3-(Hydroxymethyl)-1-pentene

Endpoint summary

Description of key information

The informtion for this endpoint study record was obtained from an experimental study. The OECD GLP criteria were met and the methods applied are fully compliant with OECD TG 407. Daily oral treatment with 100, 300 and 1000 mg/kg the test material  to Wistar (Han) rats was clinically tolerated over 28 days. The No Observed Adverse Effect Level (NOAEL) in Wistar (Han) rats was established at 300 mg/kg/d.

Key value for chemical safety assessment

Toxic effect type:

dose-dependent

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Reference 1

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

January 31, 2007 - June 21, 2007

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

equivalent or similar to guideline

Guideline:

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

GLP compliance:

no

Limit test:

no

Species:

rat

Strain:

Wistar

Details on species / strain selection:

The Han Wistar rat was chosen because it is accepted by many regulatory authorities and there is ample experience and background data on this species and strain.

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Harlan Italy S.r.l., San Pietro al Natisone, Italy
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: 7 weeks
- Weight at study initiation: 90 - 96 g
- Fasting period before study: not specified
- Housing: up to 5 of one sex in polycarbonate cages
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 17 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 2
- Humidity (%): 55 +/- 15
- Photoperiod (hrs dark / hrs light): 12 / 12

IN-LIFE DATES: From days 1 to 8

Route of administration:

oral: gavage

Vehicle:

polyethylene glycol

Details on oral exposure:

The test item was administered orally at a dose volume of 5 mL/kg. Control animals received the vehicle alone (PEG 400) at the same dose volume. The dose was administered to each animal on the basis of the most recently recorded body weight and the volume administered was recorded for each animal.

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

7 days

Frequency of treatment:

once daily

Dose / conc.:

0 mg/kg bw/day (nominal)

Dose / conc.:

40 mg/kg bw/day (nominal)

Dose / conc.:

200 mg/kg bw/day (nominal)

Dose / conc.:

1 000 mg/kg bw/day (nominal)

No. of animals per sex per dose:

2 m / 2 f

Control animals:

yes, concurrent vehicle

Details on study design:

Dose levels were selected in consultation with the Sponsor based on the results of an acute toxicity study in Wistar rats after oral administration.

Positive control:

no

Observations and examinations performed and frequency:

Mortality: Throughout the study, all animals were checked early in each working day and again in the afternoon. At weekends and Public Holidays a similar procedure was followed except that the final check was carried out at approximately mid-day. A complete necropsy was performed.
Pre- and post-dose observations: All observations were recorded for individual animals. Examination of individual animals for signs of reaction to treatment was carried out daily prior to dosing, immediately after and approximately 1 and 2 hours after dosing.
Clinical signs: All clinical signs were recorded for individual animals. Once before commencement of treatment, once during the treatment period and on Day 8 of the study, each animal was observed and any clinical signs were recorded.
Body weight: Each animal was weighed on the day of allocation to treatment group and on Days 1, 4 and 8 (just prior to necropsy).
Food consumption: The weight of food consumed by each cage of rats was recorded at weekly intervals following allocation. The group mean daily intake per rat was calculated.

Sacrifice and pathology:

Terminal studies: Animals that had completed the scheduled test period were killed with carbon dioxide. All animals were subjected to necropsy.
Necropsy: The clinical history of the animal was studied and a detailed post mortem examination was conducted (including examination of the external surface and orifices). Changes were noted, the requisite organs weighed but no tissue samples were preserved.
Organ weights: From all animals completing the scheduled test period, the routinely examined organs were dissected free of fat and weighed. The ratios of organ weight to body weight were calculated for each animal.

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

Ataxia, salivation and hyperactivity were observed approximately 5-10 minutes after dosing from day 3 up to day 5 in the males dosed at 1000 mg/kg/day and from day 2 onward in the females from the same dose group. Hunched posture was also observed in the females. Salivation was occasionally seen in the females dosed at 200 mg/kg/day. No signs of reaction to treatment were observed in the high dose males by day 6 of the study. No clinical signs were observed at weekly observations.

