Registration Dossier

Data platform availability banner - registered substances factsheets

Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.

The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.

Diss Factsheets

Administrative data

Description of key information

The oral administration of 1-(2-Hydroxyethyl)-2-Tall Oil-2-Imidazoline to rats by gavage, at dose levels of 15, 30 and 60 mg/kg bw/day, resulted in local irritant gastric irritation in all treatment groups. Therefore, a no observed-effect-level NOEL for local irritant effects can only be claimed for 15 mg/kg bw/day males. However, in relation to systemic and reproductive toxicity in the absence of any toxicologically significant effects the NOEL was considered to be 60 mg/kg bw/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
Remarks:
combined repeated dose and reproduction / developmental screening
Type of information:
experimental study
Adequacy of study:
key study
Study period:
04 July 2011 and 19 August 2011
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Study conducted in compliance with agreed protocols, with no or minor deviations from standard test guidelines and/or minor methodological deficiencies, which do not affect the quality of the relevant results. The study report was conclusive, done to a valid guideline and the study was conducted under GLP conditions.
Qualifier:
according to guideline
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Deviations:
no
Qualifier:
according to guideline
Guideline:
other: Commission Regulation (EC) No 440/2008 of 30 May 2008 laying down test methods pursuant to Regulation (EC) No 1907/2006 of the European Parliament and of the Council on the Registration, Evaluation, Authorisation and Restriction of Chemicals
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
Animals and Animal Husbandry:
Sufficient number of male and female Wistar Han™:RccHan™:WIST strain rats were obtained from a reputable supplier. For full details please see full study report. On receipt the animals were examined for signs of ill-health or injury.  The animals were acclimatised for a total of twelve days during which time their health status was assessed.  A total of eighty animals (forty males and forty females) were accepted into the study.  At the start of treatment the males weighed 288 to 380g, the females weighed 186 to 216g, and were approximately twelve weeks old.
Initially, all animals were housed in groups of five in solid floor polypropylene cages with stainless steel mesh lids and softwood flake bedding.  During the mating phase, animals were transferred to polypropylene grid floor cages suspended over trays lined with absorbent paper on a one male: one female basis within each dose group.  Following evidence of successful mating, the males were returned to their original cages.  Mated females were housed individually during gestation and lactation, in solid floor polypropylene cages with stainless steel mesh lids and softwood flakes.
The animals were allowed free access to food and water. Mains drinking water was supplied from polycarbonate bottles attached to the cage.  The diet and drinking water were considered not to contain any contaminant at a level that might have affected the purpose or integrity of the study.  Environmental enrichment was provided in the form of wooden chew blocks and cardboard fun tunnels except for mated females during gestation and lactation.
The animals were housed in a single air-conditioned room within the Laboratories Barrier Maintained Rodent Facility. The rate of air exchange was at least fifteen air changes per hour and the low intensity fluorescent lighting was controlled to give twelve hours continuous light and twelve hours darkness. Environmental conditions were continuously monitored by a computerised system and print-outs of hourly mean temperatures and humidities are included in the study records. The temperatures and relative humidity controls were set to achieve target values of 21 ± 2°C and 55 ± 15% respectively. Short term deviations from these targets were considered not to affect the purpose or integrity of the study.
The animals were allocated to dose groups using a randomisation procedure based on stratified body weights and the group mean body weights were then determined to ensure similarity between the dose groups. The animals were uniquely identified within the study, by an ear punching system routinely used in these laboratories.
Route of administration:
oral: gavage
Vehicle:
arachis oil
Details on oral exposure:
Preparation of Test Item
For the purpose of this study the test item was prepared at the appropriate concentrations as a solution in Arachis oil BP. The stability and homogeneity of the test item formulations were previously determined by Harlan Laboratories Ltd., Shardlow, UK, Analytical Services (Harlan Laboratories Ltd., Project Number: 41101676). Results from the previous study showed the formulations to be stable for up to three days. Formulations were therefore prepared daily and stored at 4ºC in the dark.
Samples of test item formulations were taken and analysed for concentration of 1-(2-Hydroxyethyl)-2-Tall Oil-2-Imidazoline at Harlan Laboratories Ltd., Shardlow, UK, Analytical Services. The results indicate that the prepared formulations were generally within 10± % of the nominal concentration.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The concentration of 1-(2-Hydroxyethyl)-2- Tall Oil-2-Imidazoline in the test item formulations was determined by high performance liquid chromatography (HPLC) using an external standard technique.
Duration of treatment / exposure:
The test item was administered by gavage to three groups, each of ten male and ten female Wistar Han™:RccHan™:WIST strain rats, for up to eight weeks (including a two week maturation phase, pairing, gestation and early lactation for females)
Frequency of treatment:
Daily
Remarks:
Doses / Concentrations:
15 mg/kg bw/day
Basis:
actual ingested
Remarks:
Doses / Concentrations:
30 mg/kg bw/day
Basis:
actual ingested
Remarks:
Doses / Concentrations:
60 mg/kg bw/day
Basis:
actual ingested
No. of animals per sex per dose:
10 animals per sex per dose (including control).
Control animals:
yes, concurrent vehicle
Details on study design:
The test item was administered daily by gavage using a stainless steel cannula attached to a disposable plastic syringe. Control animals were treated in an identical manner with 4 ml/kg bw/day of Arachis oil BP.
The volume of test and control item administered to each animal was based on the most recent scheduled body weight and was adjusted at regular intervals.
Chronological Sequence of Study

