Sodium acrylate

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

No experimental data on the test substance is available. Data on the structural analogue acrylic acid which has been extensively studied, is included for assessment.

In oral reproductive toxicity studies (rats) no effects on reproductive function (i.e. fertility) were observed. The NOAEL for reproductive function was 460 mg/kg bw/d.

Link to relevant study records

Reference

Reference 1

Endpoint:

one-generation reproductive toxicity

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 415 [One-Generation Reproduction Toxicity Study (before 9 October 2017)]

Principles of method if other than guideline:

10 male and 20 female rats per group were administered acrylic acid at dosage goals of 0, 83, 250 and 750 mg/kg bw/day in drinking water. At the end of 13 weeks, the male and female rats from each group were mated one male to two females for a 15-day period. Females were introduced into male cages. Rats ware assigned to treatment groups using a computer generated random number scheme. The F0 generation rats were sacrificed after weaning of the F1 generation and were approximately 194 days old at the time of sacrifice. The F1 generation rats were sacrificed at 21 days of age. Treatment effects were determined by statistical comparison of mortality, body weight change, food and water consumption, organ weight change and histological evaluation of tissues from sacrificed animals.

GLP compliance:

no

Limit test:

no

Specific details on test material used for the study:

- Name of test material (as cited in study report): Acrylic acid
- Analytical purity: 97.8%
- Lot No.: 42-19

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Microbiological Associates, Inc., Walkersville, MD.
- Age at study initiation: (P): 41 days
- Weight at study initiation: (P) Males: 111-139 g; Females: 85-118 g
- Housing: During mating, two females were placed in a cage with one male; at this time all rats received acrylic acid at the concentration in the water for the respective female groups. Fifteen days after the first mating, cohabitation was discontinued and the individual females were placed in plastic cages fitted with wire rod metal tops. Ab-sorb-dri hardwood chips were used for bedding in the plastic cages.
- Diet (ad libitum): Zeigler Brothers NIH-07
- Water (ad libitum): Tap water

ENVIRONMENTAL CONDITIONS
- Temperature (°C): no data
- Humidity (%): no data
- Photoperiod (hrs dark / hrs light): no data

Route of administration:

oral: drinking water

Vehicle:

water

Details on mating procedure:

- M/F ratio per cage: 1/2
- Length of cohabitation: 15 days
- After successful mating each pregnant female was caged (how): Fifteen days after the first mating, cohabitation was discontinued and the individual females were placed in plastic cages fitted with wire rod metal tops.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

The stability of aqueous solutions of acrylic acid was determined using a gas chromatographic procedure. The mean dosage levels attained were quite close to the dosage goals for each group. The mean overall dosages of acrylic acid were 0.73, 0.25 and 0.085 g/kg bw/day for males and 0.72, 0.25 and 0.083 g/kg bw/day for females.

Duration of treatment / exposure:

Exposure period: 13 weeks
before the mating and afterwards during the gestation and lactation periods.
Premating exposure period (males): 13 weeks
Premating exposure period (females): 13 weeks
Duration of test: approx. 6 months

Frequency of treatment:

continuously

Dose / conc.:

0 mg/kg bw/day (nominal)

Dose / conc.:

83 mg/kg bw/day (nominal)

Dose / conc.:

250 mg/kg bw/day (nominal)

Dose / conc.:

750 mg/kg bw/day (nominal)

No. of animals per sex per dose:

10 males and 20 females

Control animals:

yes, concurrent vehicle

Positive control:

none

Parental animals: Observations and examinations:

DETAILED CLINICAL OBSERVATIONS:
Daily observation for clinical signs

BODY WEIGHT:
Individual body weights for each F0 animal were determined weekly.

FOOD CONSUMPTION:
The food consumption rate was recorded weekly. Fresh diet was added to the jars every week.

WATER CONSUMPTION:
The water consumption rate was recorded weekly. Fresh solutions were prepared each week, with the percentage of acrylic acid in the water (X) adjusted to maintain a relatively constant dosage level (K) in g/kg according to formula:

X = 100 KW / G

Where X and K are explained above:
W = predicted mean body weight, kg
G = mean water consumption, mL

Oestrous cyclicity (parental animals):

not examinated

Sperm parameters (parental animals):

not examinated

Litter observations:

PARAMETERS EXAMINED
The following parameters were examined in F1 offspring:
number and sex of pups, stillbirths, live births, postnatal mortality, presence of gross anomalies, weight gain, physical or behavioural abnormalities.

Postmortem examinations (parental animals):

SACRIFICE
Five male and five female rats, randomly selected from each dosage level of the F0 parents, were anesthetized with methoxyflurane and sacrificed by severing the brachial vesseis to permit exsanguination.

GROSS NECROPSY
- All sacrificed rats were given a complete gross necropsy examination and organ weights were recorded for the liver, kidneys, heart, spleen, brain and testes.

HISTOPATHOLOGY / ORGAN WEIGHTS
The following tissues were taken and fixed in 10% neutral buffered formalin, processed for paraf in embedding, sectioned at 5 microns and stained with hematoxylin and eosin on all high dose and control animals. Only those tissues with gross lesions were examined microscopically from the intermediate and low level animals.
Pituitary, thyroids, parathyroids, adrenals, heart, thymus, spleen, testes, epididymides, kidneys, urinary bladder, tongue, submandibular salivary gland, esophagus, stomach, duodenum, colon, mesenteric lymph node, nasal cavity, trachea, lungs, ovaries, oviduct, liver, pancreas, brain, eyes, skin, mammary gland, sternum, any lesions.

Postmortem examinations (offspring):

SACRIFICE
Five male and five female rats, randomly selected from each dosage level of the F1 weanlings, were anesthetized with methoxyflurane and sacrificed by severing the brachial vesseis to permit exsanguination.

GROSS NECROPSY
- All sacrificed rats were given a complete gross necropsy examination and organ weights were recorded for the liver, kidneys, heart, spleen, brain and testes.

HISTOPATHOLOGY / ORGAN WEIGHTS
The following tissues were taken and fixed in 10% neutral buffered formalin, processed for paraf in embedding, sectioned at 5 microns and stained with hematoxylin and eosin on all high dose and control animals. Only those tissues with gross lesions were examined microscopically from the intermediate and low level animals.
Pituitary, thyroids, parathyroids, adrenals, heart, thymus, spleen, testes, epididymides, kidneys, urinary bladder, tongue, submandibular salivary gland, esophagus, stomach, duodenum, colon, mesenteric lymph node, nasal cavity, trachea, lungs, ovaries, oviduct, liver, pancreas, brain, eyes, skin, mammary gland, sternum, any lesions.

Statistics:

For every experimental parameter or index measured, the results of each of the three test levels were compared with the control group. To evaluate the statistical significance of possible changes in continuous data, the analysis of variance (ANOVA) validated by Bartlett's test for homogeneity of variance, was used. Individual mean differences were identified by Duncan's multiple range test when indicated by a significant F value for ANOV. In the case of heterogeneous variances, as indicated by Bartlett's test, the paired group F test, and either the Cochran or the Student t-test were used to identify significant differences. Enumerative data were evaluated statistically by NXR Chi Square test; differences between groups were delineated by Fisher's Exact test. Non-parametric data were compared by a distribution-free multiple comparison method. The fiducial limit of 0.05 was employed as the critical level of difference not attributable to chance

Reproductive indices:

The following reproductive parameters were evaluated statistically:
1. Fertility index - the proportion of females that were pregnant of the number that were mated or the proportion of the males shown to be fertile of the number that were mated.
2. Gestation Index - the proportion of pregnancies that resulted in litters with live pups.
3. Gestation Survival Index - the proportion of newborn pups that were alive at birth.
4. Pups born alive per litter.
5. Days from mating to litter.

Offspring viability indices:

The following reproductive parameters were evaluated statistically:
1. 5-Day Survival Index - the proportion of liveborn that survived 5 days.
2. 21-Day Survival Index - the proportion of pups retained on day 5 that survived 21 days.
3. Pups weaned per pups alive at birth.

Clinical signs:

no effects observed

Description (incidence and severity):

There were no significant abnormal clinical signs observed.

Mortality:

no mortality observed

Description (incidence):

No deaths occurred during the study.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Body weight gain was depressed markedly for both sexes at the high dosage level. This effect was statistically highly significant in these groups throughout the study. At the highest dosage level there were effects on diet and water consumption, body weight gain and organ weights (liver, kidneys, spleen, testes, brain). At the intermediate dosage level, a decrease in water consumption was noted for both sexes. Body weight gain was reduced while liver and kidney weights (absolute and/or relative) were increased for the female rats. At the lowest dosage level, absolute liver and kidney weights and relative liver weights were increased for the females. These changes were possibly chemically induced.

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

no effects observed

Description (incidence and severity):

Histopathological examination revealed no treatment-related lesions associated with the ingestion of acrylic acid.

Other effects:

effects observed, treatment-related

Reproductive function: oestrous cycle:

not examined

Reproductive function: sperm measures:

not examined

Reproductive performance:

effects observed, treatment-related

Description (incidence and severity):

At the highest dose, a numerical reduction of the fertility (male and female) and gestation indices, pups born alive and pups weaned was observed.

Key result

Dose descriptor:

NOAEL

Effect level:

83 mg/kg bw/day

Sex:

male/female

Basis for effect level:

body weight and weight gain

organ weights and organ / body weight ratios

Key result

Dose descriptor:

NOAEL

Effect level:

250 mg/kg bw/day

Sex:

male/female

Basis for effect level:

reproductive performance

Critical effects observed:

not specified

Clinical signs:

no effects observed

Description (incidence and severity):

There were no significant abnormal clinical signs observed. There were no consistent findings in the spontaneous death of neonatal rats.

Mortality / viability:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

The effects at the highest dosage level of the parent generation were similar to those observed for the highest dosage level of the progeny. Here also, there were effects on body weight gain and organ weights (liver, heart, kidneys, brain, spleen).

Sexual maturation:

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Gross pathological findings:

no effects observed

Description (incidence and severity):

There were no gross lesions which could be attributed to treatment with acrylic acid.

Histopathological findings:

no effects observed

Description (incidence and severity):

Histopathological examination revealed no treatment-related lesions associated with the ingestion of acrylic acid.

