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Effects on fertility

Additional information

Toxicity to reproduction (fertility)

No experimental data on sodium acrylate are available. Data on the structural analogue acrylic acid which has been extensively studied are included for assessment.

 

Possible effects on reproductive performance were investigated by oral administration (via drinking water) in two different studies with rats.

In a one-generation study with F344 rats (Inter-Company Acrylate Study Group, 1980; DePass et al., 1983), the animals (10 males and 20 females per dose group) received acrylic acid at dose levels corresponding to 0, 83, 250 or 750 mg/kg bw/d for 13 weeks. Each male was then mated with 2 females and exposure continued for both sexes throughout gestation and lactation. Dose-related reductions in food and water consumption and consequently in body weight gain were observed in the F0 animals, most pronounced and statistically significant at the 750 mg/kg bw/d dose level. In the high-dose group, pups of both sexes showed decreased body weight gain. Also in F0 males of the high-dose group a reduction in absolute and relative liver weights and in F0 females a reduction in both absolute and relative spleen weights was observed. At the high-dose level the fertility index of males and females, the gestation index, the number of pups born alive and the percentage of pups weaned were numerically, but not statistically significantly reduced. However, the data should be interpreted cautiously because of a relatively atypical control group, in which the female fertility index and the mean number of pups born alive/litter were reduced compared to the historical control of the testing laboratory.

Therefore, based on the above findings the maximum dosage level that did not produce a deleterious reproductive effect for one generation of exposure of acrylic acid in the drinking water of F344 rats was estimated to be 250 mg/kg bw/day (= NOAEL for reproductive effects in the F0 and F1 generation).

 

 

In a two-generation study according to OECD TG 416 acrylic acid was administered orally in the drinking water to male and female Wistar rats at doses of 0, 500, 2500, 5000 ppm (corresponding to approx. 53, 240, 460 mg/kg bw/day). At least 70 days after the beginning of treatment, F0 animals were mated to produce one litter (F1). Mating pairs were from the same dose group and F1 animals selected for breeding were continued in the same dosing group as their parents. Groups of 25 males and 25 females selected from F1 pups as F1 parental generation were offered drinking water containing 0, 500, 2500 and 5000 ppm of the test substance post weaning, and the breeding program was repeated to produce F2 litter. The study was terminated with the terminal sacrifice of the F2 weanlings and F1 adult animals.

The following results were observed (BAMM, 1994; Hellwig et al., 1997):

 

F0 generation:

 

460 mg/kg bw/day group:

 

- statistically significantly reduced food consumption in the males only during the first week of the premating period and in the females only during the second week of the lactation period,

- reduced water intake (11% - 13%) in both sexes during the premating period and in the females (12% - 14%) during gestation and lactation of F1 pups,

- impairment of body weights/body weight gains in males and - much less pronounced - in females,

- no treatment-related changes in organ weights,

- thickening of the limiting ridge (margo plicatus) of the forestomach in most male and female rats,

- minimal hyperkeratosis at the limiting ridge of the forestomach in most male and female rats,

- edema in the submucosa of the glandular stomach of most male (19/25) and female (14/25) rats, minimal in most cases.

 

In the two lower doses no treatment-related changes in clinical signs, organ weights and gross- and histopathological findings were recorded.

 

 

F1 generation:

 

460 mg/kg bw/day group:

 

- reduced body weights/body weight gains of the male and female pups,

- reduced food consumption (in the males and females) during the premating period and in the F1 dams during gestation and lactation,

- decrease in water consumption (18% - 27%) in both sexes during the premating period, and in the females (18% - 22%) during gestation and lactation,

- statistically significantly lower mean body weights compared to controls (both sexes ),

- no treatment-related changes in organ weights,

- thickening of the limiting ridge (margo plicatus) of the forestomach in most male and female rats,

- minimal hyperkeratosis at the limiting ridge of the forestomach in most male and all female rats,

- edema in the submucosa of the glandular stomach of 2 male and 10 female rats, minimal in all cases.

 

240 mg/kg bw/day group:

 

- marginally lower mean pup body weights compared to controls on day 21 p.p. and impaired body weight gains between days 14 - 21 p.p.,

- reduced water intake (9% - 13%) in both sexes during the premating phase (the differences in comparison to the control being statistically significant on most days), and in the females (6% - 13%) during gestation and lactation,

- no treatment-related changes in organ weights and gross- and histopathological findings.

 

At the lowest dose level no treatment-related changes in clinical signs, organ weights and gross- and histopathological findings were recorded.

 

 

F2 generation:

 

460 mg/kg bw/day group:

 

- reduced body weights/body weight gains (both sexes),

- lower incidence of pups/litter with eye opening on time.

