2-Propenamide, N-(2-hydroxyethyl)-

Endpoint summary

Description of key information

Repeat dose oral:

Oral administration of HEAA for 28 days to SD rats at dosages of 150 or 500 mg/kg/day gave rise to marked toxicity, though at 500 mg/kg/day the changes were more severe. The sciatic nerve, spleen, testes and epididymides were identified as target organs.

A No-Observed-Effect-Level (NOEL) was not established in this study; since the findings at 50 mg/kg/day were restricted reduced motor activity amongst male animals the No-Observed-Adverse-Level (NOAEL) was considered to be 50 mg/kg/day.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

30 June 2006 to 7 November 2007

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)

Deviations:

no

Qualifier:

according to guideline

Guideline:

other: OPPTS 870.3050, Repeated dose 28-day oral toxicity study in rodents, July 2000.

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Limit test:

yes

Specific details on test material used for the study:

Batch number: 050804
Purity: >99%

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River (UK) Ltd.
- Age at study initiation: 37 to 43 days
- Weight at study initiation: 189 to 226 g for males and 149 to 177 g for females.
- Fasting period before study: none
- Housing: The animals were housed five of one sex per cage unless this number was reduced by mortality. The cages were made of a polycarbonate body with a stainless steel mesh lid. Wood flakes used as bedding (Lignocel Type 3/4) were sterilised by autoclaving; cages, food hoppers and water bottles were changed at appropriate intervals.
- Diet (e.g. ad libitum): The animals were allowed free access to a standard rodent diet (Rat and Mouse No. 1 Maintenance Diet), except overnight before routine blood sampling. This diet contained no added antibiotic or other chemotherapeutic or prophylactic agent.
- Water (e.g. ad libitum): Potable water taken from the public supply was freely available via polycarbonate bottles
fitted with sipper tubes.
- Acclimation period: 8 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 to 23°C
- Humidity (%): 40 to 70%
- Air changes (per hr): Unknown. Periodic checks were made on the number of air changes in the animal rooms.
- Photoperiod (hrs dark / hrs light): Artificial lighting was controlled to give a cycle of 12 hours continuous light and 12 hours continuous dark per 24 hours.

IN-LIFE DATES: From: 9 August 2006 To: 14 September 2006

Route of administration:

oral: gavage

Vehicle:

water

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 0, 5 15 and 50 mg/ml
- Amount of vehicle (if gavage):
- Justification for choice of vehicle: Test substance readily soluble.

MAXIMUM DOSE VOLUME APPLIED: 10 mg/kg

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: Administration at 1000 mg/kg was not tolerated resulting in the death of all animals.

Duration of treatment / exposure:

Animals received the test substance or vehicle control formulations orally at a volume-dosage of 10 mL/kg bodyweight, using a suitably graduated syringe and a rubber catheter inserted via the mouth into the stomach.
All animals were dosed in sequence of cage-number within each group, once each day at approximately the same time each day, seven days per week. The volume administered to each animal was calculated from the most recently recorded bodyweight.
A daily record of the weight of each formulation dispensed and the amount remaining after dosing was made. The balance of these two weights was compared with the predicted usage as a check that the doses had been administered correctly. No significant discrepancy was found.
Formulations were stirred using a magnetic stirrer before and throughout the dosing
procedure.

Frequency of treatment:

Group Treatment Dose (mg/kg/day) Concentration (mg/mL) Volume dosage (mL/kg)

1 Control 0 0 10
2 HEAA 50 5 10
3 HEAA 150 15 10
4 HEAA 500 50 10

Dose / conc.:

50 mg/kg bw/day (actual dose received)

Dose / conc.:

150 mg/kg bw/day (actual dose received)

Dose / conc.:

500 mg/kg bw/day (actual dose received)

No. of animals per sex per dose:

Group Treatment Dose# No. of animals Animal numbers Cage numbers
(mg/kg/day) Male Female Male Female Male Female
1 Control 0 5 5 1-5 36-40 1 8
2 HEAA 50 5 5 11-15 31-35 3 7
3 HEAA 150 5 5 6-10 21-25 2 5
4 HEAA 500 5 5 16-20 26-30 4 6

