effects after inhalation or dermal exposure, because route-specificity cannot be excluded. However, the risk for reproductive effects after these exposure routes is considered to be low because (1) acrolein is very reactive and will bind primarily to the application site, (2) the effects observed in the inhalation studies are primarily limited to local effects, and (3) reproductive/developmental effects in the oral reproduction studies occurred only at clear-cut parentally toxic doses.” quotation from EU, 2001, p87

In Detail:

Toxicity to Reproduction: Oral:

“There are two publications of oral studies available: a 2-generation reproduction study and a teratogenicity study, both from Parent et al., (1992c, 1993). Beside these studies, three other unpublished oral reproduction studies are cited in US ATSDR, 1990: an oral 2-generation reproduction study (King, 1984 (Remark: also cited in US ATSDR 2007)), and two teratogenicity studies, one with rabbits (Hoberman, 1987) and the other with rats (King, 1982).”

“In an oral 2-generation reproduction study in male and female rats the only effects observed were a decreased body weight gain in the F0 generation at the highest dose of 7.2 mg per kg bw per day and stomach ulcerations at 5.4 mg/kg bw per day and higher (King, 1984 cited in US ATSDR, 1990 (Remark: also cited in US ATSDR 2007)). From this study a NOAEL of 7.2 mg/kg bw per day (the highest dose tested) for developmental and of 4 mg/kg bw per day for parental toxicity is established.”

“In an adequately performed 2-generation oral gavage study, male and female rats were given daily 0, 1, 3, or 6 mg acrolein/kg bw by stomach tube. Reproductive parameters, including male and female fertility, were not affected by acrolein treatment with the exception of reduced pup weights of the F1- generation pups at the high dose level (6 mg/kg bw per day). Parental toxicity seen as increased mortality, clinical signs, decreased body weight gain and histopathological stomach changes (erosions of glandular stomach and hyperplasia/hyperkeratosis of the forestomach) occurred in the mid and high dose groups (Parent et al., 1992c). From this study a NOAEL of 3 mg/kg bw per day for developmental and of 1 mg/kg bw per day for parental toxicity is established.”

“In an oral teratology study in rats (exposure by gavage) increased incidences of skeletal anomalies and delayed ossification and decreased mean fetal weight and total litter weights were observed at a dose level of 10 mg/kg bw per day. The number of implantations or resorptions or the ratio of live/dead fetuses per litter was not affected in the 10 mg group. This dose level, however, was toxic to the dams resulting in the death of 14 out of 40 females in this group. The only effect seen at 6 mg/kg bw per day was a decreased maternal body weight gain, there were no developmental effects (King, 1982 cited in US ATSDR, 1990 (Remark: also cited in US ATSDR 2007)). From this study a NOAEL of 6 mg/kg bw per day for developmental and of 3.6 mg/kg bw per day for maternal toxicity is established.”

“Fetal/embryonal mortality was not affected in a teratology study, in which rabbits were exposed to 2 mg/kg bw per day or less during gestation. However, in the preliminary dose-range finding study preceding the final teratology study, exposure to 1 mg/kg bw per day or more resulted in dose-related increased incidences of fetal resorption. No explanation for the discrepancy was provided. No developmental effects were found at 0.5 mg/kg bw per day. In dams a decreased body weight gain was found at 0.5 mg/kg bw per day, and increased mortality and gastric ulcerations were observed at 4 mg (Hoberman, 1987 cited in US ATSDR, 1990 (Remark: not longer cited in US ATSDR 2007). It is concluded that this study is not suitable for the assessment of maternal or developmental NOAEL, in view of the unexplained discrepancy between the results of the range-finding study and those of the main study.”

“Parent et al., 1993 treated pregnant female rabbits orally by stomach tube with 0.1, 0.75 or 2.0 mg acrolein/kg bw per day on gestational days 7 through 19. In the 2 mg group a transient decrease in maternal body weight gain accompanied by a decreased food intake pointing to maternal toxicity was observed during days 7 through 10. In the subsequent days food intake in this group increased resulting in body weights exceeding those of the other groups. In addition, the high dose group showed an increase in mean fetal body weights, which is not considered to be an adverse effect in this study (P ≤ 0.01). Acrolein did not induce irreversible developmental effects. From this study a NOAEL of ≥ 2 mg/kg bw per day for developmental effects and a NOAEL of 0.75 mg/kg bw per day for maternal toxicity is established.” quotations from EU, 2001, p77-78

Toxicity to Reproduction: Dermal:

No data available.

Toxicity to Reproduction: Inhalation:

“There is only one inhalation study (Bouley et al., 1975, 1976) available. In this study groups of 3 male and 21 female rats were exposed continuously for 26 days to 0 or 1.26 mg/m3 (0.55 ppm) acrolein (nature not reported) and allowed to mate on day 4 of the exposure period. No significant differences were observed between control and intoxicated animals with respect to pregnancy rate and number and weight of fetuses. This study is not considered appropriate for evaluation of the reproductive properties of acrolein since the exposure period did not cover the whole spermatogenic cycle, the premating exposure was only 4 days and only a restricted number of parameters was studied  In addition, no details concerning study design and results were presented.” quotation from EU, 2001, p77

Toxicity to Reproduction: Other Routes:

“When pregnant rabbits were intravenously injected with single doses of 3, 4.5 and 6 mg/kg bw per day at day 9 of gestation, maternal toxicity (mortality) was observed in the animals of the mid and high dose group. In the high dose group embryotoxicity (statistically significant increased resorption rate) was found as well (Claussen et al., 1980).”