i)Groups of ten male and ten female animals were treated daily at the appropriate dose level throughout the study (except for females during parturition where applicable).  The first day of dosing was designated as Day 1 of the study.

ii) Prior to the start of treatment and once weekly thereafter, all animals were observed for signs of functional/behavioural toxicity.

iii) On Day 15, animals were paired on a 1 male: 1 female basis within each dose group for a maximum of fourteen days.

iv) Following evidence of mating (designated as Day 0 post coitum) the males were returned to their original cages and females were transferred to individual cages.

v) On completion of mating (during Week 6), five selected males per dose group were evaluated for functional/sensory responses to various stimuli.

vi) Pregnant females were allowed to give birth and maintain their offspring until Day 5 post partum.  Evaluation of each litter size, litter weight, mean offspring weight by sex, clinical observations and landmark developmental signs were also performed during this period.

vii)At Day 4 post partum, five selected females per dose group were evaluated for functional/sensory responses to various stimuli.

viii) Blood samples were taken from five males from each dose group for haematological and blood chemical assessments on Day 42.  Following completion of the female gestation and lactation phases, the male dose groups were killed and examined macroscopically.

ix) Blood samples were taken from five randomly selected females from each dose group at termination for haematological and blood chemical assessment on Day 4 post partum.  At Day 5 post partum, all females and surviving offspring were killed and examined macroscopically.
Positive control:
Not applicable
Observations and examinations performed and frequency:
Observations
Clinical Observations
All animals were examined for overt signs of toxicity, ill-health and behavioural change immediately before dosing, up to thirty minutes after dosing, and one and five hours after dosing, during the working week.  Animals were observed immediately before dosing, soon after dosing, and one hour after dosing at weekends (except for females during parturition where applicable).  All observations were recorded.
Functional Observations
Prior to the start of treatment and at weekly intervals thereafter, all animals were observed for signs of functional/behavioural toxicity.  Functional performance tests were also performed on five selected males and females from each dose level, prior to termination, together with an assessment of sensory reactivity to various stimuli.
Behavioural Assessments
Detailed individual clinical observations were performed for each animal using a purpose built arena.  The following parameters were observed:
Gait
Hyper/Hypothermia
Tremors
Skin colour
Twitches
Respiration
Convulsions
Palpebral closure
Bizarre/Abnormal/Stereotypic behaviour
Urination
Salivation
Defecation
Pilo-erection
Transfer arousal
Exophthalmia
Tail elevation
Lachrymation
 
This test was developed from the methods used by Irwin (1968) and Moser et al (1988).  The scoring system used is outlined in The Key to Scoring System and Explanation for Behavioural Assessments and Sensory Reactivity Tests.

Functional Performance Tests
Motor Activity.  Purpose-built 44 infra-red beam automated activity monitors were used to assess motor activity.  Animals were randomly allocated to the activity monitors.  The tests were performed at approximately the same time each day, under similar laboratory conditions.  The evaluation period was thirty minutes for each animal.  The percentage of time each animal was active and mobile was recorded for the overall thirty minute period and also during the final 20% of the period (considered to be the asymptotic period, Reiter and Macphail, 1979).