Control animals:

yes, concurrent vehicle

Details on study design:

- Duration of observation period following administration: none
- Frequency of observations and weighing:The weight of each rat was recorded on the day that treatment commenced, weekly throughout the treatment period (last scheduled bodyweight recorded on Day 28 prior to removal of food for routine blood sampling), and before necropsy.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight,organ weights, histopathology

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily
- Cage side observations checked

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Immediately before dosing
Immediately after dosing on return of the animal to its cage*
On completion of dosing of each group*
Between one and two hours after completion of dosing of all groups
As late as possible in the working day.
* Week 1 only

BODY WEIGHT: Yes
- Time schedule for examinations:The weight of each rat was recorded on the day that treatment commenced, weekly throughout the treatment period (last scheduled bodyweight recorded on Day 28 prior to removal of food for routine blood sampling), and before necropsy. More frequent weighings were instituted, when appropriate, for animals displaying ill-health, so that the progress of the observed condition could be monitored. These data are not reported here.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes
The weight of food supplied to each cage, that remaining and an estimate of any spilled was recorded each week throughout the treatment period. From these records the mean weekly consumption per animal (g/rat/week) was calculated for each cage. Food consumption during Week 4 was measured over a six day period as food was removed on Day 28 prior to routine blood sampling on Day 29.

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No data

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes / No / No data
- Time schedule for examinations:Water intake was assessed by daily visual assessment. In order to investigate an apparent effect during Week 4 of treatment, water consumption was recorded by weight (over a 3-day period) for each cage of animals, using water bottles fitted with sipper tubes.

OPHTHALMOSCOPIC EXAMINATION: No
- Time schedule for examinations:
- Dose groups that were examined:

HAEMATOLOGY: Yes
- Time schedule for collection of blood: On Day 29 blood samples were obtained from all animals after overnight withdrawal of food.
- Anaesthetic used for blood collection: Animals were held under light general anaesthesia induced by isoflurane and blood samples
were withdrawn from the sublingual vein.
- Animals fasted: Yes

CLINICAL CHEMISTRY: Yes / No / No data
- Time schedule for collection of blood:
- Animals fasted: Yes / No / No data
- How many animals:All (40)
- Parameters checked in table [No.?] were examined.

URINALYSIS: No
- Time schedule for collection of urine:
- Metabolism cages used for collection of urine: Yes / No / No data
- Animals fasted: Yes / No / No data
- Parameters checked in table [No.?] were examined.

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations:
- Dose groups that were examined: all
- Battery of functions tested: Approach response / grip strength / auditory startlr reflex / tail pinch response / touch response.

Sacrifice and pathology:

GROSS PATHOLOGY: Yes. All animals were subject to a detailed necropsy.
After a review of the history of each animal, a full macroscopic examination of the tissues was performed. All external features and orifices were examined visually. The cranial roof was removed to allow observation of the brain, pituitary gland and cranial nerves. After ventral mid-line incision, the neck and associated tissues and the thoracic, abdominal and pelvic cavities and their viscera were exposed and examined in situ. Any abnormal position, morphology or interaction was recorded. The requisite organs were weighed and external and cut surfaces of the organs and tissues were examined as appropriate. Any abnormality in the appearance or size of any organ and tissue was recorded and the required tissue samples preserved in appropriate fixative. The retained tissues were checked before disposal of the carcass.

