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Diss Factsheets

Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
January 27 - March 10, 1987
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1988
Report date:
1988

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
not specified
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Acrylamide
EC Number:
201-173-7
EC Name:
Acrylamide
Cas Number:
79-06-1
Molecular formula:
C3H5NO
IUPAC Name:
Prop-2-enamide
Details on test material:
- Name of test material (as cited in study report): Acrylamide
- Substance type: organic
- Physical state: crystalline solid
- Analytical purity:95%
- Impurities (identity and concentrations): no data
- Composition of test material, percentage of components: 100%
- Purity test date: April 1987
- Lot/batch No.: 085F0006
- Expiration date of the lot/batch: no data
- Stability under test conditions: stable
- Storage condition of test material: under refigeration in amber screw-cap bottles

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories
- Age at study initiation: no data
- Weight at study initiation: 201-263 g
- Fasting period before study: no
- Housing: 1 per cage
- Diet: Purina 502 ad libitum
- Water: ad libitum
- Acclimation period: 7 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22°C
- Humidity (%): 48-49%
- Air changes (per hr):12-14 per hour
- Photoperiod (hrs dark / hrs light): 12:12 (0700-1900)
IN-LIFE DATES: January 27 - March 18, 1987

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
VEHICLE
- Concentration in vehicle: 0, 0.5, 1.5 and 3 mg/ml
- Amount of vehicle (if gavage): 5 ml/kg
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
IR, UV, MS, NMR and TLC and GC, KF conducted on receipt of test article and following completion of study
Details on mating procedure:
- Impregnation procedure: cohoused
- Proof of pregnancy: sperm positive referred to as GD0
Duration of treatment / exposure:
Gestational days 6 to 20
Frequency of treatment:
Once/day
Duration of test:
20 days
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 2.5, 7.5 and 15 mg/kg
Basis:
analytical conc.
No. of animals per sex per dose:
Groups of 29-30
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: based on preliminary study
- Rationale for animal assignment: body weight

Examinations

Maternal examinations:
Animals were observed daily for clinical signs.
CAGE SIDE OBSERVATIONS: No data
DETAILED CLINICAL OBSERVATIONS: Yes (neurotoxicty)
- Time schedule: daily up to GD6 the twice daily
BODY WEIGHT: Yes
- Time schedule for examinations: daily
POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day #20
- Organs examined: uterus
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:
Fetuses were thoroughly examined macroscopically for visceral and skeletal abnormalities (including the head).
- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: half per litter
- Skeletal examinations: Yes: half per litter
- Head examinations: Yes: half per litter
Statistics:
GLM procedures were applied for the ANOVA of maternal and fetal parameters. GLM analysis determined the significance of dose-response relationships and the significance of dose effects, replicate effects and dose x replicate interactions. If the ANOVA was significant, William’s or Dunnett’s Multiple Comparison Tests compared ACRL exposed to control groups. One tailed tests were used for all pairwise comparisons except maternal body and organ weights and fetal body weight. Nominal scale measures were analysed by chi square test for independence and by a test for linear trend on proportions. When a chi square showed significant group differences, a one-tailed Fisher’s exact probability test was used for pairwise comparisons of ACRL and control groups
Indices:
Percent foetuses malformed per litter, percent litters with malformed foetuses, percent foetuses with variations per litter, percent litters with variations, percent foetuses with extra ribs per litter, percent litters with extra ribs
Historical control data:
Percent litters with 1 or more:
- malformed foetuses: 22.9
- non-live implants: 33.8
- dead foetuses: 1.1
- resorptions: 33.2
Percent malformed foetuses: 3.2

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
There were no maternal mortalities and no clear clinical signs of toxicity. When corrected for gravid uterine weight, maternal body weight gain was decreased amongst animals receiving 7.5 and 15 mg/kg/day (12% and 18% reductions respectively).

Effect levels (maternal animals)

open allclose all
Key result
Dose descriptor:
NOAEL
Effect level:
2.5 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Key result
Dose descriptor:
NOAEL
Effect level:
15 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: developmental toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
There were no apparent effects on embryo/fetal viability, growth or malformations. There was a slight, but not statistically significant, increase in the incidence of skeletal variations (percentage of litters with variations - 61% in controls, 92% at 15 mg/kg/day, and percentage of foetuses with variations per litter - 14% in controls, 24% at 15 mg/kg/day). The most frequently observed variation was the presence of a rudimentary extra lumbar rib. This finding is considered likely to be an indirect consequence of maternal toxicity or stress and is of limited toxicological importance.

Effect levels (fetuses)

Key result
Dose descriptor:
NOAEL
Remarks on result:
not measured/tested

Overall developmental toxicity

Key result
Developmental effects observed:
no
Lowest effective dose / conc.:
7.5 mg/kg bw/day (nominal)
Treatment related:
yes

Any other information on results incl. tables

DEVELOPMENTAL TOXICITY IN PREGNANT CD RATS FOLLOWING MATERNAL EXPOSURE TO ACRYLAMIDE BY GAVAGE ON GESTATIONAL DAYS 6 THROUGH 20

 

Acrylamide (mg/kg/day, po)

 

0

2.5

7.5

15

All littersa

23

26

26

24

No. implantation sites per litter

13.5±0.9

14.6±0.8

14.8±0.7

14.5±0.8

% resorptions per litter

3.4±1.4

3.2±1.4

3.7±1.6

2.0±0.9

% litters with resorptions

30.4

26.9

26.9

20.8

Live littersb

 

 

 

 

No. live foetuses per litter

13.0±0.9

14.1±0.8

14.2±0.6

14.3±0.8

Average male foetal body weight (g) per litter

3.72±0.17

3.44±0.12

3.38±0.14

3.52±0.12

Average female foetal body weight per litter (g)

3.44±0.13

3.29±0.11

3.20±0.13

3.29±0.11

% foetuses malformed per litter

0.3±0.3

1.7±0.6

0.2±0.2

0.8±0.6

% litters with malformed foetuses

4.4

23.1

3.8

8.3

% foetuses with variations per litter

14.3±3+

16.5±3.6

18.3±4.5

24.0±3.9

% litters with variations

60.9+

69.2

73.1

91.7

% foetuses with extra ribs per litterc

11.1±3.6

11.1±2.9

13.5±4.5

16.4±4.0

% litters with extra ribs

47.8

57.7

53.8

70.8

 

a Includes all dams pregnant at termination; litter size = No. implantation sites per dam; means ± SE.

b Includes only dams with live foetuses; litter = No. live foetuses per dam; means ± SE.

c Includes foetuses with one or more rudimentary or full extra lumbar rib.

+ Linear trend test,p< 0.05.

Applicant's summary and conclusion

Conclusions:
2.5 mg/kg/d was considered to be the NOAEL for maternal toxicity (reduced body weight gain) and 15 mg/kg/d was considered to be the NOAEL for developmental toxicity.