Forelimb/Hindlimb Grip Strength. An automated meter was used.  Each animal was allowed to grip the proximal metal bar of the meter with its forepaws.  The animal was pulled by the base of the tail until its grip was broken.  The animal was drawn along the trough of the meter by the tail until its hind paws gripped the distal metal bar.  The animal was pulled by the base of the tail until its grip was broken.  A record of the force required to break the grip for each animal was made.  Three consecutive trials were performed for each animal.  The assessment was developed from the method employed by Meyer et al (1979).

Sensory Reactivity
Each animal was individually assessed for sensory reactivity to auditory, visual and proprioceptive stimuli.  This assessment was developed from the methods employed by Irwin (1968) and Moser et al (1988). 
The following parameters were observed:
Grasp response
Touch escape
Vocalisation
Pupil reflex
Toe pinch
Blink reflex
Tail pinch
Startle reflex
Finger approach
 
Body Weight
Individual body weights were recorded on Day 1 (prior to dosing) and then weekly for males until termination and weekly for females until mating was evident.  Body weights were then recorded for females on Days 0, 7, 14 and 20 post coitum, and on Days 1 and 4 post partum. 

Food Consumption
During the maturation period, weekly food consumption was recorded for each cage of adults.  This was continued for males after the mating phase.  For females showing evidence of mating, food consumption was recorded for the periods covering post coitum Days 0-7, 7-14 and 14-20.  For females with live litters, food consumption was recorded on Days 1 and 4 post partum. 

Food efficiency (the ratio of body weight change/dietary intake) was calculated retrospectively for males throughout the study period (with the exception of the mating phase) and for females during the pre-mating phase.  Due to offspring growth and milk production, food efficiency could not be accurately calculated during gestation and lactation.

Water Consumption
Water intake was observed daily by visual inspection of water bottles for any overt changes.

Reproductive Screening
Mating
Animals were paired on a 1 male: 1 female basis within each dose group, for a period of up to fourteen days.  Cage tray-liners were checked each morning for the presence of ejected copulation plugs and each female was examined for the presence of a copulation plug in the vagina.  A vaginal smear was prepared for each female and the stage of oestrus or the presence of sperm was recorded.  The presence of sperm within the vaginal smear and/or vaginal plug in situ was taken as positive evidence of mating (Day 0 of gestation) and the males were subsequently returned to their original holding cages (unless required for additional pairing). Mated females were housed individually during the period of gestation and lactation.

Pregnancy and Parturition
Each pregnant female was observed at approximately 0830, 1230 and 1630 hours and around the period of expected parturition.  Observations were carried out at approximately 0830 and 1230 hours at weekends and public holidays.  The following was recorded for each female:
i) Date of pairing
ii) Date of mating
iii) Date and time of observed start of parturition
iv)Date and time of observed completion of parturition

Litter Data
On completion of parturition (Day 0 post partum), the number of live and dead offspring was recorded.  Offspring were individually identified within each litter by tattoo on Day 1 post partum.
For each litter the following was recorded:
i) Number of offspring born
ii) Number of offspring alive recorded daily and reported on Days 1 and 4 post partum
iii) Sex of offspring on Days 1 and 4 post partum
iv) Clinical condition of offspring from birth to Day 5 post partum
v) Individual offspring weights on Days 1 and 4 post partum (litter weights were calculated retrospectively from this data)

Physical Development
All live offspring were assessed for surface righting reflex on Day 1 post partum.