“Acrolein induced embryotoxic and teratogenic effects in rats and rabbits by intra-amniotic injection (Claussen et al., 1980; Hales, 1982; Slott and Hales, 1985).” quotations from EU, 2001, p79

Toxicity to reproduction: in vitro:

“A number of in vitro experiments using rat embryo cultures (Hales and Slott, 1987; Mirkes et al., 1981, 1984; Schmid et al., 1981; Slott and Hales, 1987a,b,) murine preimplantation embryos (Spielmann and Jacob-Müller, 1981) or limb bud cultures (Ghaida and Merker, 1992; Hales, 1989; Stahlmann et al., 1985), or hen eggs (Chibber and Gilani, 1986; Kankaanpää et al., 1979; Korhonen, 1983) showed the potency of acrolein to cause growth retardation or embryo lethality and malformations.” quotation from EU, 2001, p77

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: Further developmental toxicity studies on rats and on mice conducted oral by gavage are cited but not referred in detail (BSC, 1982c,d): The results of these two studies (BSC, 1982c,d) have been summarized with the result of studies also cited in the European Union Risk Assessment Report 2001 (Parent et al., 1992c, Parent et al., 1993 and Bouley et al., 1976) as follows: “On the basis of these investigations, effects generally at the site of contact (e.g., gastric lesions) in the parental generation have been limiting (i.e., adverse effects have been confined primarily to the parental generation, although in studies involving nonphysiological routes of administration, feto/embryotoxic and teratogenic effects have been observed). quotation from WHO, 2002, p27 (Remark: No further information given)

US-EPA, 2008: The rat developmental toxicity study cited in WHO, 2002 as BSC, 1982c is also described in US-EPA, 2008: ",Developmental Toxicity- Rat 00156438 (1982), acceptable/guideline, 40 time-mated females per group dosed via gavage at 0,3.6,6 or 10 mg/kg/day from GD 7 through 19. Maternal LOAEL = 3.6 mg/kg/day based on mortality with no clinical signs but in a 2-gen repro study,(MRID 41869101) mortality at 3 mg/kg/day with histopathology in the forestomach was observed. Maternal NOAEL is less than 3.6 mg/kg/day. Developmental LOAEL = 10 mg/kg/day based on decreased fetal weights and litter weights and on incomplete ossification of the skeleton and general retarded development of fetuses. Developmental NOAEL = 6 mg/kg/day." quotation from US-EPA, 2008, p39 (table, detailed study description on p42 -43 of the assessment report:

US-EPA 2003: The study of Claussen et al. (1980) already cited in EU, 2001 is described in more detail: “Claussen et al. (1980) intravenously injected white rabbits on day 9 of gestation with 3, 4.5, or 6 mg/kg acrolein. Embryolethal effects increased in a dose-dependent manner, but few malformations were noted. After direct injection into the rabbit embryos at doses of 10, 20 and 40 μL, resorptions and malformations increased in a dose-dependent manner. The highest dose by both routes showed that direct embryo injection of acrolein induced malformation at doses 50-60 times lower than those inducing embryolethal effects via intravenous injection.” quotation from US-EPA, 2003, p35

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

None

Justification for classification or non-classification

Acrolein has been the subject of a risk assessment carried out under Community Regulation (EEC) No 793/93 (EU, 2001). This assessment came to the following conclusion: "In oral studies on reproductive toxicity, developmental effects, and effects on reproduction parameters occur only at parental toxic dose levels. The oral NOAELs from reproduction studies are higher than the overall oral NOAEL from the repeated dose studies and therefore, it is concluded that the risk for reproductive effects after oral exposure will be low when other effects due to repeated exposure are avoided. The data available do not allow a definite conclusion on the risk for reproductive effects after dermal exposure, because route-specificity cannot be excluded. However, the risk for reproductive effects after these exposure route is considered to be low because (1) acrolein is very reactive and will bind primarily to the application site, (2) the effects observed in oral and inhalation studies are primarily limited to local effects, and (3) reproductive/developmental effects in the oral reproduction studies occurred only at clear-cut parentally toxic doses." quotation from EU, 2001, 87 -88

The theoretical consideration on missing reproductive effects after inhalative exposure as given in EU, 2001, is affirmed by an inhalative study (Kutzman, 1981) not evaluated EU, 2001, but in US assessment reports (United States Environmental Protection Agency, Toxicological Review of Acrolein (2003), United States Agency for Toxic Substances and Desease Registry, Toxicological Profile for Acrolein (2007) and United States Environmental Protection Agency, HED Risk Assessment for Reregistration Eligibility Decision (RED) Document for Acrolein (US-EPA, 2008)). No effect on the reproductive fitness of rats exposed up to and including 4 ppm (highest concentration tested) at 5 days/week for 12,4 weeks prior to mating were found. The LOAEL for bronchiolar epithelial hyperplasia and necrosis in this study was 1.4 ppm.

In conclusion, there is no evidence on toxicity to reproduction of acrolein relevant to humans.

Thus, acrolein does not comply with the classification requirements regarding reproductive toxicity outlined in regulation (EC) 1272/2008 or the former directive on classification and labelling 67/548/EWG.

Additional information