Key result

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

250 mg/kg bw/day

Sex:

male/female

Basis for effect level:

other: Pup body and organ weights; number of pups born alive and pups weaned

Critical effects observed:

not specified

Reproductive effects observed:

not specified

Mean body weight changes (g)

Week of treatment	0 mg/kg/bw/d		83 mg/kg/bw/d		250 mg/kg/bw/d		750 mg/kg/bw/d
	male	female	male	female	male	female	male	female
Mean bw at day 0	124.5	99.4	124.0	101.3	125.3	102.4	121.4	99.0
1	29.8	12.7^x	28.6	14.2	31.2	13.8^x	24.1^a	10.6^a
2	62.2	26.8	56.8	27.6	63.1	23.5^a	51.3^b	21.4^c
3	89.2	37.6	83.4	38.1	91.7	36.6	75.7^b	30.0^c
4	112.2	47.6	106.5	46.7	111.1	45.4	93.6^b	36.9^c
5	130.3	55.6	126.7	55.8	128.6	52.5	106.7^b	41.6^c
6	145.3	63.6	142.2	63.8	141.8	58.6^a	119.0^c	47.2^c
7	159.5	69.4	154.2	70.3	153.0	63.6^a	127.8^c	49.8^c
8	171.8	73.3	167.7	74.1	162.6	67.1^a	125.6^c	52.1^c
9	181.1	75.9	176.4	77.2	170.1	69.2^a	131.6^c	53.0^c
10	191.4	79.9	187.6	81.0	180.0	73.3^a	139.2^c	55.2^c
11	200.1	82.4	194.9	83.3	185.4	74.5^b	142.8^c	57.4^c
12	205.2	84.4	200.6	86.0	191.7	78.0^a	144.7^c	58.6^c

^a0.05>p>0.01

^b0.01>P>0.001

^cP<0.001

^xOne clinically ill rat excluded from statistical evaluation of body weight gain.

Reproductive Performance

Parameter	Dose (mg/kg/bw/d)
	0	83	250	750
Fertility index (males)^a	80	100	80	60
Fertility index (female)^b	50	95	75	45
Gestation index^c	100	100	100	89
Gestation survival index^d	100	100	100	100
5-Day survival index^e	100	100	100	100
21-Day survival index^f	100	100	100	100
Pups born alive/Litter^g	6	8	9	4
Pups weaned/Pups alive at birth (100)^g	100	100	100	42

 ^aLitters sired per males mated x 100

^bDeliveries per females mated x 100

^cLitters with live pups/total pregnancies x 100

^dPups born viable/total pups delivered x 100, median per litter

^ePups viable at day 5/pups born viable x 100, median per litter

^fPups viable on day 21/pupe retained at day 5 x 100, median per litter

^gMedians

Reference 2

Endpoint:

two-generation reproductive toxicity

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

From May 19, 1992 to April 19, 1993

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 416 (Two-Generation Reproduction Toxicity Study)

GLP compliance:

yes

Limit test:

no

Specific details on test material used for the study:

- Name of test material (as cited in study report): Acrylic acid
- Analytical purity: ≥98.9%

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Strain: Wistar rats (Chbb = THOM (SPF))
- Source: Karl THOMAE, Biberach an der Riss, Germany
- Age at study initiation: (P): 35 ± 1 days
- Weight at study initiation: (P) Males: 140.0 (127 - 154) g; Females: 118.8 (106 - 130) g
- Housing: Single in type DK III stainless steel wire mesh cages, with the following exceptions: during mating periods, the males designated for mating were kept individually in Makrolon cages, type M III; for the overnight mating the females were put into the cages of the males. From day 18 of pregnancy until day 14 after birth, the pregnant animals and their litters were also housed in Makrolon type M III cages.
- Diet (ad libitum): Kliba maintenance diet rat/ mouse/hamster GLP 343 meal (KLINGENTALMUEHLE AG, Kaiseraugst, Switzerland)
- Water (ad libitum): Tap water
- Acclimation period: 8 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 24
- Humidity (%): 30 - 70
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

oral: drinking water

Vehicle:

water

Details on mating procedure:

- M/F ratio per cage: 1/1
- Length of cohabitation: a maximum of 3 weeks.
- Proof of pregnancy: sperm in vaginal smear referred as day 0 of pregnancy

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

The content of Acrylic acid in the aqueous solutions was determined by gas chromatography.

Duration of treatment / exposure:

Exposure period: F0: at least 70 days before the mating and afterwards during the gestation and lactation periods.
F1: at least 98 days before the mating and afterwards during the gestation and lactation periods.
Premating exposure period (males): at least 70 days
Premating exposure period (females): at least 70 days
Duration of test: approx. 12 months

Frequency of treatment:

continuously

Dose / conc.:

0 ppm (nominal)

Dose / conc.:

500 ppm (nominal)

Remarks:

corresponding to approx. 53 mg/kg bw/day

Dose / conc.:

2 500 ppm (nominal)

Remarks:

corresponding to approx. 240 mg/kg bw/day

Dose / conc.:

5 000 ppm (nominal)

Remarks:

corresponding to approx. 460 mg/kg bw/day

No. of animals per sex per dose:

25

Control animals:

yes, concurrent vehicle

Positive control:

none

Parental animals: Observations and examinations:

CLINICAL OBSERVATIONS:
All parental animals were checked daily for clinically evident signs of toxicity. Particular attention was given to the nesting, littering and lactation behaviour of the dams, but only special findings were documented.

BODY WEIGHT:
- Parental animals: generally, body weight was determined once weekly until the end of the study, and at the time of necropsy.
- F0 and F1 fertilized females and females with litter: body weight was determined on the day of sperm evidence in the vaginal smear and thereafter on days 7, 14 and 20 of gestation, one day after parturition, and on days 7, 14 and 21 post-parturition.
- Females without positive evidence of sperms: body weight was not determined during the mating interval.
- Females without litter: body weight was not determined during the lactation phase.

FOOD CONSUMPTION:
- F0 and F1 parental animals: food consumption was determined once weekly (over 7 days) during the period prior mating.
- Pregnant females: food consumption was determined for days 0-7, 7-14, 14-20 post coitum (pc).
- Lactating females: food consumption was determined for days 0-4, 4-7, 7-14 post parturition (pp).
- F0 and F1 dams between day 14 and 21 pp: food consumption was not determined for the F0 and F1 dams between day 14 and 21 pp, since during this period the pups started consumption of solid food; therefore there was no point in such a measurement.
- Females during mating period, females without positive evidence of sperms, females without litter: food consumption was not determined respectively during mating period, gestation period or lactation phase.

WATER CONSUMPTION:
- F0 and F1 parental animals: water consumption was determined once weekly (over 3 days) during the period prior mating.
- Pregnant females: water consumption was determined for days 0-1, 6-7, 13-14, 19-20 post coitum (pc).
- Lactating females: water consumption was determined for days 1-2, 3-4, 6-7, 13-14 post parturition (pp).
- F0 and F1 dams from day 20 and 21 pp: water consumption was not determined for the F0 and F1 dams for days 20 - 21, since during this period the pups started consumption of water; therefore there was no point in such a measurement.
- Females during mating period, females without positive evidence of sperms, females without litter: water consumption was not determined respectively during mating period, gestation period or lactation phase.

INTAKE OF TEST SUBSTANCE:
The intake of test substance (IT, in mg/kg bw/day) was calculated according to the following formula:

ITx = WCx * D / BWy

D = dose in ppm
WCx = daily water consumption on day x; in g
BWy = body weight on day y; in g

Oestrous cyclicity (parental animals):

not examined

Sperm parameters (parental animals):

not examined

Litter observations:

The pups (F1 and F2 litters) were examined as soon as on their day of birth for the determination of the total number of pups and the number of liveborn and stillborn pups (pups died on day of birth prior the first examination). Thereafter the pups were checked twice daily on workdays (once a day on week ends and public holidays) for mortality (i.e. dead and moribund pups) and the mortality (number and percentage) was determined for the day of birth (i.e. day 0) and for the periods: days 1 - 4, 5 - 7, 8 - 14 and 15 - 21 of lactation. Pups that died accidentally and had to be sacrificed because of maternal death were not considered for calculation. The number of surviving pups was determined for days 0, 4, 7, 14 and 21 of lactation and served for the calculation of the viability index and the lactation index.

The sex of the pups was determined on day 0 and day 21 (measurement of the anogenital distance, which is known to be greater in male pups than in females), and the sex ratio was calculated according to following formula:

- Sex ratio = number of live male or female pups on day 0/21 * 100 / number of live male and female pups on day 0/21

The pups were weighed on days 1, 4, 7, 14 and 21 after birth, and they were examined daily for clinical symptoms or gross morphological abnormalities. The determination of the relative organ weight was based on the pup body weight on day 21 after birth. The bodies of the sacrificed pups were examined for external abnormalities and the organs also were subjected to gross pathology; skeletal staining according to the modified Dawson´s method and/or further processing of the head according to Wilson´s method was done in case of abnormal findings. Stillborn pups as well as pups that died during weaning also were subjected to necropsy.

Development stages / Behavioral tests:
Physical development was assessed by monitoring pinna unfolding, opening of the auditory canal and opening of the eyes. Additional tests
were performed to assess grip reflex, hearing and pupillary reflex as follows :
- Grip reflex: Tested on day 13 after birth by placing front paws onto 3-mm diameter rod. For a positive response, the animal had to grip the bar and pull itself up.
- Hearing test: On day 21 after birth, animals were placed in a soundproof box and exposed to a sound (0 .1 sec, 5000 Hz, about 90 dB); a startle reflex was considered a response to this stimulus.
- Pupillary reflex: On day 2l after birth, pupillary constriction reflex was assessed by shining a penlight on the eye and observing the reaction.

Postmortem examinations (parental animals):

SACRIFICE
Parental animals were killed by decapitation under CO2 anaesthesia and examined macroscopically.

GROSS NECROPSY
Terminal body weights as well as the weights of liver, kidneys, epididymides and testes were recorded .

HISTOPATHOLOGY / ORGAN WEIGHTS
Liver, kidneys and stomach (non-glandular and glandular).

Postmortem examinations (offspring):

SACRIFICE
Pups were killed by CO2 asphyxiation, examined externally, eviscerated and their organs assessed macroscopically.

GROSS NECROPSY
External and internal examinations including the cervical, thoracic, and abdominal viscera.

HISTOPATHOLOGY
Vagina, cervix, uterus, ovaries, oviducts, testes, epididymides, seminal vesicles, coagulation gland, oesophagus and duodenum.

Statistics:

The statistical assessment of the different data obtained within the present study was based on following methods, depending on the parameters considered: Dunnett test, Fisher`s exact test and Wilcoxon test.

Reproductive indices:

Mating and fertility indices were calculated according to following formulas:

- Male mating index (%) = number of males with confirmed mating * 100 / number of males placed with females

- Male fertility index (%) = number of males proving their fertility * 100 / number of males placed with females

Remark:
Males were defined as “with confirmed mating” by the presence of vaginal sperm in the female, or by the production of a litter, or by the presence of fetuses in the uterus.
Males were defined as “proving their fertility” by female giving birth to a litter or having pups or fetuses in the uterus.