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Description (incidence and severity):

No significant intergroup differences were observed in body weights and terminal body weights between treated animals and controls.

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

not specified

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

not specified

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):

Absolute and relative liver weights showed slight increases in the males (+18% and 20%, respectively) and in the females (+12% and 18% respectively) of the high dose group (1000 mg/kg/day). No other variations were observed.

Gross pathological findings:

no effects observed

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

not examined

Histopathological findings: neoplastic:

not examined

Other effects:

not specified

Key result

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

organ weights and organ / body weight ratios

Conclusions:

The oral toxicity of the test item when given by daily over 7 days via gavage to rats was investigated. Three groups, each of 2 male and 2 female Han Wistar rats, received the test item at dosages of 40, 200 and 1000 mg/kg/day. A slight effect of the test item on liver weight was seen at the highest dose level investigated (1000 mg/kg/day). No significant effects were noted at the lower dose levels (40 and 200 mg/kg/day). Therefore the high dose of 1000 mg/kg/day may be considered the NOAEL in this study.

Executive summary:

Study design

The oral toxicity of the test item when given by daily administration to rats, has been investigated over a period of 7 consecutive days. Three groups, each of 2 male and 2 female Han Wistar rats, received the test item by gavage at dosages of 40, 200 and 1000 mg/kg/day, at a dose volume of 5 ml/kg, for 7 consecutive days. A fourth, similarly constituted group, received the vehicle alone (PEG 400) and acted as a control. The animals were examined daily for signs of reaction to treatment immediately after and approximately 1 and 2 hours after dosing. Clinical signs were recorded for each animal on days -5, 4 and 8 of the study. Body weight was recorded on the day of allocation to groups and on days 1, 4 and 8. The weight of food consumed by each cage was recorded on days 1 and 8. All animals were subjected to necropsy examination.

 

Results

No mortality occurred during the study. Ataxia, salivation, hyperactivity and, only in the females, hunched posture were seen approximately 5-10 minutes after dosing at 1000 mg/kg/day. Salivation was occasionally observed also in the females dosed at 200 mg/kg/day. No clinical signs were observed in any animal at weekly observations. No treatment-related changes were observed in body weights of the animals. Food consumption was not affected by treatment. Absolute and relative liver weights were slightly increased in the high dose males. No other variations were observed. No macroscopic change was reported at necropsy in the examined organs/tissues of the animals killed at termination.

 

Conclusion

A slight effect of the test item on liver weight was seen at the highest dose level investigated (1000 mg/kg/day). No significant effects were noted at the lower dose levels (40 and 200 mg/kg/day). Therefore the high dose of 1000 mg/kg/day may be considered the NOAEL in this study and may potentially be used as a high dose level in a longer duration study.

Reference 2

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

February 27, 2007 - October 31, 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)

Version / remarks:

07-1995

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Limit test:

no

Species:

rat

Strain:

Wistar

Details on species / strain selection:

The Han Wistar rat was chosen because it is accepted by many regulatory authorities and there is ample experience and background data on this species and strain.

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Harlan Italy S.r.l., San Pietro al Natisone, Italy
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: 6 weeks
- Weight at study initiation: 87 - 100 g
- Fasting period before study: not specified
- Housing: up to 5 of one sex in polycarbonate cages
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 12 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 2
- Humidity (%): 55 +/- 15
- Photoperiod (hrs dark / hrs light): 12 / 12

IN-LIFE DATES: From days 1 to 28

Route of administration:

oral: gavage

Vehicle:

polyethylene glycol

Details on oral exposure:

The test item was administered orally at a dose volume of 5 mL/kg. Control animals received the vehicle alone (PEG 400) at the same dose volume. The dose was administered to each animal on the basis of the most recently recorded body weight and the volume administered was recorded for each animal.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Prior to commencement of treatment the proposed formulation procedure was checked by chemical analysis to confirm that the method was acceptable. The test item formulations were found to be stable for 6 hours at room temperature. Samples of the formulations prepared in weeks 1 and 4 were analysed to check the concentration. Results were satisfactory being inside the limits of acceptance (90-110%).