Laboratory Investigations
Haematological and blood chemical investigations were performed on five males and five females selected from each test and control group prior to termination (Day 42 for males and Day 4 post partum for females).  Blood samples were obtained from the lateral tail vein.  Where necessary repeat samples were taken by cardiac puncture at termination.  Animals were not fasted prior to sampling. 
Sacrifice and pathology:
Pathology
Adult males were killed by intravenous overdose of a suitable barbiturate agent followed by exsanguination on Day 43.  Adult females were killed by intravenous overdose of a suitable barbiturate agent followed by exsanguination on Day 5 post partum.  Surviving offspring were terminated via intracardiac overdose of sodium pentobarbitone.  Any females which failed to achieve pregnancy or produce a litter were killed on or after Day 26 post coitum.
For all females, the uterus was examined for signs of implantation and the number of uterine implantations in each horn was recorded.  This procedure was enhanced; as necessary, by staining the uteri with a 0.5% ammonium polysulphide solution (Salewski 1964).
All adult animals and offspring, including those dying during the study, were subjected to a full external and internal examination, and any macroscopic abnormalities were recorded.
Other examinations:
None
Statistics:
Please see "any other information on materials and methods" for details.
Clinical signs:
no effects observed
Description (incidence and severity):
See "Details on results" for more information.
Mortality:
no mortality observed
Description (incidence):
See "Details on results" for more information.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
See "Details on results" for more information.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
See "Details on results" for more information.
Food efficiency:
effects observed, treatment-related
Description (incidence and severity):
See "Details on results" for more information.
Water consumption and compound intake (if drinking water study):
no effects observed
Description (incidence and severity):
Daily visual inspection of water bottles did not reveal any significant intergroup differences between control and treated animals.
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Description (incidence and severity):
See "Details on results" for more information.
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
See "Details on results" for more information.
Urinalysis findings:
not examined
Behaviour (functional findings):
no effects observed
Description (incidence and severity):
See "Details on results" for more information.
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
There were no treatment-related differences detected in the organ weights measured.
Gross pathological findings:
no effects observed
Description (incidence and severity):
See "Details on results" for more information.
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
See "Details on results" for more information.
Histopathological findings: neoplastic:
no effects observed
Description (incidence and severity):
See "Details on results" for more information.
Details on results:
Mortality
On study Day 36 one male treated with 60 mg/kg bw/day was terminated on animal welfare grounds due to respiratory distress. The exact cause of death of this animal could not be established microscopically therefore, in the absence of similar findings in animals treated with 60 mg/kg bw/day this death was considered to be incidental. There were no further unscheduled deaths.

Clinical Observations
There were no clinical signs of toxicity detected in any treated animal.

Clinical findings were largely confined to either sex of 60 mg/kg bw/day animals and involved transient episodes of post dose increased salivation accompanied on occasion by episodes of noisy respiration. Observations of this nature are commonly observed following the oral administration of an unpalatable or slightly irritant test item formulation and in isolation are considered not to be of toxicological importance.

Isolated occurances of similar findings were observed in one 15 mg/kg bw/day male on Day 38 and in three males receiving 30 mg/kg bw/day, two of which on Day 31 and one on Day 35. One female at 30 mg/kg bw/day showed increased salivation on day 31. No clinical signs were observed in females at 15 mg/kg bw/day and

Functional Observations
Behavioural Assessments
Weekly open field arena observations did not reveal any treatment-related effects for treated animals when compared to controls.
All inter and intra group differences in urination, defecation and transfer arousal scores were considered to be a result of normal variation for rats of the strain and age used, and the differences were of no toxicological importance.

Functional Performance Tests
There were no treatment-related changes in the functional performance parameters measured.

Sensory Reactivity Assessments
There were no treatment-related changes in sensory reactivity.
All inter and intra group differences in sensory reactivity scores were considered to be a result of normal variation for rats of the strain and age used and the differences were of no toxicological importance.

Body Weight
Males treated with 60 mg/kg bw/day showed weight gains lower than that of the concurrent control throughout the study achieving statistical significance p<0.01 at Week 1 and 4. During the maturation phase females at 60 mg/kg bw/day also showed lower weight gains than controls returning to values comparable to female controls during the gestation and lactation phases.

No adverse effects on body weight change were detected for either sex of animals treated with 15 and 30 mg/kg bw/day during the pre-mating, gestation or lactation phases of the study when compared to controls.

Food Consumption and Food Efficiency
Males treated with 60 mg/kg bw/day showed lower dietary intake and reduced food efficiency throughout the treatment period in comparison with controls. Similar changes were evident in females from this test group but this was limited to the maturation phase only.

No convincing evidence of adverse effects on food consumption or food efficiency was detected in test animals of either sex at 15 and 30 mg/kg bw/day in comparison with controls.