Reevaluation of fertility:
If an animal of the F0 or F1 generation parental animals had not produced any offspring after the scheduled mating of F0 parents (to get F1 litter) or after the scheduled mating of F1 parents (to get of F2 litter), those animals treated with the test substance were mated with fertile animals of the control groups. Animals of the control groups which seemed to be infertile were mated with mating partners with proven fertility of the controls.
After fertility had been reevaluated, the animals were sacrificed and subjected to gross-pathological and histopathological assessments. The uteri of the females reevaluated for fertility were examined for live and dead implantations. In the case of an apparently non-pregnant animal or of an empty uterus horn in the case of single-horn pregnancy, the uterus was stained with sodium sulfide and assessed for early implantations. Then the uteri were rinsed carefully under running water. After these examinations were completed, the uteri were transferred to the pathology lab for further fixation and evaluation.

Offspring viability indices:

- Viability index (%) = number of live pups on day 4 after birth * 100 / number of liveborn pups on the day of birth

- Lactation index (%) = number live pups on day 21 after birth * 100 / number of live pups on day 4 after birth

Remark:
Day 4 after birth preceded standardization of the litters.
Day 21 after birth followed standardization of the litters.

Clinical signs:

no effects observed

Description (incidence and severity):

No clinical signs which might be attributed to the test substance were detected in male or female F0 generation parental animals. The 3 concentrations administered in the drinking water did not lead to disturbances of the general behaviour in any of the F0 parental animals.
There were no particular substance-related clinical findings in F0 females during the gestation period for F1 litter. Insufficient nesting activity was observed for several dams of all groups including the controls.
No substance-related clinical findings were recorded for the F0 dams during the F1 lactation period.

Mortality:

no mortality observed

Description (incidence):

There were no mortalities in any of the F0 generation parental animals in any of the groups.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

In the F0 males statistically significant reductions in mean body weights were seen in the highest dose group (5000 ppm) from week 12 until week 20 of the study period. Body weight changes of the high dose males were statistically significantly diminished only at certain study intervals (weeks 0-1, 6-7, 11-12); if calculated for the total study period (weeks 0-20), body weight gain of the high dose males was about 9% lower than that of the respective controls.
Body weights and weight gains of the substance-treated females were similar to control values during the premating period and during gestation and lactation. Only during the first week of gestation did the high dose dams gain statistically significantly less weight than the corresponding controls. Finally the impairments in body weight/body weight gain in the high dose F0 males and - to a lesser extent - in the F0 females are assessed as being substance-related effects. All other statistically significant differences in body weights and body weight gains are considered unrelated to the test substance because the values were not influenced in a dose-dependent manner and/or are within the biological range of variation.

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

In general, the food consumption of the males (during the premating period) and of the females (during premating, gestation and lactation periods) of all test groups was not influenced by the test substance administration. It was, however, slightly, but statistically significantly reduced in the high dose males during the first week of the premating period and in the females of 5000 ppm test group during the second week of the lactation period. The sporadic and only marginal reductions in food consumption of the 5000 ppm rats are probably related to the reduced consumption of aqueous acrylic acid solutions of these animals and thus are likely indirectly associated with the administration of the test substance. All other observable differences between the groups are without biological relevance, because they are not dose-related; this includes the statistically significantly increased food consumption of the low dose females during study weeks 0-1 and 6-7 of the premating period.

Water consumption and compound intake (if drinking water study):

effects observed, treatment-related

Description (incidence and severity):

The water consumption of the high dose male and female animals was clearly reduced. This reduction was statistically significant during the premating period. It was also diminished in the 5000 ppm females during gestation and lactation of F1 litter. In total the 5000 ppm males consumed about 11% and the high dose females about 13% less drinking water (aqueous acrylic acid solutions) then the respective controls during the first 10 study weeks. The marked reduction in the drinking water consumption of the high dose rats was associated with the test substance administration. All other observable differences between the groups in respect to water consumption are without biological relevance, because they are not dose-related; this includes the statistically significantly increased water consumption of the 500 ppm female animals during premating weeks 6-7 and 9-10.

Organ weight findings including organ / body weight ratios:

no effects observed

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Other effects:

effects observed, treatment-related

Reproductive function: oestrous cycle:

not examined

Reproductive function: sperm measures:

not examined

Reproductive performance:

no effects observed

Description (incidence and severity):

For all F0 males which were placed with females to generate F1 pups mating was confirmed; thus, the male mating index was 100% in all groups. For nearly all F0 males fertility could be confirmed within the scheduled mating interval; the fertility index varied between 92% and 96% with no treatment related effect. Thus, the fertility of the F0 generation parental males was not adversely influenced by the administration of aqueous acrylic acid solutions.
The female mating index calculated after the mating period for F1 litter was 100% for all groups. The mean duration until sperm was detected (day 0 pc) varied between 1.8 and 3.8 days and was statistically significantly longer for the high dose dams; the high dose value (3.8 days), however, is substantially similar to the mean cohabitation time value of the control group (3.2 days) of the second parental generation (F1 animals) and therefore was not considered treatment-related. Only one or two females in all groups, including the controls, did not become pregnant within the scheduled mating interval. The fertility index varied between 92% and 96% without any dose-response relationship. All females in question except the 2 low dose females proved to be fertile after being mated again with control males. The mean duration of gestation was similar in all groups and the gestation index reached 100% for all groups. The mean number of pups delivered/dam was uninfluenced by the test substance administered. The number of liveborn and stillborn pups was comparable between the groups, and the live birth index was 98% in test groups. Thus, the administration of aqueous acrylic acid solutions did not adversely affect reproduction and delivery data of the F0 generation parental females.

Key result

Dose descriptor:

NOAEL

Remarks:

sytemic

Effect level:

240 mg/kg bw/day

Sex:

male/female

Basis for effect level:

other: general toxicity

Key result

Dose descriptor:

NOAEL

Remarks:

fertility

Effect level:

460 mg/kg bw/day

Sex:

male/female

Basis for effect level:

other: highest dose tested

Key result

Critical effects observed:

no

Clinical signs:

no effects observed

Description (incidence and severity):

No clinical signs which might have been attributed to the test substance administered were detected in male or female F1 generation parental animals. The 3 doses administered in drinking water did not lead to disturbances of the general behavior in any of the F1 parental animals. One male animal of 2500 ppm test group developed a severe skin lesion on the base of the tail and was sacrificed in a moribund state. Another male of the same dose group showed unilateral chromodacryorrhea. The clinical findings which occurred in just two intermediate dose males were spontaneous in nature.
No particular clinical findings were noted for F1 dams with positive sperm detection except insufficient or no nesting activity, which was recorded for several dams of all groups (0, 500, 2500 and 5000 ppm) and which occurred without a clear dose-response relationship. One female of the low dose group showed vaginal hemorrhage towards or after the end of the gestation period (days 23 - 26 pc), and was not able to deliver the pups, which were palpable earlier in the abdomen of this dam. After day 26 pc, no pups could be palpated for this dam.
There were no substance-related clinical findings in the F1 dams during the lactation of F2 litters. Only one dam of the low dose group and one dam of the high dose group did not nurse their pups properly; all pups of high dose dam were cannibalized and/or died intercurrently. Furthermore, another low dose dam showed blood in bedding during the first days of the lactation period, and was not able to deliver its litter completely. It delivered only 2 pups which were cannibalized on day 1 pp.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

In the F1 males, statistically significant reductions in mean body weights were seen in the highest dose group (5000 ppm) throughout the total study period (about 87% of the control value at the end of this study interval). Body weight gains of the 5000 ppm males, however, were generally similar to the respective control values. In total, the weight gain of the high dose F1 males was only about 5% lower than the body weight gain of the control males. Body weights of the 5000 ppm females were also statistically significantly reduced during the premating period (about 89% of the control value at the end of the premating phase). During gestation and lactation of F2 litter, mean body weights of the high dose F1 dams were statistically significantly lower than the corresponding control values. During premating, gestation and lactation periods body weight gain of the high dose females reached or even exceeded body weight gain of the controls.
The statistically significantly lower body weights recorded for the 5000 ppm F1 males and females were considered to be related to the test substance administration. A lower body weight was also recorded for these animals at the pup stage; during the following premating period the F1 parental animals of the high dose group gained substantially as much weight as the controls, but the body weights of the 5000 ppm rats were still reduced. All differences between the controls and 500 or 2500 ppm groups concerning body weights/weight gains, however, were regarded as spontaneous in nature.

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

The mean food consumption of the males and females of 5000 ppm test group was clearly reduced during the premating period, the differences in comparison to the controls being statistically significant at most time intervals. In total, the high dose males consumed about 9% and the females about 8% less food than the respective control animals during the premating phase. Food intake was also statistically significantly diminished in the females of this test group (5000 ppm) during the gestation period (days 7-20 pc) and during the lactation period (days 7-14 pp only). The reduction in food consumption of the 5000 ppm males and females was considered to be related to the administration of the test substance. All other differences in food consumption between the groups are without any biological relevance.

Water consumption and compound intake (if drinking water study):

effects observed, treatment-related

Description (incidence and severity):

In comparison to the respective control values the water consumption of the 2500 and 5000 ppm F1 males and females was distinctly lower during the premating period, the differences being statistically significant at all intervals in the high dose level and in several but not all intervals at the intermediate dose. In total a clear dose-response relationship was observed: high dose males consumed about 18%, intermediate dose males about 9% less water than control males; for high dose females about 27% and for intermediate dose females about 13% less water intake than in the female controls was recorded. Water consumption was also reduced during gestation and lactation periods in these test groups, again more pronounced in the high than in the 2500 ppm group. The water consumption of the animals of the low dose group (500 ppm) reached or even exceeded the relevant control values during premating, gestation and the lactation periods. The distinct reductions in the drinking water consumption in both sexes at 2500 and 5000 ppm are considered treatment-related, whereas the differences in water consumption between the low dose group and the control are considered to be without toxicological relevance.

Gross pathological findings:

effects observed, non-treatment-related

Description (incidence and severity):

- 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.

Reproductive performance:

no effects observed

Description (incidence and severity):

For all F1 males which were placed with females to generate F2 pups, mating was confirmed. The male mating index was 100% in all groups. The female mating index reached 100% in all groups. The mean duration until sperm was detected (day 0 pc) varied between 2.1 and 3.2 days and was highest for the control group, because one dam of this group had a prolonged cohabitation time. In the scheduled mating interval (F2), 2 control females did not become pregnant. Therefore, the fertility index was lowest in the control group (92%), whereas it was 100% in all substance-treated groups. There were no biologically relevant differences between test groups and the controls concerning the mean duration of gestation and the number of liveborn and stillborn F2 pups. All pregnant females - except one low dose female which had palpable pups in the uterus but did not deliver - gave birth to litters with liveborn pups. Consequently, the gestation and the live birth indices were not influenced by the administration of the test substance. The mean number of delivered pups/dam was not influenced by the test substance administered.