Duration of treatment / exposure:

28 days followed by a 2 week recovery period (control and high-dose group)

Frequency of treatment:

once daily

Dose / conc.:

0 mg/kg bw/day (nominal)

Dose / conc.:

100 mg/kg bw/day (nominal)

Dose / conc.:

300 mg/kg bw/day (nominal)

Dose / conc.:

1 000 mg/kg bw/day (nominal)

No. of animals per sex per dose:

5 m / 5 f. Five additional rats per each sex were added to the control and high-dose for the two week recovery period.

Control animals:

yes, concurrent vehicle

Details on study design:

Dose levels were selected in consultation with the Sponsor based on the results of an acute toxicity study in Wistar rats after oral administration.

Positive control:

no

Observations and examinations performed and frequency:

Mortality: Throughout the study, all animals were checked early in each working day and again in the afternoon. At weekends and Public Holidays a similar procedure was followed except that the final check was carried out at approximately mid-day.
Pre- and post-dose observations: All observations were recorded for individual animals. Examination of individual animals for signs of reaction to treatment was carried out daily before dosing and approximately after 5 minutes, 1 and 2 hours after dosing up to Day 7 of the study. Starting from Day 8, since animals showed slight post-dose effects, examinations were reduced to pre-dose, approximately 5 minutes and 1 hour after dosing until the end of treatment.
Clinical signs and neurotoxicity assessment: All clinical signs were recorded for individual animals. Once before commencement of treatment and once a week thereafter each animal was subjected to a detailed clinical examination, which included an evaluation of neurotoxicity. Following removal from the cage, animals were examined in an open arena for a minimum of three minutes and standardised parameters were examined. All observed parameters, with the exception of the pre-dose, are reported in a group incidence table. Individual data were not included in the report. Once during week 4 of treatment and once during week 2 of recovery, an evaluation of sensory reactivity to stimuli of different modalities (e.g. auditory, visual and proprioceptive stimuli) and assessment of grip strength were also performed.
Motor activity assessment: The motor activity of all animals was measured once during week 4 of treatment and once during week 2 of recovery by an automated activity recording. Measurements were performed using a computer generated random order. Activity of the animals was recorded for 10 minute intervals over a period of 60 minutes. These data and the total activity were reported.
Body weight: Each animal was weighed on the day of allocation to treatment groups, on the day that treatment commenced, weekly thereafter and just prior to necropsy.
Food consumption: The weight of food consumed by each cage of rats was recorded at weekly intervals following allocation. The group mean daily intake per rat was calculated.
Clinical pathology investigations: At the end of the 4-week treatment period, samples of blood were withdrawn of all surviving male and female animals from each group, under conditions of food and water deprivation. At the same time interval, individual overnight (approximately 16 hours) urine samples were also collected from the same animals under the same conditions. Before starting urine collection water bottles were removed from each cage and each animal received approximately 10 mL/kg of drinking water by gavage, in order to obtain urine samples suitable for analysis. Prior to necropsy, blood samples were taken from the abdominal vena cava of all surviving rats from each group to perform coagulation tests. During week 2 of the recovery period blood and urine samples were also taken from all surviving animals under identical conditions in order to re-evaluate haematological (including coagulation tests), clinical chemistry and urine parameters.

Sacrifice and pathology:

Terminal studies: Animals that had completed the scheduled test period were killed and also that found dead subjected to necropsy.
Necropsy: The clinical history of the animal was studied and a detailed post mortem examination was conducted (including examination of the external surface and orifices). Changes were noted, the requisite organs weighed and the required tissue samples preserved in fixative and processed for histopathological examination.
Organ weights: From all animals completing the scheduled test period, the routinely examined organs were dissected free of fat and weighed. The ratios of organ weight to body weight were calculated for each animal.
Tissues fixed and preserved: Samples of all examined tissues were fixed and preserved.
Histopathological examination: All routinely examined organs were prepared for the histopathological examination. In the first instance the examination was restricted to tissues from all animals in the control and high dose groups killed after 4 weeks of treatment, tissues from the animal dying during the treatment period and all abnormalities in all main phase groups. Due to the finding observed in the initial analysis, the examination was then extended to the kidneys, of all other animals killed after 4 weeks of treatment or 2 weeks of recovery, to analyse treatment-related changes when compared with those of the high dose level.