Haematology
A statistically significant reduction (p<0.05) for activated partial thromboplastin time (APTT) was seen for males at 60 mg/kg bw/day. In the absence of supporting haematological changes and in view that examnation of the individual data showed only one individual value outside the background control range; this finding was considered to be incidental and of no toxicological importance.

Blood Chemistry
There were no toxicologically significant effects detected in the blood chemical parameters examined.

Males treated with 60 mg/kg bw/day showed a statistically significant reduction (p<0.05) in total protein. Females at this dosage showed a slight increase (p<0.05) for alanine aminotransferase plasma levels. However, in the absence of histopathological correlates and on the basis all individual values were within the normally expected ranges; these intergroup differences were considered of no toxicological importance.

Females treated with 15 mg/kg bw/day showed a statistically significant increase in blood glucose levels in comparison with controls. In isolation and in the absence of a dose related response this finding was considered not to be related to test item toxicity.

Necropsy
There were no toxicologically significant macroscopic abnormalities detected.

A small mass in the stomach lining was observed in one 15 mg/kg bw/day female. There was no other evidence of possible treatment-related macroscopic findings detected.

Incidental findings were limited to one 15 mg/kg bw/day female with an enlarged spleen, an increased pelvic space (hydronephrosis) noted in the left kidney of one further 15 mg/kg bw/day female. The left testes of one 15 mg/kg bw/day male was observed to be small and flaccid. Such observations represent common sporadic finding amongst rats of the strain and age used in the study and since there was neither a dose-response relationship nor a similar finding amongst the remaining animals at any dose level, these isolated changes were considered not to represent treatment-related effects.

Histopathology
The histopathological evaluation of the reproductive organs did not reveal any relevant changes in the high-dose animals.

A treatment-related macroscopic finding was observed in a low dose female as a mass in the non-glandular stomach, correlating with severe microscopic findings in non-glandular stomach. These lesions are considered to be associated with the local irritative properties of the test item.
Dose descriptor:
NOAEL
Remarks:
systemic toxicity
Effect level:
60 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: See discussion on results
Dose descriptor:
NOAEL
Remarks:
reproductive toxicity
Effect level:
60 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: See discussion on results
Critical effects observed:
not specified
Conclusions:
The oral administration of 1-(2-Hydroxyethyl)-2-Tall Oil-2-Imidazoline to rats by gavage, at dose levels of 15, 30 and 60 mg/kg bw/day, resulted in local irritant gastric irritation in all treatment groups. Therefore, a no observed-effect-level NOEL for local irritant effects can only be claimed for 15 mg/kg bw/day males. However, in relation to systemic and reproductive toxicity in the absence of any toxicologically significant effects the NOEL was considered to be 60 mg/kg bw/day.
Executive summary:

Introduction.The study was designed to investigate the systemic toxicity and potential adverse effects of the test item on reproduction (including offspring development) and are compatible with the requirements of the OECD Guidelines for Testing of Chemicals No. 422 “Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test” (adopted 22 March 1996).

This study was also designed to be compatible with the Commission Regulation (EC) No 440/2008 of 30 May 2008 laying down test methods pursuant to Regulation (EC) No 1907/2006 of the European Parliament and of the Council on the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH).

Methods.The test item was administered by gavage to three groups, each of ten male and ten female Wistar Han™:RccHan™:WIST strain rats, for up to eight weeks (including a two week maturation phase, pairing, gestation and early lactation for females), at dose levels of 15, 30 and 60 mg/kg bw/day. A control group of ten males and ten females was dosed with vehicle alone (Arachis oil BP).

Clinical signs, behavioural assessments, body weight change, food and water consumption were monitored during the study. 

Pairing of animals within each dose group was undertaken on a one male: one female basis within each treatment group on Day 15 of the study, with females subsequently being allowed to litter and rear their offspring to Day 5 of lactation.

During the lactation phase, daily clinical observations were performed on all surviving offspring, together with litter size, sex ratio and offspring weights and assessment of surface righting reflex.

Extensive functional observations were performed on five selected males from each dose group after the completion of the mating phase, and for five selected parental females from each dose group on Day 4 post partum. Haematology and blood chemistry were evaluated prior to termination on five selected males and females from each dose group. 