Clinical signs:

no effects observed

Description (incidence and severity):

- None of the F1 pups of any one group showed abnormal clinical findings during the lactation period.
- There were no biologically relevant differences between the control and the substance-treated F1 pups in the several morphological development stages monitored up to weaning.
- No remarkable differences between the groups were observed in the different behavioral tests which the pups underwent up to weaning.
- Only spontaneous findings were seen at necropsy (e.g. incisors sloped, hernia diaphragmatica, dilated renal pelvis) in very few of the pups examined. All findings were present in the concurrent control at a comparable frequency and/or did not show a clear relation to dosing.

Mortality / viability:

no mortality observed

Description (incidence and severity):

No substance-induced effects on pup mortality/viability were recorded during the lactation period. Both the viability index, as an indicator of the viability of the pups during the first 4 days after birth, and the lactation index, as an indicator how the pups were nursed during the rest of their rearing, do not show differences of biological relevance.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Mean body weights of F1 male and female pups were clearly reduced in 5000 ppm test group from day 14 pp onwards and impaired in the intermediate dose (2500 ppm) on day 21 pp when compared to the controls. On day 21 pp the pup weights (both sexes combined) in the high dose group were about 35% and those of the 2500 ppm pups about 11% lower than the corresponding control values. Body weight gains of the 2500 ppm and 5000 ppm pups were also statistically significantly decreased from days 7 (5000 ppm) or 14 pp (2500 ppm) up to weaning (day 21 pp). The reductions in pup body weights/body weight gains in the 5000 and 2500 ppm groups were attributed to the test substance administration. All other differences concerning pup body weights/body weight gains are without any biological relevance and lie within the biological range of variation.

Sexual maturation:

no effects observed

Description (incidence and severity):

The sex distribution and sex ratios of live F1 pups on the day of birth and on day 21 post parturition (pp) did not show any substantial difference between controls and treated groups; all differences observed are regarded as spontaneous.

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Gross pathological findings:

no effects observed

Histopathological findings:

no effects observed

Key result

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

53 mg/kg bw/day

Sex:

male/female

Basis for effect level:

other: general toxicity

Key result

Critical effects observed:

no

Clinical signs:

no effects observed

Description (incidence and severity):

F2 generation pups did not show any clinical signs up to weaning which could be attributed to the treatment. Hydrocephaly, which occurs also occasionally in control pups was recorded in one 500 ppm pup. No substantial differences could be noted between the F2 pups of all test groups and the control pups in the different behavioral tests. The observable differences were without biological relevance.

Mortality / viability:

mortality observed, non-treatment-related

Description (incidence and severity):

The mean number of delivered F2 pups/dam in the treatment groups was similar to the relevant control value; moreover, the percentages of liveborn and stillborn F2 pups were comparable between the groups; all differences between the groups are in the range of biological variation.
During the lactation period a statistically significant increase in pups cannibalized by dams was noted in the high and intermediate dose groups. The increased cannibalization rate was predominantly caused by just one intermediate dose dam and two high dose dams. One Female of the high group, however, neglected her pups during the lactation period, thus nearly all pups of this dam died before schedule and/or were cannibalized. Occasionally insufficient nursing behaviour and cannibalism occurred also in control females, and thus the higher rate of cannibalized pups at these dose levels was not considered treatment-related.
There were no differences in biological relevance between the control and the 500, 2500 and 5000 ppm F2 pups concerning viability and mortality; consequently the viability and lactation indices were not affected by the test substance administration (although some statistically significant differences existed). All relevant values are inside the historical control range and/or do not show a clear relation to dosing; moreover it had to be taken into consideration, that the high dose dams delivered on average distinctly more pups (14.0 pups/dam) than the controls (12.9 pups/dam).

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Mean body weights/body weight gains of the F2 male and female pups of the 5000 ppm and 2500 ppm groups were clearly influenced by the test substance administration. Mean pup body weights of the 5000 ppm pups were statistically significantly lower than the corresponding control values from days 14 (males and females) until weaning on day 21 pp, when the high dose pups (both sexes combined) weighed about 32% less than the controls. Mean pup body weights of the 2500 ppm pups were statistically significantly (about 12%) lower than the corresponding control values on day 21 pp (both sexes combined). Weight gains of the pups of the 2500 and 5000 ppm test groups were also statistically significantly reduced from the second week of the lactation period onward, the reduction more pronounced in the 5000 ppm than in the 2500 ppm pups. All differences between the control group and the 500 ppm group concerning pup body weight data of the F2 generation were considered spontaneous in nature.

Sexual maturation:

no effects observed

Description (incidence and severity):

No remarkable differences between the control and the substance-treated groups were found in respect to the sex ratio of the F2 pups. The observable differences are in the range of biological variation.

Gross pathological findings:

effects observed, non-treatment-related

Description (incidence and severity):

The examinations of F2 pups at necropsy did not reveal any differences considered to be of biological relevance between the controls and the substance-treated groups either in the type or in the number of pup necropsy observations. A few pups of the different groups showed some spontaneous findings like hernia diaphragmatica, incisors sloped, dilated renal pelvis, hydroureter, hydrocephaly, focal liver necrosis, cardiomegaly, septal defect and post mortem autolysis.

Histopathological findings:

effects observed, non-treatment-related

Description (incidence and severity):

There was a statistically significantly lower incidence of F2 pups/litter with auditory canal opening on time in the intermediate dose group and with eye opening on time in the 5000 ppm group. The relevant values were within the historical control ranges and a clear relation to dosing was not observed. These effects must be considered in conjunction with the retarded weight gain of these pups and were therefore assessed as being possibly substance-related. There were no differences of biological relevance in different stages of development between the low dose and the control pups.

Key result

Dose descriptor:

NOAEL

Generation:

F2

Effect level:

53 mg/kg bw/day

Sex:

male/female

Basis for effect level:

other: general toxicity

Key result

Critical effects observed:

no

Key result

Reproductive effects observed:

no

Mean Body Weight Changes (F0 parental animals), grams

Treatment week	0 mg/kg bw/d		53 mg/kg bw/d		240 mg/kg bw/d		460 mg/kg bw/d
	male	female	male	female	male	female	male	female
0 - 1	52.6	23.8	52.2	24.8	52.3	23.6	46.7^**	23.1
1 - 2	53.7	22.1	55.5	22.0	54.4	22.3	51.6	21.8
2 - 3	47.2	16.2	45.8	17.2	46.9	17.5	44.8	14.6
3 – 4	35.4	12.9	34.8	17.1^*	35.1	14.9	32.4	17.8^*
4 – 5	29.1	15.7	27.6	13.3	28.6	12.6	27.0	13.7
5 – 6	21.0	9.4	21.8	8.8	23.3	12.5	23.2	11.0
6 – 7	23.2	8.5	24.7	11.7	21.2	10.1	19.3^*	10.7
7 – 8	20.4	7.7	17.7	10.3	19.8	7.8	18.5	8.6
8 – 9	19.3	9.8	19.1	7.1	18.0	7.2	16.6	8.1
9 – 10	13.1	4.7	13.0	4.5	14.6	7.9^*	11.9	6.0
10 – 11	-7.0		-2.8		-2.8		-2.8
11 – 12	21.8		18.5		18.4		14.7^**
12 – 13	14.8		13.3		13.7		11.1
13 – 14	8.0		10.7		9.7		6.1
14 – 15	9.2		7.0		7.5		8.1
15 – 16	10.5		10.4		8.0		9.9
16 – 17	5.7		7.9		7.3		4.6
17 – 18	2.7		4.6		1.7		1.4
18 – 19	1.1		0.2		1.3		1.6
19 - 20	4.1		6.7		5.8		5.0

^*P<0.05

^**P<0.01

Reproduction and litter data for F0 parents /F1 pups

	0 ppm	500 ppm	2500 ppm	5000 ppm
Parents
Females mated	25	25	25	25
Females pregnant	24	23	23	24
Females with delivery	24	23	23	24
Mean duration of gestation (d)	22.0	21.9	21.9	21.9
Litter means
Live births/litter	13.8	13.8	13.7	14.3
Survivors day 4 preculling	13.3	13.5	13.4	13.8
Survivors day 4 postculling	7.5	7.9	7.9	7.9
Survivors day 21	7.5	7.9	7.8	7.8
Weight at day 1 (g) M/F	6.4/6.1	6.6/6.2	6.5/6.2	6.5/6.2
Weight at weaning (g) M/F	52.3/50.01	52.1/49.4	46.6^**/44.6^**	34.2^**/32.7^**
Sex ratio of live newborns % M/F	51/49	49/51	55/45	53/47
Selected as parents for the next generation M/F	25/25	25/25	25/25	25/25

^**P≤0.01

Reproduction and litter data for F1 parents /F2 pups

	0 ppm	500 ppm	2500 ppm	5000 ppm
Parents
Females mated	25	25	25	25
Females pregnant	23	23	23	24
Females with delivery	23	23	23	24
Mean duration of gestation (d)	22.0	21.9	21.9	21.9
Litter means
Live births/litter	12.5	11.6	12.0	13.8
Survivors day 4 preculling	11.8	10.6	10.8	12.5
Survivors day 4 postculling	7.7	7.0	7.5	7.8
Survivors day 21	7.7	6.9	7.5	7.4
Weight at day 1 (g) M/F	6.3/5.9	6.5/6.2	6.1/5.8	6.4/6.1
Weight at weaning (g) M/F	50.4/48.4	52.1/49.4	44.6^**/42.4^**	34.5^**/33.2^**
Sex ratio of live newborns % M/F	47/53	55/45	53/47	49/51

^**P≤0.01

Development landmarks in the F2 (mean % of pups reaching criteria/litter)

Parameter	0 ppm	500 ppm	2500 ppm	5000 ppm	Historical control range
Pinna unfolding	93.6 (16.65)	93.5 (20.87)	80.7 (33.37)	86.9 (26.87)	74-100
Auditory canal opening	98.8 (3.87)	95.1 (20.90)	91.4^*(18.09)	94.2 (12.26)	81-100
Eye opening	93.2 (18.08)	92.4 (21.89)	92.4 (21.89)	86.5^*(21.15)	85-100

^*P≤0.05

Figures in parentheses indicate standard deviations.

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

460 mg/kg bw/day

Species:

rat

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

No experimental data on the test substance is available.

Sodium acrylate is the sodium salt of acrylic acid, only the proton of the hydroxy group has been replaced by a sodium ion in NaA. Both are equally charged ions.pH dependent sodium acrylate dissociates into acrylic acid and sodium hydroxid in aqueous media.

According to Henderson-Hasselbalch: pH = pKs + lg (c(NaAcrylate) / c(Acrylic acid))

With the pKa-value of acylic acid = 4.25.

