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Diss Factsheets

Administrative data

Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1983
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Well documented report of a guideline study conducted to GLP.
Cross-reference
Reason / purpose for cross-reference:
reference to same study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1989
Report date:
1989

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
other: NTP 90-day rodent gavage
Deviations:
no
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
N-(hydroxymethyl)acrylamide
EC Number:
213-103-2
EC Name:
N-(hydroxymethyl)acrylamide
Cas Number:
924-42-5
Molecular formula:
C4H7NO2
IUPAC Name:
N-(hydroxymethyl)acrylamide
Details on test material:
- Name of test material (as cited in study report): N-Methylolacrylamide
- Substance type: Non-volatile, organic
- Physical state: Solid
- Analytical purity: approximately >98%
- Impurities (identity and concentrations): unkown but evidence indicates that 1% may have been a polymer of Nmethylolacrylamide,
which would not have been detected by the analytical methods used
- Composition of test material, percentage of components: 100%
- Isomers composition: not applicable
- Purity test date: no data
- Lot/batch No.: 1-45-000
- Expiration date of the lot/batch: no data
- Stability under test conditions: stable
- Storage condition of test material: storage at 5°C

Test animals

Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories (Portage, MI)
- Age at study initiation: 7 weeks
- Weight at study initiation: Males: 135±3 - 145±3; Females: 113±2 - 117±1
- Fasting period before study: No
- Housing: 5 animals per cage
- Diet: NIH 07 Rat and Mouse Ration available ad libitum
- Water: available ad libitum by automatic watering system
- Acclimation period: 19-20 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21-23
- Humidity (%): 40-60
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12
IN-LIFE DATES: From: 14/07/1981To: 12/10/1981

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Weighed amounts of N-methylolacrylamide and deionised water were mixed to give the desired concentrations). The stability of N-methylolacrylamide in water was determined by the gas chromatographic system previously described after dilution with methanol containing decyl alcohol as an internal standard; 1% solutions were stable when stored for 2 weeks at room temperature in the dark or when exposed for 3 hours to light and air. During the studies, N-methylolacrylamide/deionised water mixtures were stored at 23" C for up to 2 weeks. Subsequent stability studies specifically designed to evaluate possible formaldehyde formation during storage indicated a slow production of formaldehyde, with a maximum concentration of approximately 25 ppm in the high concentration mixture at the end of 2 weeks. f'eriodic analysis of formulated N-methylolacrylamide/deionised water dose mixtures was conducted at the study laboratory and the analytical chemistry laboratory. Dose mixtures were diluted with methanol containing decyl alcohol as an internal standard and analyzed by gas chromatography with a 10% Carbowax 20MTPA column. Dose mixtures were analyzed once before the 13-week studies began and once during the 13-week studies; the concentration of one sample differed from the target concentration by more than 10%.
Duration of treatment / exposure:
90 days
Frequency of treatment:
5 days/week
Doses / concentrations
Remarks:
Doses / Concentrations:
12.5, 25, 50, 100 and 200 mg/kg;
Basis:
nominal in water
No. of animals per sex per dose:
10 male and 10 female
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: doses were 50% of the preliminary 16 day gavage study
- Rationale for animal assignment: assigned to weight classes, and distributed to cages according to a table of random numbers. Cages were assigned to groups according to another table of random numbers.
- Post-exposure recovery period: none
Positive control:
No

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: 2 times per day
DETAILED CLINICAL OBSERVATIONS: No
BODY WEIGHT: Yes
- Time schedule for examinations: initially and the once a week
OPHTHALMOSCOPIC EXAMINATION: No
HAEMATOLOGY: No
CLINICAL CHEMISTRY: No
URINALYSIS: No
NEUROBEHAVIOURAL EXAMINATION:
- Time schedule for examinations: weeks 6 and 13
- Dose groups that were examined: all animals
- Battery of functions tested: motor activity, forelimb/hind limb grip strength, acoustic startle reflex measurement, and landing foot spread.
Sacrifice and pathology:
GROSS PATHOLOGY: Yes (see table)
HISTOPATHOLOGY: Yes (see table)
Statistics:
Dunnett's test