HISTOPATHOLOGY: Yes.
The following organs, taken from each animal killed after 4 weeks of treatment, were dissected free of adjacent fat and other contiguous tissue and the weights recorded:
Adrenals
Brain
Epididymides
Heart
Kidneys
Liver
Ovaries
Spleen
Testes
Thymus
Bilateral organs were weighed together. Organ weights were also adjusted for terminal bodyweight, using the weight recorded immediately before necropsy.
Testes and epididymides were fixed in Bouin’s solution prior to transfer to 70% industrial
methylated spirit. Samples (or the whole) of the other tissues listed below from all animals
were preserved in 10% neutral buffered formalin:
Adrenals Ovaries
Brain Pancreas#
Caecum Prostate
Colon Rectum
Duodenum Sciatic nerves+
Epididymides Seminal vesicles
Femurs+ Spinal cord
Head# Spleen
Heart Sternum#
Ileum Stomach
Jejunum Testes
Kidneys Thymus
Liver Thyroid with parathyroids
Lungs Trachea
Lymph nodes - mandibular Urinary bladder
- mesenteric Uterus and cervix
Oesophagus#
+ Only one processed for examination
# Not processed for examination
Samples of any abnormal tissues were also retained and processed for examination. In those cases where a lesion was not clearly delineated, contiguous tissue was fixed with the grossly affected region and sectioned as appropriate.
Samples of the head (including nasal cavity, paranasal sinuses and nasopharynx), oesophagus, pancreas and sternum and the remaining femur and sciatic nerve were not examined histologically, but are retained against any future requirement for microscopic examination.

Other examinations:

Histology
For those animals specified in the Pathology section, the relevant tissues were subject to histological processing.
Tissue samples were dehydrated, embedded in paraffin wax, sectioned at approximately four to five micron thickness and stained with haematoxylin and eosin, except the testes which were stained using a standard periodic acid/Schiff (PAS) method.
Those tissues subject to histological processing included the following regions:
Adrenals - cortex and medulla
Brain - cerebellum, cerebrum and midbrain
Femur with joint - longitudinal section including articular surface, epiphysial
plate and bone marrow
Heart - included auricular and ventricular regions
Kidneys - included cortex, medulla and papilla regions
Liver - section from all main lobes
Lungs - section from two major lobes, to include bronchi
Spinal cord - transverse and longitudinal section at the cervical, lumbar
and thoracic levels
Stomach - included keratinised, glandular and antrum in sections
Thyroid - included parathyroids in section where possible
Uterus - uterus section separate from cervix section
For bilateral organs, sections of both organs were prepared. A single section was prepared
from each of the remaining tissues required for microscopic pathology.
PATHOLOGY
Light microscopy
Microscopic examination was performed as follows:
All tissues preserved for examination (as specified above) were examined for all animals of Groups 1 (Control) and 4 (500 mg/kg/day) sacrificed on completion of the scheduled treatment period and for the animal killed during the study. Sciatic nerves,
spleen, testes and epididymides were examined for animals of Group 2 (50 mg/kg/day) and 3 (150 mg/kg/day).
Tissues reported at macroscopic examination as being grossly abnormal were examined for all animals in line with current practice.
Findings were either reported as "present" or assigned a severity grade. In the latter case one of the following five grades was used - minimal, slight, moderate, marked or severe. A reviewing pathologist undertook a peer review of the microscopic findings.

Clinical signs:

effects observed, treatment-related

Mortality:

mortality observed, treatment-related

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Food efficiency:

not examined

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

effects observed, treatment-related

Ophthalmological findings:

not examined

Haematological findings:

effects observed, treatment-related

Clinical biochemistry findings:

effects observed, treatment-related

Urinalysis findings:

effects observed, treatment-related

Behaviour (functional findings):

effects observed, treatment-related

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Gross pathological findings:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

not specified

Histopathological findings: neoplastic:

not specified

Details on results:

CLINICAL SIGNS AND MORTALITY
On Day 27, a male (no. 20) receiving 500 mg/kg/day was killed, due to poor clinical condition. Clinical signs recorded prior to early termination comprised underactivity (present since pre-dose on Day 26), piloerection (constantly present since Day 16), abnormal gait
(constantly present since pre-dose Day 21 and recorded as hind limbs splayed and animal uncoordinated) and rapid respiration (noted immediately prior to termination).
Treatment-related signs were evident amongst animals treated at 500 mg/kg/day, the main signs being underactivity, piloerection and abnormal gait.
On Days 19 and 21 all males receiving 500 mg/kg/day showed underactivity at the 1-2 hour post-dose check. This sign was again present on Day 25 at the same time-point but then it persisted until the end of treatment; being recorded at all post-dose and pre-dose timepoints. Underactivity in similarly treated females was confined to the 1-2 hour post-dose point on Day 19 and in 4/5 females.
Piloerection, was first evident for all males at the 1-2 hour post-dose check on Day 16 and then generally persisted in all surviving animals until the end of treatment. Females receiving 500 mg/kg/day also first showed piloerection on Day 16, however unlike similarly treated males, this finding was seen intermittently; it was mainly confined to the 1-2 hour post-dose check Days 16-18, 20 and 22.
For males at 500 mg/kg/day abnormal gait was first recorded prior to dosing on Day 21 and then was evident at the majority of post-dose and pre-dose timepoints until the end of treatment. Females at this dose level showed abnormal gait, generally continuously, from the last check on Day 22.
On Day 21 only, all males receiving 500 mg/kg/day showed partially closed eyes (pre-dose and 1-2 hours post-dose) and skin reddening (1-2 hours post-dose). Considering the transient and isolated nature of these signs, they are considered to be of a doubtful relationship to treatment and not of any toxicological importance within the context of this study.
Two males receiving 150 mg/kg/day also showed underactivity, but this was confined to a single day and time-point (Day 21, 1-2 hours after dosing). Due to the isolated nature of this finding and the low number of animals displaying the sign, at 150 mg/kg/day there is considered to be no clear association with treatment. There was no sign recorded in animals receiving 50 mg/kg/day which was considered to be a reaction to treatment.

BODY WEIGHT AND WEIGHT GAIN
Overall (Weeks 0-4) bodyweight gain was less than Control for animals at 150 (0.79 – 0.81 x Controls) or 500 (0.35 – 0.54 x Controls) mg/kg/day. Lower than Control weekly bodyweight gain was apparent for these animals throughout the majority of the study period; bodyweight loss was evident for males treated at 500 mg/kg/day during Week 4.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
Overall (Week 1-4) food consumption of animals treated at 500 mg/kg/day was lower than Controls (0.82 – 0.86 x Controls). Overall (Week 1-4) food consumption of animals treated at 50 or 150 mg/kg/day was similar to Controls, although in Week 4 the mean value for males at 150 mg/kg/day was slightly lower than Controls and values recorded for this group in previous weeks. Whether this is associated with treatment is unclear.

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study)
Daily visual appraisal of the water bottles revealed an apparent effect of treatment on water consumption during Week 4, as a result of this gravimetric measurements were undertaken at the end of Week 4. Lower than Control water consumption was apparent in males treated at 500 mg/kg/day (0.56 x Controls).

HAEMATOLOGY
Haematology investigations after four weeks of treatment revealed, when compared with Controls, increased prothrombin times were evident amongst males treated at 500 mg/kg/day (1.11 x Controls); slightly increased prothrombin times (1.06 x Controls) were apparent amongst females treated at 500 mg/kg/day, however, since the individual values were within the Control range, this finding is thought not to be related to treatment. Slightly higher than Control mean cell haemoglobin concentration was apparent in males treated at 500 mg/kg/day (1.02 x Controls); in the absence of a concomitant treatment related effect on haemoglobin concentration or erythrocyte numbers and since the individual vales are within or close to the Control values this is finding considered not to be due to treatment.

ORGAN WEIGHTS
Lower than Control spleen, thymus and brain weights were apparent amongst males (0.57 x, 0.45 x or 0.89 x Controls) and females (0.66 x, 0.68 x or 0.93 x Controls) receiving 500 mg/kg/day. Other apparent variations were considered to be secondary to the lower bodyweight gains or losses of the animals treated at 500 mg/kg/day when compared with Controls.

OTHER FINDINGS Biochemical analysis of the plasma after four weeks of treatment revealed lower than Control inorganic phosphorous (0.87 x Controls) concentration and higher than Control albumin/globulin ratio and bilirubin and urea concentrations (1.15 x, 2.0 x or 1.54 x Controls respectively) amongst males treated at 500 mg/kg/day. Lower than Control creatinine concentration was apparent in both males and females receiving 500 mg/kg/day and higher than Control urea concentration (1.21 x Controls) was noted amongst males treated at 150 mg/kg/day.