The ratio c(NaAcrylate) / c(Acrylic acid) was caluclated according to the Henderson-Hasselbalch equation: c(NaAcrylate) / c(Acrylic acid)) = 10 pH - pKs

pH 1 : c(NaAcrylate) / c(Acrylic acid)) = 10 1 – 4,25 = 0,00056; ~ 99,94 % as acrylic acid

pH 3 : c(NaAcrylate) / c(Acrylic acid)) = 10 3 – 4,25 = 0,056; t ~ 94,7 % as acrylic acid

pH 5 : c(NaAcrylate) / c(Acrylic acid) = 10 5 – 4,25 = 5,62; ~ 15,1 % as acrylic acid

pH 7 : c(NaAcrylate) / c(Acrylic acid) = 10 7 – 4,25 = 562,3; ~ 0,2 % as acrylic acid

Especially after oral uptake in the acidic environment in the stomach sodium acrylate is nearly completely dissociated to acrylic acid. Therefore, it is appropriate to use the human health hazard data of acrylic acid for the assessment of sodium acrylate. In respect to the hazard data on ecotoxicity, using the acrylic acid data assuming a complete dissociation reflects the worst case.

Therefore, the evaluation of the endpoint toxicity to reproduction is based on a weight of evidence approach using the toxicological data of the structural analogue acrylic acid (CAS 79-10-7) (for WoE information, see chapter 13.2).

 

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 (IATG, 1980), 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/d). 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):

F0 generation:

460 mg/kg bw/d 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 bw/d)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 bw/d) 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 bw/d) 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 bw/d). The NOAEL with respect to general toxicity of the test substance was 2500 ppm (= approx. 240 mg/kg bw/d) for the F0 generation parental animals and 500 ppm (= approx. 53 mg/kg bw/d)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 similarities to acrylic acid, the test substance is not anticipated to have any effect on fertility.

Effects on developmental toxicity

Description of key information

No experimental data on the test substance is available.

Sodium acrylate is the sodium salt of acrylic acid, only the proton of the hydroxy group has been replaced by a sodium ion in NaA. Both are equally charged ions.pH dependent sodium acrylate dissociates into acrylic acid and sodium hydroxid in aqueous media.

According to Henderson-Hasselbalch: pH = pKs + lg (c(NaAcrylate) / c(Acrylic acid))

With the pKa-value of acylic acid = 4.25.

The ratio c(NaAcrylate) / c(Acrylic acid) was caluclated according to the Henderson-Hasselbalch equation: c(NaAcrylate) / c(Acrylic acid)) = 10 pH - pKs

pH 1 : c(NaAcrylate) / c(Acrylic acid)) = 10 1 – 4,25 = 0,00056; ~ 99,94 % as acrylic acid

pH 3 : c(NaAcrylate) / c(Acrylic acid)) = 10 3 – 4,25 = 0,056; t ~ 94,7 % as acrylic acid

pH 5 : c(NaAcrylate) / c(Acrylic acid) = 10 5 – 4,25 = 5,62; ~ 15,1 % as acrylic acid

pH 7 : c(NaAcrylate) / c(Acrylic acid) = 10 7 – 4,25 = 562,3; ~ 0,2 % as acrylic acid

Especially after oral uptake in the acidic environment in the stomach sodium acrylate is nearly completely dissociated to acrylic acid. Therefore, it is appropriate to use the human health hazard data of acrylic acid for the assessment of sodium acrylate. In respect to the hazard data on ecotoxicity, using the acrylic acid data assuming a complete dissociation reflects the worst case.

Data on the structural analogue acrylic acid which has been extensively studied, is 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 two-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 air) and 225 ppm (rabbits) (= approx. 0.673 mg/L air), respectively. According to the present database acrylic acid does not show any potential to cause toxicity to reproduction.

Link to relevant study records

Reference

Reference 1

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

GLP compliance:

yes

Limit test:

no

Specific details on test material used for the study:

- Name of test material (as cited in study report): Acrylic acid, pure
- Analytical purity: 99.74%
- Impurities (identity and concentrations): Diacrylic acid 0.22%, Acetic acid 0.12%, Propionic acid 0.12%, the concentrations of other imputies were < 0.02%
- Test substance No.: 80/386

Species:

rat

Strain:

Sprague-Dawley

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River, Wiga GmbH, D-Sulzfeld
- Age at study initiation: 10 weeks old
- Weight at study initiation: mean weight 215 g
- Housing: Single in Makrolon/wire cages (type MD III supplied by Becker & Co., Castrop-Rauxel)
- Diet (ad libitum): SSNIFF R meal, Ssniff Versuchstierdiaeten GmbH, CH-Soest
- Water (ad libitum): Tap water

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 2
- Humidity (%): 55 ± 5
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

inhalation: vapour

Type of inhalation exposure (if applicable):

whole body

Vehicle:

unchanged (no vehicle)

Details on exposure:

Exposures were conducted using a continuous infusion pump (type Infu 362). Acrylic acid was metered into the inner coil of a glass evaporator heated by hot water. The acrylic acid vapours were diluted with a flow of fresh conditioned air with a flow meter. This mixture of acrylic acid vapour and air was passed through a glass cooler, thermostated cold water at 8-10°C being passed through its inner coil. The mixture of acrylic acid vapour and air was thus cooled to 23°C and passed to the exposure chambers (made of glass and steel, volume about 500 liters). The following amounts of test substance were used: 1.15 ml/h (study group 1, 40 ppm), 3.4 ml/h (study group 2, 120 ppm), 10.2 ml/h (study group 3, 360 ppm). The temperature in all exposure chambers was continuously monitored using NTC sensors and the measured values were recorded using a 12-channel printer.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

The concentration of acrylic acid in the exposure chambers was determined using a continuously operating total hydrocarbons analyzer equipped with a flame ionization detector.
Nominal concentrations (ppm): 40.7, 120.3, 361
Analytical concentrations (ppm): 39.4, 114.0, 356.2

Details on mating procedure:

- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1/1
- Length of cohabitation: 15.5 hours
- Verification of same strain and source of both sexes: yes
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy

Duration of treatment / exposure:

from day 6 to day 15 of gestation

Frequency of treatment:

6 hours/day

Duration of test:

until day 20 of gestation

Dose / conc.:

40 ppm

Remarks:

corresponding to approx. 0.12 mg/L. Recalculation based on the equation c(mg/m3) = molar mass (g) / molar volume (L) x c(mL/m3) with molecular weight (72.06 g/mol) and molar volume (24.1 L at 20 °C and 1013 hPa) [DFG, 2005]

Dose / conc.:

120 ppm

Remarks:

corresponding to approx. 0.36 mg/L. Recalculation based on the equation c(mg/m3) = molar mass (g) / molar volume (L) x c(mL/m3) with molecular weight (72.06 g/mol) and molar volume (24.1 L at 20 °C and 1013 hPa) [DFG, 2005]

Dose / conc.:

360 ppm

Remarks:

corresponding to approx. 1.08 mg/L. Recalculation based on the equation c(mg/m3) = molar mass (g) / molar volume (L) x c(mL/m3) with molecular weight (72.06 g/mol) and molar volume (24.1 L at 20 °C and 1013 hPa) [DFG, 2005]

No. of animals per sex per dose:

30

Control animals:

yes, sham-exposed

Maternal examinations:

CAGE SIDE OBSERVATIONS: not specified

DETAILED CLINICAL OBSERVATIONS: Yes
Prior to the exposure period, animals were observed for clinical signs once daily. Preceding and following each exposure, individual does were observed for clinical signs of toxicity.

BODY WEIGHT: Yes
- Time schedule for examinations: On gestation day 0, 3, 6 9 12, 15, 18 and 20

FOOD CONSUMPTION: Yes
- The feed consumption by each animal was determined on gestation day 0, 3, 6 9 12, 15, 18 and 20

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20
- Organs examined: The uteri and ovaries were removed. The uteri were weighed. The number of corpora lutea, implantation sites for each hern of the uterus, dead and live implatations and fetuses were determined.

Ovaries and uterine content:

The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes

Fetal examinations:

Living fetuses were weighed, sexed, and examined for externally detectable changes. In addition, attention was paid to the viability of the fetuses, the length of the umbilical cord and the condition of the fetal membranes and amniotic fluid. One-third of the fetuses of each dam were fixed in Bouin's solution and examined for internal soft tissue changes. In order to assess the skeletal system, two-thirds of the living fetuses of each dam were initially fixed in 96% alcohol, then clarified with potassium hydroxide solution and stained with Alizarin red S. The fetuses were stored in 100% glycerol.

- External examinations: Yes: all per dam
- Soft tissue examinations: Yes: one-third per dam
- Skeletal examinations: Yes: two-thirds per dam

Statistics:

Quantitative continuous random variables, eg. body weight data or food consumption data, were examined with the Williams test. Discrete random variables, eg. number of corpora lutea, number of implantations, or percentage values, such as live fetuses as a percentage of total implantations, fetuses with anomalies (or variations, retardations) as a percentage of total fetuses investigated, were examined with a linear rank test of Krauth. The Fisher test was used for the comparison of frequencies, eg. number of litters with anomalies (or variations, retardations) in relation to the number of litters investigated. All tests were performed with type I error of = 0.05 and = 0.01. The linear rank test and the Fisher test were carried out with a Bonferroni correction, but including additional information. If the Bonferroni corrected test did not show any significance for = 0.05, the comparison was calculated with uncorrected = 0.05. The linear rank test and the Fisher test were calculated by counting all possible permutations.

Clinical signs:

effects observed, non-treatment-related

Description (incidence and severity):

The animals in groups 0, 1 and 2 showed no signs of behavior differing from normal during the period of exposure. Starting with the 1st exposure, the animals in group 3 showed pronounced watery discharge from the eyes and nose, and there was occasional wiping of their snouts and restless behavior. The signs disappeared rapidly after each exposure so that the animals were normal again after 1 - 2 hours.

Mortality:

no mortality observed

Description (incidence):

No animal died in any group.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

The body weights and the body weight gains of the pregnant animals in groups 1 and 2 (40 ppm and 120 ppm) show, compared to the control group, no relevant differences which could be attributed to an effect of the substance.
An effect of the substance of the nature of a significantly (99% significance) Lower body weight, and an appropriate adverse effect on the body weight gain, was noticeable in group 3 (360 ppm) during the exposure period (6th - 15th day of gestation). After the end of the period of exposure to acrylic acid, the pregnant animals in all groups increased in weight to the same extent (no adverse effect on the body weight gain), but the body weights of the animals in group 3 (360 ppm) remained significantly (99% significance) Lower than in the control group up to the Last day of the observation period (20th day of gestation). Thus, a marked toxic effect on the dams due to inhalation of acrylic acid was demonstrated in the group at the highest concentration (360 ppm).

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

The feed consumption of the animals in groups 1 and 2 (40 ppm and 120 ppm) did not differ from the control group over the entire period of the study. A marked effect of exposure to acrylic acid was detected at the highest concentration (360 ppm) in group 3. The feed consumption was lower, with 99% significance, during the exposure period (6th - 15th day of gestation), but no effect of this type was detectable in the follow up observation period.