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
hindlimb ataxia
Mortality:
mortality observed, treatment-related
Description (incidence):
hindlimb ataxia
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Lower values than controls at 100 and 200 mg/kg.
Food consumption and compound intake (if feeding study):
not examined
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):
effects observed, treatment-related
Description (incidence and severity):
Decreased forelimb and hind limb grip strength was seen at doses as low as 25 mg/kg for female rats and 12.5 mg/kg for male rats. A decreased startle response was seen for females at doses as low as 25 mg/kg. The landing foot spread was significantly incr
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
Inflammation and/or hemorrhage and edema of the urinary bladder mucosa were seen with doses of 25 mg/kg or more in a few rats that had distended bladders.
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Axon filament and myelin sheath degeneration of the brain stem, spinal cord, and/or peripheral nerves was seen in rats at increased incidences at 25 mg/kg and higher doses.
Histopathological findings: neoplastic:
not examined
Details on results:
CLINICAL SIGNS AND MORTALITY
MORTALITY: There was 100% mortality in both sexes of the 200 mg/kg group before the 6th study week. No other test substance related mortality occurred.
CLINICAL OBSERVATIONS:
At 200 mg/kg, the male and female rats showed a generalised irritability to handling during the first study week. Most animals exhibited decreased cage activity. Only those animals in the 200 mg/kg dose group which survived until the third week of dosing had a hind limb ATAXIA which then progressed to a hind limb paralysis. Weak appearance and rough hair coats were additional observations recorded from many of these animals until death.
At 100 mg/kg, hind limb ataxia, beginning in the third week of dosing, did not progress to hind limb paralysis in the males until the 6th or 7th week. All male rats exhibited burrowing behaviour after gavage beginning the 4th study week. In many animals of this dose group a weakened condition, thin appearance and rough hair coats were observed.
At 50 mg/kg, all appeared to be ataxic in the hind limbs during the 8th week which progressed to hind limbs paresis during the 11th week of the study. No significant clinical observations were noted in the lower dose groups or control groups of either sex.
BODY WEIGHT AND WEIGHT GAIN
There was a dose response relationship with respect to depression of body weight gain during the study in both sexes of rats. In the 50 mg/kg dose group, males were 30.5% and females 20.6% less in weight gain than the controls. In the 25 mg/kg dose group, these figures were -15.3% (males) and -12.2 % (females).
NEUROBEHAVIOUR
Behavioural tests performed after 6 and 13 weeks of treatment showed dose-related (one-way analysis of variance) decreases in forelimb and hind limb. GRIP STRENGTH in week 13 was significantly different from controls (Dunnett's test) at doses down to 25 mg/kg/day in males and down to 50 mg/kg/day in females. MOTOR ACTIVITY was not significantly different at any dose group. At 13 weeks, female animals of the 50 mg/kg dose group exhibited significantly lower STARTLE RESPONSE SCORES as compared with control animals. LANDING FOOT SPREAD was increased at 6 weeks only for female rats receiving 50 mg/kg/day (not tested at 13 weeks since hind limb paresis was present in both sexes). No other group showed effects on landing foot spread. These findings are consistent with the development of peripheral neuropathy.
ORGAN WEIGHTS
No differences between any of the organ to body weight rations of any of the dose groups and the control groups of either sex except for the testicle weight in the 50 mg/kg dose group. The respective mean ratio was approx. 20% greater than the control's mean ratio. However, this difference could be explained by the lower body weights in this dose group
HISTOPATHOLOGY: NON-NEOPLASTIC
Degeneration in the CNS and in peripheral nerves was observed at doses of 25 mg/kg/day and higher. No compound-related lesions were observed in the lowest dose level, 12.5 mg/kg.

Effect levels

Dose descriptor:
LOAEL
Effect level:
12.5 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
In this study, the No Observed Adverse Effect Level (NOAEL) and Lowest Observed Adverse Effect Level (LOAEL) of N-methylolacrylamide (NMA) administered by gavage to male and female rats for 13 weeks were 12.5 and 25 mg/kg bw respectively based on degeneration of peripheral nerves and decreased bodyweight.