Surviving adult males were terminated on Day 43, followed by the termination of all females and offspring on Day 5 post partum. All animals were subjected to a gross necropsy examination and histopathological evaluation of selected tissues was performed.

Results.

Adult Responses:

Mortality.On study Day 36 one male treated with 60 mg/kg bw/day was terminated on animal welfare grounds due to respiratory distress. There were no further unscheduled deaths. Macroscopic examination revealed no abnormalities.

Clinical Observations.Treatment-related clinical signs were largely confined to either sex of 60 mg/kg bw/day animals and involved transient episodes of increased salivation accompanied on occasion by episodes of noisy respiration that were observed shortly after dosing.

Behavioural Assessment.Detailed behavioural assessments supported the signs seen clinically in 60 mg/kg bw/day animals.

Functional Performance Tests.There were no treatment-related changes in the functional performance parameters measured.

Sensory Reactivity Assessments.There were no treatment-related changes in sensory reactivity.

Body Weight.Males treated with 60 mg/kg bw/day showed statistically significant weight gains lower than that of the concurrent control throughout the study. During the maturation phase females at 60 mg/kg bw/day also showed lower weight gains than controls returning to values comparable to female controls during the gestation and lactation phases.

No such effects were detected in either sex of animals treated with 15 and 30 mg/kg bw/day.

Food Consumption.Males treated with 60 mg/kg bw/day showed lower dietary intake and reduced food efficiency throughout the treatment period in comparison with controls. Similar changes were evident in females from this test group but this was limited to the maturation phase only.

There was no convincing evidence of an affect on food consumption or food efficiency in either sex of treated with 15 or 30 mg/kg bw/day.

Water Consumption.No adverse effect on water consumption was detected.

Reproductive Performance:

MatingThere were no treatment-related effects on mating for treated animals.

Fertility.There were no treatment-related effects on conception rates for treated animals.

Gestation Lengths.There were no differences in gestation lengths. The distribution for treated females was comparable to controls.

Litter Responses:

Offspring Litter Size and Viability. Of the litters born, litter size at birth and subsequently on Days 1 and 4 post partum were comparable to controls. There were no intergroup differences in sex ratio.

Offspring Growth and Development. Offspring body weight gain and litter weights at birth and subsequently on Days 1 and 4 post partum were comparable to controls. No effect on surface righting reflex was detected.

Offspring Observations. No clinically observable signs of toxicity were detected for offspring from all treatment groups.

Laboratory Investigations:

Haematology. There were no treatment-related changes detected in the haematological parameters measured.

Blood Chemistry. There were no toxicologically significant effects detected in the blood chemical parameters measured.

Pathology:

Necropsy.There were no toxicologically significant macroscopic abnormalities detected.

A small mass in the stomach lining was observed in one 15 mg/kg bw/day female. There was no other evidence of possible treatment-related macroscopic findings detected.

Organ Weights.There were no treatment-related changes detected in the organ weights evaluated.

Histopathology.The following treatment-related microscopic findings were detected:

Focal to multifocal minimal to moderate squamous cell hyperplasia was seen in the non-glandular stomach of 30 and 60 mg/kg bw/day males and in all female test groups. This finding in most instances was associated with minimal to moderate submucosal inflammation in males and minimal to marked submucosal inflammation in females. One 60 mg/kg bw/day male showed a minimal focal and one 60 mg/kg bw/day female a moderate focal erosion. A further 60 mg/kg bw/day female was noted to have focal slight epithelial degeneration. In addition, one 15 mg/kg bw/day female showed a marked ulceration with marked submucosal inflammation and marked peritonitis.

Conclusion.The oral administration of 1-(2-Hydroxyethyl)-2-Tall Oil-2-Imidazoline to rats by gavage, at dose levels of 15, 30 and 60 mg/kg bw/day, resulted in local irritant gastric irritation in all treatment groups. Therefore, a no observed-effect-level NOEL for local irritant effects can only be claimed for 15 mg/kg bw/day males. However, in relation to systemic and reproductive toxicity in the absence of any toxicologically significant effects the NOEL was considered to be 60 mg/kg bw/day.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
60 mg/kg bw/day
Study duration:
subacute
Species:
rat
Organ:
other: local effects to the gastro-intestinal tract

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

The oral administration of 1-(2-Hydroxyethyl)-2-Tall Oil-2-Imidazoline to rats for a period of up to eight weeks (including two weeks pre-mating, gestation and early lactation period for females) at dose levels of 15, 30 and 60 mg/kg bw/day resulted in treatment related effects detected in animals of either sex treated with 60 mg/kg bw/day.