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

At the highest dose group smaller difference between body weight and uterus weight was reported.

Gross pathological findings:

no effects observed

Description (incidence and severity):

No pathological changes which could be attributed to the inhaled substance were found on macroscopic examination of the internal organs of the animals.

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

not examined

Histopathological findings: neoplastic:

not examined

Number of abortions:

no effects observed

Pre- and post-implantation loss:

no effects observed

Total litter losses by resorption:

no effects observed

Early or late resorptions:

no effects observed

Dead fetuses:

no effects observed

Changes in pregnancy duration:

not examined

Changes in number of pregnant:

no effects observed

Details on maternal toxic effects:

Indications of a toxic effect on the dams emerged at 120 ppm (decreased consumption of feed during the exposure phase and a smaller difference between the body weight and uterus weight after necropsy). A marked toxicity on the pregnant animals was detected at 360 ppm (lower body weight, body weight gain slowed down, decreased consumption of feed, smaller difference between body weight and uterus weight, and clinical signs of an irritant effect caused by acrylic acid vapours).

Key result

Dose descriptor:

NOAEC

Effect level:

0.12 mg/L air (nominal)

Basis for effect level:

other: maternal toxicity

Key result

Dose descriptor:

LOAEC

Effect level:

0.36 mg/L air (nominal)

Basis for effect level:

other: maternal toxicity

Key result

Abnormalities:

no effects observed

Fetal body weight changes:

effects observed, non-treatment-related

Description (incidence and severity):

Although the dams lost weight, no negative effect on the fetal weight was seen. In fact, the fetuses in the 120 ppm and 360 ppm groups were heavier, but this is very probably an incidental finding.

Reduction in number of live offspring:

no effects observed

Changes in sex ratio:

no effects observed

Changes in litter size and weights:

no effects observed

Changes in postnatal survival:

not examined

External malformations:

effects observed, non-treatment-related

Description (incidence and severity):

No significant difference between the groups was found.

Skeletal malformations:

effects observed, non-treatment-related

Description (incidence and severity):

No significant difference between the groups was found.

Visceral malformations:

effects observed, non-treatment-related

Description (incidence and severity):

No significant difference between the groups was found.

Key result

Dose descriptor:

NOAEC

Remarks:

teratogenicity

Effect level:

>= 1.08 mg/L air (nominal)

Basis for effect level:

other: highest dose tested

Key result

Abnormalities:

no effects observed

Key result

Developmental effects observed:

no

ANlMALS WITH CESAREAN SECTION

	Group 0 0 PPM	Group 1 40 PPM	Group 2 120 PPM	Group 3 360 PPM
Number of Animals	25	27	26	25
CORPORA LUTEA
Total	424	430	437	410
M	16.96	15.93	16.81	16.40
ME	16.00	16.00	16.00	17.00
QD	2.00	2.00	1.63	1.50
K (A)
IMPLANTATIONS
Total	324	337	324	310
M	12.96	12.48	12.46	12.40
ME	14.00	14.00	13.50	14.00
QD	3.00	2.00	2.63	2.50
K (A)
LIVE FETUSES
Total	298	319	309	292
M	11.92	11.81	11.88	11.68
% IMPLANTATIONS/P.ANIMAL
M	93.10	93.21	95.66	90.70
ME	100.00	100.00	100.00	93.33
QD	6.97	3.85	3.39	4.55
K (A)
DEAD IMPLANTATIONS
Total	26	18	15	18
M	1.04	0.67	0.58	0.72
% IMPLANTATIONS/P.ANIMAL
M	6.90	6.79	4.34	9.30
ME	0.0	0.0	0.0	6.67
QD	6.97	3.85	3.39	4.55
K (A)
Resorptions Early (Salewski)	0	0	0	0
Resorptions Early	24	14	13	17
Resorptions Intermediate	1	3	2	0
Resorptions Late	1	1	0	0
Dead Fetuses	0	0	0	0

 Symbols

+/++ = Level of Significance 5%/1% in Relation to group 0

Uterus an Body weight of Pregnant Animals

		Test Group 0 0 PPM	Test Group 1 40 PPM	Test Group 2 120 PPM	Test Group 3 360 PPM
Uterus	N	25.00	27.00	26.00	25.00
	MV	64.40	65.74	67.54	65.32
	SD	18.76	25.51	23.61	21.14
	SE	3.75	4.91	4.63	4.23
BWS	N	25.00	27.00	26.00	25.00
	MV	216.38	216.00	213.82	215.24
	SD	9.36	11.34	7.70	9.85
	SE	1.87	2.18	1.51	1.97
BWE	N	25.00	27.00	26.00	25.00
	MV	354.33	348.90	345.93	332.61
					**
	SD	19.94	33.27	26.98	26.08
	SE	3.99	6.40	5.29	5.22
BWE-Uterus	N	25.00	27.00	26.00	25.00
	MV	289.93	283.15	278.39	267.30
				**	**
	SD	12.03	17.77	16.57	13.36
	SE	2.41	3.42	3.25	2.67
BWE-BWS-Uterus	N	25.00	27.00	26.00	25.00
	MV	73.56	67.15	64.57	52.06
			*	**	**
	SD	11.45	11.18	13.06	9.54
	SE	2.29	2.15	2.56	1.91

 Key                             Test Group      Significance 95 %        Significance 99%

Analysis of Trend                    0                                 *                                 **

Uterus an Body weight of Non-Pregnant Animals

		Test Group 0 0 PPM	Test Group 1 40 PPM	Test Group 2 120 PPM	Test Group 3 360 PPM
Uterus	N	5.00	3.00	3.00	4.00
	MV	1.00	1.00	1.00	1.50
	SD	0.0	0.0	0.0	0.0
	SE	0.0	0.0	0.0	0.5
BWS	N	5.00	3.00	3.00	4.00
	MV	214.50	208.57	213.67	217.10
	SD	4.25	15.31	6.70	3.52
	SE	1.90	8.84	3.87	1.76
BWE	N	5.00	3.00	3.00	4.00
	MV	255.88	242.70	247.00	251.02
	SD	20.93	10.91	3.96	7.94
	SE	9.36	6.30	2.29	3.97
BWE-Uterus	N	5.00	3.00	3.00	4.00
	MV	254.88	241.70	246.00	249.52
	SD	20.93	10.91	3.96	7.11
	SE	9.36	6.30	2.29	3.56
BWE-BWS-Uterus	N	5.00	3.00	3.00	4.00
	MV	40.38	33.13	32.33	32.42
	SD	18.43	6.95	7.92	7.05
	SE	8.24	4.01	4.57	3.52

 Key                             Test Group      Significance 95 %        Significance 99%

Analysis of Trend                    0                                 *                                 **

Findings in Fetuses: Cesarean Section

	Group 0 0 PPM	Group 1 40 PPM	Group 2 120 PPM	Group 3 360 PPM
Fetuses Investigates	298	319	309	292
Litters Investigated	25	27	26	24
Anomalies
Litters	0	1	0	0
(% Litters)	0.0	3.70	0.0	0.0
F (E)
Fetuses	0	1	0	0
(% Fetuses / Litter)
M	0.0	0.25	0.0	0.0
ME	0.0	0.0	0.0	0.0
QD	0.0	0.0	0.0	0.0
K (E)
Variations
Litters	0	0	0	0
(% Litters)	0.0	0.0	0.0	0.0
F (E)
Fetuses	0	0	0	1
(% Fetuses / Litter)
M	0.0	0.0	0.0	0.42
ME	0.0	0.0	0.0	0.0
QD	0.0	0.0	0.0	0.0
K (E)
Retardations
Litters	0	0	0	0
(% Litters)	0.0	0.0	0.0	0.0
F (E)
Fetuses	0	0	0	0
(% Fetuses / Litter)
M	0.0	0.0	0.0	0.0
ME	0.0	0.0	0.0	0.0
QD	0.0	0.0	0.0	0.0
K (E)	0.0	0.0	0.0	0.0

 Symbols

+/++ = Level of Significance 5%/1% in Relation to group 0

 

Findings in Fetuses: Cesarean Section

Anomalies

		Test Group 0 0 PPM	Test Group 1 40 PPM	Test Group 2 120 PPM	Test Group 3 360 PPM
Litters		25	27	26	24
Fetus Investigated		298	319	309	292
Head	BI		1

 

Findings in Fetuses: Cesarean Section

Variations

		Test Group 0 0 PPM	Test Group 1 40 PPM	Test Group 2 120 PPM	Test Group 3 360 PPM
Litters		25	27	26	24
Fetus Investigated		298	319	309	292
LIMBS	PAB				1

 

 

Findings in Fetuses: Cesarean Section

Retardations

	Test Group 0 0 PPM	Test Group 1 40 PPM	Test Group 2 120 PPM	Test Group 3 360 PPM
Litters	25	27	26	24
Fetus Investigated	298	319	309	292

 

Mean Litter Data

			Test Group 0 0 PPM	Test Group 1 40 PPM	Test Group 2 120 PPM	Test Group 3 360 PPM
Fetuses Males			145.00	140.00	149.00	133.00
Fetuses Females			153.00	179.00	160.00	159.00
Fetuses Total			298.00	319.00	309.00	292.00
Weight	Males	N	24.00	26.00	25.00	24.00
		MV	3.60	3.77	3.83	3.83
					*	*
		SD	0.29	0.25	0.45	0.28
		SE	0.06	0.05	0.09	0.06
	Females	N	25.00	27.00	24.00	24.00
		MV	3.42	3.51	3.62	3.70
					*	**
		SD	0.26	0.27	0.30	0.26
		SE	0.05	0.05	0.06	0.05
	Total	N	25.00	27.00	26.00	24.00
		MV	3.51	3.63	3.77	3.76
					**	**
		SD	0.27	0.23	0.46	0.26
		SE	0.05	0.04	0.09	0.05
Runts	Total		3.00	1.00	2.00	0.0

 Key                             Test Group      Significance 95 %        Significance 99%

Analysis of Trend                    0                                 *                                 **

 

Reference 2

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

GLP compliance:

yes

Limit test:

no

Specific details on test material used for the study:

- Name of test material (as cited in study report): Acrylic acid
- Analytical purity: 99.6%
- Impurities (identity and concentrations): Acetic acid 0.07%, acrylic acid dimer 0.08 %, 4-Methoxy phenol 0.15, all others impurities (approx.) 0.08%
- Lot No.: TF2-66011

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Hazleton Research Products, Inc. (Denver, PA)
- Age at study initiation: 5.5-6 months old
- Weight at study initiation: 2.8-4.0 kg
- Housing: Single in in stainless steel, wire-mesh cages (61 x 61 x 41 cm)
- Diet (ad libitum): AGWAY® PROLAB® Animal Diet (Agway Inc.) Except during exposures
- Water (ad libitum): Tap water (except during exposures)


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 16-21
- Humidity (%): 40-60
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

inhalation: vapour

Type of inhalation exposure (if applicable):

whole body

Vehicle:

unchanged (no vehicle)

Details on exposure:

Females assigned to the study were exposed to acrylic acid vapour or filtered air for 6 hours/day during the period of major organogenesis (gestation day -gd- 6 through 18). Filtered air was bubbled through a glass reservoir containing liquid acrylic acid. For all vapour concentrations, a Dwyer Flowmeter was used to measure airflow prior to passing the air through the acrylic acid. The vapour, was introduced into the exposure chambers through 1 inch glass tubing containing stainless steel wool.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

The concentration of acrylic acid vapour in each exposure chamber was monitored throughout the 15 days of exposure by sampling with XAD-8 sorbent tubes and subsequent analysis using high performance liquid chromatography (HPLC) analysis. The HPLC system was composed of a Model 981 Lambda Max LC Spectrophotometer, a Programmable Systems 680 Gradient Controller, a 712 WISP, and a Model 501 Solvent Delivery System. A Spectra Physics SP4270 computing Integrator provided a record of the chromatograms, chromatographic analyses, and peak height measurement. The concentration in each exposure chamber atmosphere was determined approximately 3 times during each 6-hour exposure. The control chamber was sampled once daily. The nominal concentration was calculated by dividing the total quantity of acrylic acid delivered to the chamber by the chamber airflow rate.