Statistics:

Standard statistical methods have been applied for data processing.

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

Incoordination, salivation and piloerection were seen approximately 5 minutes after dosing in animals treated with 1000 mg/kg. Salivation and piloerection were occasionally observed also in animals dosed with 300 and 100 mg/kg/day. Weekly clinical examinations (open field measurements) including an evaluation of neurotoxicity gave no changes of note.

Mortality:

mortality observed, treatment-related

Description (incidence):

One male dosed with 300 mg/kg was found dead on day 27.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

A slight retardation in body weight growth was found in males of the highest dose group, during the administration period. This change recovered on treatment discontinuation. No changes of note were recorded in treated females.

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

not specified

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

not specified

Ophthalmological findings:

not examined

Haematological findings:

effects observed, treatment-related

Description (incidence and severity):

During the treatment a slight lymphocytosis was recorded in males treated with 1000 mg/kg. This finding was no longer observed at the end of the recovery phase.

Clinical biochemistry findings:

effects observed, treatment-related

Description (incidence and severity):

Triglycerides were increased in males receiving 300 and animals treated with 1000 mg/kg. When compared with controls increments were 51% and 79% in males treated with 300 and 1000 mg/kg, respectively, and 176% in females. In addition, a 20% increase in glucose was observed in males from the same groups, without a dose-relation. No finding worthy of note was recorded at the end of the recovery period.

Urinalysis findings:

effects observed, treatment-related

Description (incidence and severity):

In females treated with 1000 mg/kg an increment of urinary protein was observed when compared with the controls. A dose-related ketonuria was also observed in all treated animals. No changes of toxicological significance were observed at the end of the recovery period.

Behaviour (functional findings):

no effects observed

Description (incidence and severity):

No significant differences between treated animals and controls were observed at evaluation of sensory reaction performed at the end of treatment. Motor activity measurements performed at the end of the treatment period did not show changes which could be ascribed to treatment.

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

At the end of the treatment period a slight increase in liver weights (both absolute and relative) was observed at 1000 mg/kg in both sexes. This change did not completely recover after 2 weeks of withdrawal.

Gross pathological findings:

effects observed, treatment-related

Description (incidence and severity):

One early decedent male dosed with 300 mg/kg and found dead on day 27 of the study showed dark colour and swelling of the liver and dark colour with incomplete collapse of the lungs. No relevant changes were observed at post mortem examination in treated animals killed either at termination of treatment or after 2 weeks of recovery period when compared with controls.

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

In the one male dosed with 300 mg/kg and found dead on day 27, slight to mild congestion was detected in the liver and lung. Multifocal, mild alveolar haemorrhage was also seen in the lung.
In rats examined after termination of the study, mild to moderate nephropathy, represented by cortical interstitial chronic inflammation, tubular cell basophilia and tubular dilatation, was seen in the kidneys of 2/5 males and all females receiving 1000 mg/kg compared with controls. This renal change was considered to be related to the treatment. In addition, 4/5 females dosed with 1000 mg/kg showed slight to mild cortical/medullary mineralization. Slight nephropathy was also detected in single males receiving doses of >= 100 mg/kg. However, this finding can be observed in control animals of this age and strain, and, thus, it is considered more likely to be spontaneous in origin in the animals administered the low and intermediate doses.
In the recovery group all treated females and some males also showed slight to moderate nephropathy. One control female also showed slight nephropathy. Slight cortical/medullary mineralization was still present in spare females.