Key result

Dose descriptor:

NOAEL

Effect level:

50 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male

Basis for effect level:

other: overall effects restricted reduced motor activity.

Critical effects observed:

yes

Lowest effective dose / conc.:

150 mg/kg bw/day (actual dose received)

System:

other: nervous system, male reproductive system

Organ:

other: sciatic nerves, spleen, testes and epididymides

Treatment related:

yes

Dose response relationship:

yes

Relevant for humans:

not specified

Oral administration of HEAA, a monomer (used in curing resin), for 28 days to Crl:CD(SD) rats was well tolerated at 50 mg/kg/day, but there were clear signs of toxicity seen at the 150 or 500 mg/kg/day levels. Male animals were generally more affected that females and sciatic nerves, spleen, testes and epididymides were identified as target organs.

At 500 mg/kg/day there was clear evidence of effects neurotoxic effects associated with movement and co-ordination, which were supported by microscopic evident degenerative changes in the sciatic nerves. The first evidence of possible neurotoxicity linked with movement was the onset of abnormal gait and underactivity in the third week of treatment. An association of these signs with treatment was further supported by the results of the Functional Observation Battery, performed in Week 4. During these observations animals receiving 500 mg/kg/day were showed uncoordinated struggling and abnormal gait and failed to make any attempt to grip or push against the bar using for measuring hindlimb strength, (resulting in a lack of hindlimb data from these animals). In addition, forelimb strength for these animals was appreciably lower than Controls as was motor activity, especially rearing activity. Findings in males tended to be more extensive than those in females. Lower brain weights were also recorded for males at the end of treatment, but without a microscopic correlate the toxicological importance of this finding is unclear. The piloerection apparent in animals receiving 500 mg/kg/day was considered most likely to be representative of general poor clinical condition, rather than a specific toxicity. There was no effect of treatment on the sensory reactions undertaken in Week 4 as part of the Functional Observation Battery.

Treatment at 500 mg/kg/day was also associated with other evidence of severe toxicity. Throughout the treatment period bodyweight gain for males was substantially lower than Control, with the difference from Controls increasing from Week 2 onwards, such that in the last week of treatment all males at 500 mg/kg/day showed bodyweight losses. For similarly treated females there was a less severe effect on bodyweight gain, however the overall mean gain for these females was still approximately 50% that of the concurrent Controls. Both sexes receiving 500 mg/kg/day also showed lower overall food intake, but the magnitude of the food effect was generally less than the bodyweight effect, although in the last week of treatment food intake for males did further decline, being approximately half that of the concurrent Controls. In this last week of treatment males receiving 500 mg/kg/day also showed lower water intake, the difference from Control being similar to that seen for the food intake for these males; often water intake in rodents shows direct correlation with food intake.

Distended urinary bladders were noted at necropsy for all males treated at 500 mg/kg/day, however, microscopically no abnormality was found. The aetiology of this finding is unknown, but it is considered that it may be linked with the neuropathy and / or reduced water intake. Blood chemistry measurements performed prior to termination revealed various disturbances. Food provides a source of phosphorus in the body thus the low plasma phosphorus levels seen in males may be a result of the low food intake. Similarly creatinine is a breakdown product resulting from muscle activity and therefore the low plasma creatinine levels may be a reflection of the underactivity reported in these animals. Bilirubin is formed from the degradation of haemoglobin and an increase is suggestive of an increase in the breakdown of erythrocytes, although there was no supporting evidence from the haematology data obtained at termination. The reason for the slightly elevated albumin/globulin ratio and higher urea levels are not clear from this study, but in the absence of any corresponding changes including histopathology there is no indication that they are of toxicological importance.

Terminal haematology investigations revealed raised PT value for males receiving 500 mg/kg/day, but the differences from Controls was small and in there were no corroborative changes evident which indicated the differences were toxicologically important.