 

240 mg/kg bw/day group:

 

- statistically significantly decreased body weight (about 12%) compared to the controls at the end of the lactation period; decreased pup body weight gains,

- fewer pups/litter with auditory canal opening on time.

 

At the lowest dose level no treatment-related changes in clinical signs, organ weights and gross- and histopathological findings were recorded.

 

 

It can be concluded from these results that the continuous administration of aqueous acrylic acid solutions to rats over two generations caused clear signs of toxicity in the highest dose group (5000 ppm =approx. 460 mg/kg body weight/day)in F0 and F1 parents. General toxicity was substantiated by e.g. reduced food and/or water consumption, impairment of body weights/body weight gains and gross and histopathological findings in the fore- and the glandular stomach (i.e. thickening of and minimal hyperkeratosis at the limiting ridge (margo plicatus), edema in the submucosa of the glandular stomach), which are a consequence of the administration of the acid solutions (indicative of the irritating properties of the test substance).

At 2500 ppm (= approx.240 mg/kg body weight/day) the water consumption of the F1 parental animals was still clearly reduced, but no further substance-related adverse effects on the parental rats were seen.

Clear adverse substance-induced effects were also noted for the progeny of the high dose of the F0 and F1. Impaired body weight/body weight gain in the F1 and F2 pups and some indications for delays in the morphological development of the F2 pups were seen. The latter finding was likely associated with the decreased body weight/body weight gain. Similar, but much less pronounced effects were also observed for the F1 and/or F2 pups at 2500 ppm.

500 ppm (= approx. 53 mg/kg body weight/day) were tolerated by both parental generations and their offspring without any changes which could be causally related to test substance administration.

Acrylic acid had no adverse effects on reproductive parameters of the parental animals of either generation (F0 and F1) of all groups (500, 2500 and 5000 ppm). No adverse effects on fertility and pre-implantation development could be detected; no effects on reproductive organs have been observed. The mating index of males in both generations and in all dose groups was 100 %. The fertility rate in the F0 generation was between 92-96 %; in the F1 generation in all dose groups the fertility rate was 100 %. The rate of pregnancy in both generations was not reduced. In both generations there were no differences in numbers of pups born alive.

Therefore, the NOAEL (no observed adverse effect level) with respect to reproductive function was 5000 ppm (=approx. 460 mg/kg body weight/day). The NOAEL with respect to general toxicity of the test substance was 2500 ppm (= approx.240 mg/kg body weight/day) for the F0 generation parental animals and 500 ppm (= approx. 53 mg/kg body weight/day)for the F1 males and females and the offspring (F1 and F2 pups).

 

 

Conclusion

 

In oral reproductive toxicity studies (rats) with acrylic acid no effects on reproductive function (i.e. fertility) were observed. Based on the structural similiarites of acrylic acid and sodium acrylate, sodium acrylate is not anticipated to have any effect on fertility.


Short description of key information:
No experimental data on sodium acrylate are available. Data on the structural analogue acrylic acid which has been extensively studied are included for assessment. In oral reproductive toxicity studies (rats) with acrylic acid no effects on reproductive function (i.e. fertility) were observed. The NOAEL for reproductive function was 460 mg/kg bw/d.
 

Effects on developmental toxicity

Description of key information
No experimental data on sodium acrylate are available. Data on the structural analogue acrylic acid which has been extensively studied are included for assessment.
Following administration of acrylic acid in the drinking water to Wistar rats some signs of postnatal developmental toxicity (retarded body weight gain of the pups) were seen, however only at dose levels that led to reduced food intake and weight gain in the dams. No gross abnormalities were observed in the offspring. A NOAEL(fertility) of 460 mg/kg bw/d was derived from an OECD TG 2-generation study in rats. No prenatal developmental toxicity was observed (rats and rabbits, inhalation), even at concentration levels that produced some signs of maternal toxicity. No specific teratogenic potential could be revealed for dose levels up to and including 360 ppm (rats) (= approx. 1.08 mg/L) and 225 ppm (rabbits) (= approx. 0.673 mg/L), respectively. According to the present database acrylic acid does not show any potential to cause toxicity to reproduction.
Additional information

Developmental Toxicity

No experimental data on sodium acrylate are available. Data on the structural analogue acrylic acid which has been extensively studied are included for assessment.

 

 

Oral administration

 

Developmental studies comprising the oral route of administration are not available.

 

 

Inhalation route

 

Groups of 30 pregnant Sprague-Dawley rats were exposed (6 h/d, whole-body) to atmospheres containing acrylic acid at 0, 40, 120, and 360 ppm (corresponding to approx. 0, 0.12, 0.36 and 1.08 mg/L) during days 6 to 15 of gestation in a developmental study according to OECD TG 414. After exposure the dams were observed up to day 20 of gestation (Inter-Company Acrylate Study Group, 1983; Klimisch and Hellwig, 1991). The animals’ body weight and food consumption were determined on gestation day 0 and subsequently on every third day up to gestation day 20. After sacrifice dams were subjected to a gross pathological examination. After external examination of each foetus their body weights and lengths were measured and they were further processed for skeletal and visceral examination.