Histopathological findings: neoplastic:

not specified

Other effects:

not specified

Key result

Dose descriptor:

NOAEL

Effect level:

300 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

histopathology: non-neoplastic

Key result

Critical effects observed:

yes

Lowest effective dose / conc.:

1 000 mg/kg bw/day (nominal)

System:

hepatobiliary

Organ:

kidney

liver

Treatment related:

yes

Dose response relationship:

yes

Relevant for humans:

not specified

Conclusions:

The oral toxicity of the test item when given daily over 28 days via gavage to rats was investigated. Four groups, each of 5 male and 5 female Wistar rats, received the test item at dosages of 0, 100, 300 or 1000 mg/kg/day. The control and high-dose group included five additional rats per each sex for a two week recovery period.
Some treatment-related effects were evident in males and females at the highest dose level of 1000 mg/kg and the kidneys and liver were identified as main target organs. The observed effects were not completely reversible in both organs over a 2-week recovery period. No significant adverse effects were observed at the low- and mid-dose levels both in males and females. Therefore, the dose level of 300 mg/kg was considered to be the No Observed Adverse Effect Level (NOAEL) for both sexes.

Executive summary:

Study design

In this GLP study performed according to OECD GL 407, groups of five Wistar rats per sex were dosed daily via gavage with 0, 100, 300 and 1000 mg/kg for 4 consecutive weeks. The control and high-dose group included five additional rats per each sex for a two week recovery period.

 

Results

One male dosed with 300 mg/kg was found dead on day 27. As clinical signs in dosed rats, incoordination, salivation and piloerection were seen approximately 5 minutes after dosing with 1000 mg/kg. Salivation and piloerection were occasionally observed also in animals dosed with 100 or 300 mg/kg. A slight retardation in body weight gain was found in males of the highest dose group during the treatment, but this change recovered on treatment discontinuation. In males dosed with 1000 mg/kg a slight lymphocytosis was seen during the treatment period, while this effect was no longer observed at the end of the recovery phase. An increase in triglycerides was noted in males receiving 300 mg/kg and in both sexes dosed with 1000 mg/kg. These findings were no longer noted at the end of the recovery period. In high-dosed females an increment of urinary protein was observed when compared with the controls and in all dosed rats a dose-related ketonuria was noted in all treated animals. Also such findings were no longer noted at the end of the recovery period. The dosing with 1000 mg/kg caused a slight increase in absolute/relative liver weights in both sexes and this change did not completely recover after 2 weeks of withdrawal. The one male rat dosed with 300 mg/kg and found dead on day 27 showed dark colour and swelling of the liver and dark colour with incomplete collapse of the lungs, while no relevant changes were observed at post mortem examination in treated animals killed either at termination of treatment or after 2 weeks of recovery period when compared with controls. The histopathological examination of the one rat found dead gave a slight to mild congestion in the liver and lung and multifocal, mild alveolar haemorrhage in the lung. At study termination mild to moderate nephropathy, represented by cortical interstitial chronic inflammation, tubular cell basophilia and tubular dilatation, was seen in the kidneys of 2/5 males and all females dosed with 1000 mg/kg when compared with controls. This renal change was considered to be related to the treatment. In addition, 4/5 females dosed with 1000 mg/kg showed slight to mild cortical/medullary mineralization. Also in single males dosed with 100 or 300 mg/kg a slight nephropathy was noted. As this finding can be observed in control animals of this age and strain, it was considered more likely to be spontaneous in origin. After the recovery period all treated females and some males also showed slight to moderate nephropathy, which was seen also in one control female. Slight cortical/medullary mineralization was still present in spare females.

 

Conclusion

On the basis of the above results, some treatment-related effects were evident in males and females at the highest dose level of 1000 mg/kg and the kidneys and liver were identified as main target organs. The observed effects were not completely reversible in both organs over a 2-week recovery period. No significant adverse effects were observed at the low- and mid-dose levels both in males and females. Therefore, the dose level of 300 mg/kg was considered to be the No Observed Adverse Effect Level (NOAEL) for both sexes.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

300 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

The information for this endpoint study record was obtained from an experimental study. The OECD GLP criteria were met and the methods applied are fully compliant with OECD TG 407
.

System:

hepatobiliary

Organ:

liver

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
This study was performed according to GLP and the methods applied are fully compliant with OECD TG 407.

Justification for classification or non-classification

Based on the provided information there is no need to classified according to the EU Regulation (EC) No 1272/2008 on Classification,Labelling andPackaging of Substances and Mixtures.