The lower spleen weights present for animals at 500 mg/kg/day are likely to be at least partly associated with the low bodyweight gains for these animals but they could also be associated with the decreased extramedullary haemopoiesis in this organ. The spleen is a secondary/minor site of haemopoiesis and in the absence of any disturbances in the peripheral red blood cell values or any treatment-related effects on bone marrow, this finding is considered not to be of toxicological significance within the context of this study. Similarly the spleen is a common site for haemosiderosis and considering the lack of effects on circulating red blood cell numbers and the minimal/slight degree of the finding, within the context of this study it is considered not to be of toxicological importance.

Microscopically elongate spermatid retention and spermatid degeneration were evident in the testes of males treated at 500 mg/kg/day along with degenerate spermatogenic cells in the ducts of the epididymides of these animals. The aetiology of these findings is not clear from this study, however they are considered to be indicative of an adverse effect.

The low thymus weights noted macroscopically did not correlate with any microscopic change and thus are considered not to be indicative of clear toxicity on this study.

Toxicologically important findings at 150 mg/kg/day consisted of low bodyweight gains in both sexes and evidence of neurotoxicity associated with movement and co-ordination in males only. Despite the lower severity of findings at 150 mg/kg/day compared with those at 500 mg/kg/day, as degenerative findings in the sciatic nerve were present for males, this level also has to be classed as toxic.

At 50 mg/kg/day males had a tendency to show lower activity counts, which fitted into a dose-related pattern with the other treated groups. There was however a degree of overlap with concurrent Control values and there were no associated microscopic findings on the sciatic nerves. Due to these facts and in the absence of any other differences from Controls at this level was considered to be non toxic.

Conclusions:

Oral administration of HEAA for 28 days to Crl:CD(SD) rats at dosages of 150 or 500 mg/kg/day gave rise to marked toxicity, though at 500 mg/kg/day the changes were more severe. The sciatic nerve, spleen, testes and epididymides were identified as target organs.
A No-Observed-Effect-Level (NOEL) was not established in this study; since the findings at 50 mg/kg/day were restricted reduced motor activity amongst male animals the No-Observed-Adverse-Level (NOAEL) was considered to be 50 mg/kg/day.

Executive summary:

The systemic toxic potential of HEAA to SD rats by oral administration was assessed over a period of 4 weeks, according to OECD Guideline 407, under GLP.

Oral administration of HEAA for 28 days to SD rats at dosages of 150 or 500 mg/kg/day gave rise to marked toxicity, though at 500 mg/kg/day the changes were more severe. The sciatic nerve, spleen, testes and epididymides were identified as target organs.
A No-Observed-Effect-Level (NOEL) was not established in this study; since the findings at 50 mg/kg/day were restricted reduced motor activity amongst male animals the No-Observed-Adverse-Level (NOAEL) was considered to be 50 mg/kg/day.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

50 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

reliable without restrictions

Organ:

other: sciatic nerve, spleen, testes and epididymides

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

The systemic toxic potential of HEAA to SD rats by oral administration was assessed over a period of 4 weeks, according to OECD Guideline 407, under GLP.

Oral administration of HEAA for 28 days to SD rats at dosages of 150 or 500 mg/kg/day gave rise to marked toxicity, though at 500 mg/kg/day the changes were more severe. The sciatic nerve, spleen, testes and epididymides were identified as target organs.
A No-Observed-Effect-Level (NOEL) was not established in this study; since the findings at 50 mg/kg/day were restricted reduced motor activity amongst male animals the No-Observed-Adverse-Level (NOAEL) was considered to be 50 mg/kg/day.

Justification for classification or non-classification

Repeated oral toxicity:

Oral administration of HEAA for 28 days to SD rats at dosages of 150 or 500 mg/kg/day gave rise to marked toxicity, though at 500 mg/kg/day the changes were more severe. The sciatic nerve, spleen, testes and epididymides were identified as target organs.

Given the toxic effects, in accordance with Regulation (EC) No 1272/2008, table 3.9.1, this substance should be classified as Category 2 for this Specific target organ toxicity - repeated exposure endpoint.