Details on mating procedure:

- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1/1

Duration of treatment / exposure:

From day 6 to day 18 of gestation

Frequency of treatment:

6 hours/day

Duration of test:

29 days

Dose / conc.:

25 ppm

Remarks:

corresponding to approx. 0.075 mg/L. Recalculation based on the equation c(mg/m3) = molar mass (g) / molar volume (L) x c(mL/m3) with molecular weight (72.06 g/mol) and molar volume (24.1 L at 20 °C and 1013 hPa) [DFG 2005]

Dose / conc.:

75 ppm

Remarks:

corresponding to approx. 0.224 mg/L). Recalculation based on the equation c(mg/m3) = molar mass (g) / molar volume (L) x c(mL/m3) with molecular weight (72.06 g/mol) and molar volume (24.1 L at 20 °C and 1013 hPa) [DFG 2005]

Dose / conc.:

225 ppm

Remarks:

corresponding to approx. 0.673 mg/L. Recalculation based on the equation c(mg/m3) = molar mass (g) / molar volume (L) x c(mL/m3) with molecular weight (72.06 g/mol) and molar volume (24.1 L at 20 °C and 1013 hPa) [DFG 2005]

No. of animals per sex per dose:

16

Control animals:

yes, sham-exposed

Maternal examinations:

CAGE SIDE OBSERVATIONS: not specified

DETAILED CLINICAL OBSERVATIONS: Yes
Prior to the exposure period, animals were observed for clinical signs once daily. Preceding and following each exposure, individual does were observed for clinical signs of toxicity.

BODY WEIGHT: Yes
- Time schedule for examinations: Maternal body weights were measured on gd 0, 3, 6, 12, 18, 24, and 29.

FOOD CONSUMPTION: Yes
Food consumption was measured daily throughout the study, beginning on gd 3.

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 29
- Organs examined: The gravid uterus, ovaries (including corpora lutea), cervix, vagina, and abdominal and thoracic cavities were examined grossly. The right nasal turbinates were examined. Maternal liver and kidney weights were determined.

Ovaries and uterine content:

Each uterus was removed from the peritoneal cavity, weighed, and dissected longitudinally to expose the contents. All live and dead fetuses and resorption sites (early and late) were recorded. Ovaries were removed from the peritoneal cavity and ovarian corpora lutea of pregnancy were counted. Uteri from females that appeared nongravid were placed in a 10% ammonium sulfide solution for confirmation of pregnancy status.

Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes

Fetal examinations:

After removal from the uterus, all live fetuses received a single lethal intraperitoneal injection of sodium pentobarbital. All live and dead fetuses were weighed and examined externally for variations and malformations including cleft palate. All live fetuses in each litter were examined for thoracic and abdominal visceral abnormalities. The sex of each fetus was determined during dissection by examination of the reproductive organs. One-half of the live fetuses in each litter were decapitated. The heads were fixed in Bouin's solution for subsequent examination of craniofacial structures. All fetuses (50% intact, 50% decapitated) in each litter were eviscerated, air-dried, processed for skeletal staining with alizarin red S and examined for skeletal malformations and variations. All fetal skeletal preparations were retained.


- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: half per litter
- Skeletal examinations: Yes: all per litter
- Head examinations: Yes: half per litter

Statistics:

The unit of comparison was the pregnant doe or the litter. The data for quantitative continuous variables were intercompared for the 3 exposure groups and the control group by use of Levene's test for equality of variances; analysis of variance (ANOVA), and t-tests. The t-tests were used when the F value from the ANOVA was significant. When Levene's test indicated similar variances, and the ANOVA was significant, pooled t-tests were used for pairwise comparisons. When Levene's test indicated heterogeneous variances, all groups were compared by an ANOVA for unequal variances followed, when necessary, by separate variance t-tests for pairwise comparisons.
Nonparametric data were statistically evaluated using the Kruskal-Wallis test, followed by the Mann-Whitney U test when appropriate. Frequency data were compared using Fisher's Exact Test. With the exception of the data analysis for fetal malformations and variations, all statistical analyses were performed using BMDP Statistical Software (Dixon, 1990). For all statistical tests, the probability value of < 0.05 (two-tailed) was used as the critical level of significance.

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

Throughout the exposure period, perinasal/perioral wetness and blepharospasm were observed during actual exposures of does to 225 ppm acrylic acid vapor. Perioral wetness was observed only on the fourth day of exposure of does to the 75 ppm concentration. Individual exposure-related clinical signs observed following daily exposures were consistent with those observed during exposures. In the 225 ppm group, individual clinical signs observed included : perinaeal wetness beginning as early as the first day of exposure and ending by the second day after the last exposure ; perinasal encrustation (from Days 14 through 22) ; and nasal congestion observed during and subsequent to exposures (through Day 22) .
Nasal congestion was observed in a single doe from the 75 ppm group on Day 12 only. There were no clinical signs observed in does during or subsequent to exposures to 25 ppm acrylic acid vapor .

Mortality:

no mortality observed

Description (incidence):

No does died prior to scheduled sacrifice.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Mean gestational body weights were equivalent across groups throughout gestation. There were no statistically significant exposure-related reductions in weight gain. However, mean body weight losses were observed in all acrylic acid-exposed groups for Days 6 to 12. Losses in the 25 ppm group were not considered to be biologically significant, since body weight gains were greater than control values (by approximately 60 g) during the pre-exposure period and the reductions for Days 6 to 12 were not associated with consistent reductions in food consumption for the first half of the exposure period. Reduced body weight gain values in the 75 and 225 ppm groups for Days 6 to 12 were considered to be an exposure-related effect since the reductions were coincident with consistent reductions in food consumption for the first five days of the exposure period. Likewise, increased body weight gains in the 75 and 225 ppm groups for Days 18 to 29 were associated with increases in food consumption during the post-exposure period.

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

Exposure-related decreases in food consumption were observed in the 75 and 225 ppm groups during the first 5 days of the exposure period. Throughout the remainder of the exposure period, daily food consumption was consistently reduced in the 225 ppm group and the decreases occasionally reached statistical significance.Occasional reductions in daily food consumption were also observed during the exposure period subsequent to Day 11 (Days 17 to 19) in the 75 ppm group. Average food consumption/day calculated for the entire exposure period was reduced in the 225, but not 75, ppm group. Statistically significant increases in food consumption were observed subsequent to the exposure period in the 225 ppm group for Days 23 to 24 and 28 to 29 and in the 75 ppm group for Day 23 to 24. Mean food consumption values for Days 24 to 2.7 suggested a trend toward increased food consumption throughout the postexposure period for the 225 ppm group. Mean values for the 75 ppm group suggest a trend toward increased food consumption through Day 26. The statistically significant reduction (of approximately 168) in food consumption for Day 8 to 9 in the 25 ppm group was not considered to be biologically significant based on slightly greater food consumption values (including increases of up to 148) in the low concentration group prior to exposures. Occasional increases or decreases in food consumption values for the 25 ppm group subsequent to Day 9 were not considered to be exposure related due to the lack of a dose-response pattern of effects.

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

effects observed, non-treatment-related

Description (incidence and severity):

There were no exposure related changes in gravid uterine weight, corrected body weight, or corrected weight change. There were no significant effects of exposure on relative and absolute kidney or liver weights. (Apparently slight increases in absolute and relative liver weights in the 75 and 225 ppm groups were due to single animals in each group which had abnormally large livers.)

Gross pathological findings:

effects observed, non-treatment-related

Description (incidence and severity):

Upon necropsy on Day 29, pertinent findings included ulcerations in the nasal turbinates of 1 female in the 225 ppm group .

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

not examined

Histopathological findings: neoplastic:

not examined

Number of abortions:

no effects observed

Pre- and post-implantation loss:

effects observed, non-treatment-related

Description (incidence and severity):

Although percent preimplantation loss was statistically significantly increased in the mid and high concentration groups, the increases were not concentration dependent, were within the range of preimplantation losses observed for naturally-bred control does within this laboratory, and were, therefore, not considered to be an effect of exposure.

Total litter losses by resorption:

no effects observed

Early or late resorptions:

no effects observed

Dead fetuses:

no effects observed

Changes in pregnancy duration:

not examined

Changes in number of pregnant:

no effects observed

Key result

Dose descriptor:

NOAEC

Effect level:

0.075 mg/L air (nominal)

Basis for effect level:

body weight and weight gain

food consumption and compound intake

other: adverse effects on nasal and perinasal tissue

Key result

Abnormalities:

no effects observed

Fetal body weight changes:

no effects observed

Description (incidence and severity):

Fetal body weights were unaffected by test substance exposure .