Although there were no clinical signs of toxicity observed the irritative characteristics of the test item did result in episodes of excessive salivation and noisy respiration in 60 mg/kg bw/day animals and occasionally among males at 15 and 30 mg/kg bw/day. One 60 mg/kg bw/day male was terminated on Day 36 because of distressed respiration and while the aetiology is uncertain; the predominance of excessive salivation together with the clinical signs associated with an effect on respiration is not an uncommon finding following administration of irritant test item formulations. Furthermore it is possible that test item deposited in the upper oesophagus during dosing or by reflux from the stomach could conceivably have induced the pulmonary distress. The isolated nature of this event in the absence of toxicological evidence to the contrary was therefore considered associated with the irritant and not the toxicological properties of the test item. Treatment-related histopathology was confined to local irritative effects identified in the non-glandular stomach of three females at 15 mg/kg bw/day, three males and one female at 30 mg/kg bw/day, and in the majority of males and females at 60 mg/kg bw/day.

There were no toxicologically significant effects identified during the weekly open field arena observations, clinical pathology, organs weights or at terminal necropsy.

There were no treatment-related effects detected in the reproductive parameters observed.

Justification for classification or non-classification

Due to the known corrosive properties of the substance, a seven day repeat dose oral (gavage) range-finding

toxicity study in the rat was conducted to establish the highest dose possible to test in the main OECD 422 study.

The oral administration of the substance to rats for a period of seven consecutive days at dose levels of 15, 30 and 60 mg/kg bw/day resulted in treatment related effects in all animals of either sex from all treatment groups. However, these changes only involved minor divergences from control values and may have been more associated with the know corrosive/irritant properties of the test item than systemic toxicity. Under the conditions of the preliminary study they were considered to be within acceptable levels of tolerance. On this basis the NOAEL established in the preliminary study and one considered to be a suitable choice for the high dose level in the OECD 422 study was 60 mg/kg bw/day. However, the observations observed from the preliminary study demonstrated the potential for dosages above 60 mg/kg bw/day over a longer treatment period to present a risk to an animals health and welfare, due to the substance corrosive/irritant properties.

 

In the OECD 422 study, the oral administration of the test material to rats by gavage, at dose levels of 15, 30 and 60 mg/kg bw/day, resulted in treatment related effects detected in animals of either sex from all treatment groups.Therefore, a no observed-effect-level NOEL for local irritant effects can only be claimed for 15 mg/kg bw/day males. However, in relation to systemic and reproductive toxicity in the absence of any toxicologically significant effects the NOEL was considered to be 60 mg/kg bw/day.

 

Although a NOEL of 60 mg/kg bw/day was established in the OECD 422 Combined Repeat Dose Toxicity

Study with Reproduction/Developmental Toxicity Study, the effects seen in this study were considered to be the result of local irritancy of the test item and therefore cannot be considered indicative of true systemic toxicity.

This is supported by similar observations from the seven day repeat dose oral (gavage) range-finding toxicity study in the rat at dose levels of 15, 30 and 60 mg/kg bw/day. In view of this, it is considered that classification of the test substance for repeat dose toxicity is not justified, as no adverse systemic toxicity effects were observed at 60 mg/kg bw/day, in the OECD 422 Combined Repeat Dose Toxicity Study with Reproduction/Developmental Toxicity Study after treatment.

 

Furthermore 60 mg/kg bw/day is considered to be the highest possible test dose, it is not considered feasible or ethical to test the corrosive test substance at the dose levels used as classification guidance value ranges in the CLP regulation i.e. at equal to or greater than 300 mg/kg bw/day for subacute/28 -day repeat dose studies.

 

Additionally the substance is considered to have low potential for systemic toxicity since severe irritancy / corrosivity will limit exposure in the workplace.

 

As such the appropriate classification for the substance is considered to be that based on its’ corrosive properties.