In the dams, irritation of the respiratory tract and the eyes was observed in the highest dose group. A dose-related reduction in food and water intake resulting in a decrease in body weight gain was observed in the 120 and 360 ppm groups. Also in the 40 ppm group a slight but statistically significant effect was seen on body weight gain (between day 0 and 20 minus uterus weight) of the dams (10 % reduction as compared to the control). Since this finding at 40 ppm was the only effect observed at this dose level and with unclear biological relevance, it was concluded that the NOAEC for maternal toxicity was 40 ppm (= approx. 0.12 mg/L).

No effects on reproductive performances were observed. There were no signs of group-related trends or significant differences between groups in terms of pre-implantation losses, live foetuses, or resorptions. There were also no signs of group-related differences in the incidences of abnormalities, variations, or retardations in the foetuses in terms of general appearance, foetal body weights and the conditions of the internal organs or the skeleton.Thus, the NOAEC for developmental toxicity in rats was set at 360 ppm = approx. 1.080 mg/L.

 

Groups of 16 pregnant New Zealand rabbits were exposed (6 h/d, whole-body) to atmospheres containing acrylic acid at 0, 25, 75, and 225 ppm (corresponding to approx. 0.075, 0.224, 0.673 mg/L) during days 6-18 of gestation (BAMM, 1993; Neeper-Bradley et al., 1997). All dose groups were observed daily for morbidity and mortality. During the exposure period, animals were observed for clinical signs preceding and subsequent to daily exposures and from outside during actual exposures. Maternal body weights were measured on gestation day 0, 3, 6, 12, 24, and 29. Food consumption was measured daily throughout the study beginning on gestation day 3. After sacrifice on gestation day 29, maternal liver and kidney weights were determined. All foetuses were weighed and examined for external malformations and variations, for thoracic and abdominal visceral abnormalities including internal sex organs, for craniofacial abnormalities and for skeletal malformations and variations.

Dose-related clinical signs (as perinasal/perioral wetness and nasal congestion, as well as reduced body weight gain and food consumption) were observed in the 75 and 225 ppm groups. The overall pregnancy rate was equivalent for all groups (94-100 %). No dose-related effects were observed in the reproduction function of the dams. There were no effects on the number of ovarian corpora lutea, the number of total viable or non-viable (early and late resorptions and dead foetuses) implantations/litter. Percentage live foetuses and sex ratio were equivalent across groups. Foetal body weights were unaffected by test substance exposure. There were no exposure-related increases in the incidences of external, visceral or skeletal malformations or variations.

NOAEC for maternal toxicity was 25 ppm (= approx. 0.075 mg/L).

NOAEC for developmental toxicity: 225 ppm = 0.673 mg/L.

 

Thus, inhalation exposure of pregnant rats and rabbits to atmospheres containing acrylic acid at concentrations up to 360 ppm (rats) and 225 ppm (rabbits) produced no evidence of developmental toxicity in either species.

 

 

Conclusion

 

Following administration of acrylic acid in the drinking water to Wistar rats some signs of postnatal developmental toxicity (retarded body weight gain of the pups) were seen, however at dose levels that led to reduced food intake and weight gain in the dams. No gross abnormalities were observed in the offspring. A NOAEL/fertility of 460 mg/kg bw/d was derived from an OECD TG 2-generation study in rats (BAMM, 1994; Hellwig et al., 1997). No prenatal developmental toxicity was observed (rats and rabbits, inhalation), even at concentration levels that produced some signs of maternal toxicity. No specific teratogenic potential could be revealed for dose levels up to and including 360 ppm (rats) (= approx. 1.08 mg/L) and 225 ppm (rabbits) (= approx. 0.673 mg/L), respectively. According to the present database acrylic acid does not show any potential to cause toxicity to reproduction.

 

Due to the negligibly low vapour pressure of sodium acrylate as compared to acrylic acid, the inhalation route of exposure is not relevant for the acrylate salt. Nevertheless, it can be assumed that sodium acrylate will show a comparable toxicokinetic behaviour and pattern of toxicity with the exception of local irritating effects. Thus, based on the presented data for acrylic acid, toxicity to reproduction is not anticipated for sodium acrylate.

 

 

Justification for classification or non-classification

EU classification according to Annex VI of Directive 67/548/EEC: no classification required

GHS classification (GHS UN rev.3, 2009): no classification required