Reduction in number of live offspring:

no effects observed

Changes in sex ratio:

no effects observed

Changes in litter size and weights:

no effects observed

Changes in postnatal survival:

not examined

External malformations:

no effects observed

Skeletal malformations:

no effects observed

Visceral malformations:

no effects observed

Key result

Dose descriptor:

NOAEC

Remarks:

teratogenicity

Effect level:

>= 0.673 mg/L air (nominal)

Basis for effect level:

other: highest dose tested

Key result

Abnormalities:

no effects observed

Key result

Developmental effects observed:

no

Maternal food consumption:

Exposure-related decreases in food consumption were observed in the 75 and 225 ppm groups during the first 5 days of the exposure period. Throughout the remainder of the exposure period, daily food consumption was consistently reduced in the 225 ppm group and the decreases occasionally reached statistical significance. Occasional reductions in daily food consumption were also observed during the exposure period subsequent to Day 11 (Days 17 to 19) in the 75 ppm group. Average food consumption/day calculated for the entire exposure period was reduced in the 225, but not 75, ppm group. Statistically significant increases in food consumption were observed subsequent to the exposure period in the 225 ppm group for Days 23 to 24 and 28 to 29 and in the 75 ppm group for Day 23 to 24. Mean food consumption values for Days 24 to 27 suggested a trend toward increased food consumption throughout the post exposure period for the 225 ppm group. Mean values for the 75 ppm group suggest a trend toward increased food consumption through Day 26. The statistically significant reduction (of approximately 16%) in food consumption for Day 8 to 9 in the 25 ppm group was not considered to be biologically significant based on slightly greater food consumption values (including increases of up to 14%) in the low concentration group prior to exposures. Occasional increases or decreases in food consumption values for the 25 ppm group subsequent to Day 9 were not considered to be exposure related due to the lack of a dose-response pattern of effects.

Gestation day	Group mean food consumption (g)
	0 ppm	25 ppm	75 ppm	225 ppm
6 – 7	191.42	166.96	147.31^**	101.55^**
7 – 8	193.42	169.23	149.51^**	110.35^**
8 – 9	195.13	163.75^*	150.69^**	121.66^**
9 – 10	185.38	166.73	153.59^*	132.49^**
10 – 11	184.98	200.79	154.79^*	134.49^**
12 – 13	180.85	123.21^*	203.10	136.18^**
16 – 17	187.39	186.42	161.23	152.77^*
18 – 19	208.56	178.61	167.23^*	147.33^**
23 - 24	158.19	176.43	204.25^**	199.75^*
28 - 29	134.35	167.32^*	160.41	188.19^**

^* Significantly different from control group (p<0.05.)

^**Significantly different from control group (p<0.01.)

Maternal body weights and weight changes:

Mean gestational body weights were equivalent across groups throughout gestation. There were no statistically significant exposure-related reductions in weight gain. However, mean body weight losses were observed in all acrylic acid-exposed groups for Days 6 to 12. Losses in the 25 ppm group were not considered to be biologically significant, since body weight gains were greater than control values (by approximately 60 g) during the preexposure period and the reductions for Days 6 to 12 were not associated with consistent reductions in food consumption for the first half of the exposure period. Reduced body weight gain values in the 75 and 225 ppm groups for Days 6 to 12 were considered to be an exposure-related effect since the reductions were coincident with consistent reductions in food consumption for the first five days of the exposure period. Likewise, increased body weight gains in the 75 and 225 ppm groups for Days 18 to 29 were associated with increases in food consumption during the postexposure period.

Gestation day	Gestational mean body weight changes (g)
	0 ppm	25 ppm	75 ppm	225 ppm
0 - 3	-34.08 (150.76)	-7.47 (152.69)	-6.83 (150.42)	-43.38 (214.46)
3 - 6	203.77 (96.19)	240.45 (76.84)	206.55 (96.92)	163.45 (251.41)
6 - 12	68.43 (65.47)	-18.87 (93.75)	-37.67 (93.47)	-41.06 (201.25)
12 - 18	146.67 (69.62)	160.54 (72.07)	123.51 (63.56)	148.45 (65.59)
18 - 24	112.36 (73.58)	150.13 (109.11)	178.41 (73.84)	176.15 (86.22)
24 - 29	26.65 (89.84)	51.55 (125.51)	64.32 (87.17)	143.49^**(96.91)

^**Significantly different from control group (p<0.01.)

Numbers in parentheses indicate standard deviation

Maternal Necropsy:

Upon necropsy on Day 29, pertinent findings included ulcerations in the nasal turbinates of 1 female in the 225 ppm group. There were no exposure related changes in mean body weight at sacrifice, gravid uterine weight, corrected body weight, or corrected weight change. There were no significant effects of exposure on relative and absolute kidney or liver weights. (Apparently slight increases in absolute and relative liver weights in the 75 and 225 ppm groups were due to single animals in each group which had abnormally large livers). There were no effects of exposure on the number of ovarian corpora lutea, the number of total, viable, or nonviable (early and late resorptions and dead fetuses) implantations/litter. Although percent preimplantation loss was statistically significantly increased in the mid and high concentration groups, the increases were not concentration dependent. Percent live fetuses and sex ratio were equivalent across groups.

Gestational parameters

Group: ppm	0	25	75	225
CORPORA LUTEA
mean	8.4	9.1	9.5	8.8
S.D.	1.93	1.61	2.03	1.82
N	16	16	15	1
TOTAL IMPLANTS
mean	8.6	8.8	8.2	8.5
S.D.	1.82	2.57	2.62	2.07
N	16	16	15	15
PERCENT PREIMPLANTATION LOSS
mean	0.5	6.9	14.8**	6.4*
S.D.	2.08	18.73	18.35	10.58
N	16	16	15	15
VIABLE IMPLANTS
mean	8.4	8.6	7.5	7.9
S.D.	1.86	2.63	2.42	1.83
N	16	16	15	15
NON-VIABLE IMPLANTS
mean	0.2	0.1	0.7	0.5
S.D.	0.40	0.34	1.28	1.30
N	16	16	15	15
EARLY RESORPTIONS
mean	0.1	0.1	0.7	0.4
S.D.	0.25	0.25	1.28	1.30
N	16	16	15	15
LATE RESORPTIONS
mean	0.1	0.0	0.0	0.0
S.D.	0.25	0.00	0.00	0.00
N	16	16	15	15
DEAD FETUSES
mean	0.1	0.1	0.0	0.1
S.D.	0.25	0.25	0.00	0.35
N	16	16	15	15
PERCENT LIVE FETUSES
mean	97.8	98.4	91.3	95.0
S.D.	4.92	4.27	15.8	11.91
N	16	16	15	15
SEX RATIO (% MALE FETUSES )
mean	56.8	56.9	56.9	49.2
S.D	21.25	13.13	23.71	18.64
N	16	16	15	15
FETAL BODY WEIGHTS PER LITTER (GRAMS)
All fetuses
mean	43.99	42.44	42.82	43.13
S.D.	5.192	5.341	4.277	3.505
N	16	16	15	15
MALE FETUSES
mean	45.15	42.62	43.44	42.93
S.D.	5.198	5.489	3.244	3.396
N	16	16	14c	15
FEMALE FETUSES
mean	42.21	42.38	41.54	42.85
S.D	5.585	5.798	5.978	3.928
N	15b	16	14c	15

* Significantly different from control group (p < 0.05)

** Significantly different from control group (p < .01 )

a Percent preimplantation loss=((corpora lutea - total implants)/corpora lutea] X 100 .

b The N is reduced because one litter consisted of male fetuses only .

c The N is reduced because two litters consisted of one sex only .

Summary of distribution and fate

Group: ppm	0	25	75	225
FEMALES ON STUDY	16	16	16	16
FEMALES THAT DIED	0	0	0	0
-         pregnant	0	0	0	0
FEMALES THAT ABORDED	0	0	0	0
FEMALES THAT DELIVERED	0	0	0	0
FEMALES REMOVED FROM STUDY	0	0	0	0
FEMALES EXAMINED AT LAPAROTOMY	16	16	16	16
FEMALES NON-PREGNANT	0	0	1	1
FEMALES PREGNANAT	16	16	15	15
FEMALES WITH NON-VIABLE IMPLANTS ONLY	0	0	0	0
FEMALES WITH VIABLE FETUSES	16	16	15	15
FEMALES THAT WERE PREGNANT	16	16	15	15

Summary of malformations in fetuses and litters (a)

	FETUSES				LITTERS
Groups (ppm)	0	25	75	225	0	25	75	225
Number with external malformations	0	3	0	1	0	2	0	1
Percent with external malformations	0.0	2.2	0.0	0.8	0.0	12.5	0.0	6.7
Number with soft tissue malformations	5	4	6	6	4	4	3	6
Percent with soft tissue malformations	3.7	2.9	5.4	5.0	25.0	25.0	20.0	40.0
Number with skeletal malformations	1	3	5	3	1	3	5	3
Percent with skeletal malformations	0.8	2.2	4.5	2.5	6.3	18.8	33.3	20.0
Total number with malformations	6	8	10	9	5	6	7	9
Total Percent with malformations	4.5	5.8	8.9	7.6	31.3	37.5	46.7	60.0

(a)For all findings, the number (of fetuses affected or litters with one or more affected fetuses) is presented on top and the percentage of the total (fetuses or litters) examined is presented beneath. A single fetus may be represented more than once in listing individual defects. Only live fetuses were examined.

Summary of variations

	FETUSES				LITTERS
Groups (ppm)	0	25	75	225	0	25	75	225
Number with external variations	0	2	2	1	0	2	2	1
Percent with external variations	0.0	1.4	1.8	0.8	0.0	12.5	13.3	6.7
Number with soft tissue variations	28	27	14	37	12	9	9	11
Percent with soft tissue variations	20.9	19.6	12.5	31.1	75.0	56.3	60.0	73.3
Number with skeletal variations	133	137	112	119	16	16	15	15
Percent with skeletal variations	100.0	99.3	100.0	100.0	100.0	100.0	100.0	100.0
Total number with variations	133	137	112	119	16	16	15	15
Total Percent with variations	100.0	99.3	100.0	100.0	100.0	100.0	100.0	100.0

For all findings, the number (of fetuses affected or litters with one or more affected fetuses) is presented on top and the percentage of the total (fetuses or litters) examined is presented beneath . A single fetus may be represented more than once in listing individual defects. Only live fetuses were examined.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEC

1.08 mg/L

Species:

rat

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Additional information

No experimental data on the test substance is available. Therefore, the evaluation of the endpoint developmental toxicity is based on a weight of evidence approach using the toxicological data of the structural analogue acrylic acid (CAS 79-10-7) (for WoE information, see chapter 13.2).

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 air) 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 (IATG, 1983). 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 air).

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. 1.08 mg/L air.)

 

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 air) during days 6-18 of gestation (BAMM, 1993). 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 air).

NOAEC for developmental toxicity: 225 ppm (= approx. 0.673 mg/L air).

 

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

Due to the negligibly low vapour pressure of the test substance as compared to acrylic acid, the inhalation route of exposure is not relevant for the test substance. Nevertheless, it can be assumed that the test substance 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 the test substance.

Justification for classification or non-classification

Classification, Labeling, and Packaging Regulation (EC) No 1272/2008

The available test data are reliable and suitable for classification purposes under Regulation (EC) No 1272/2008. As a result, the substance is not considered to be classified for toxicity to reproduction or developmental toxicity under Regulation (EC) No 1272/2008, as amended for the fourteenth time in Regulation (EC) No. 2020/217.