Petrolatum (petroleum), oxidized, Bu ester

Endpoint summary

Description of key information

ORAL
NOAEL = 1000 mg/kg bw/day (distillates (pertoleum), oxidized light), rat (male/female), OECD 422, Dhinsa (2005)

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:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Study period:

4 August 2004 to 15 February 2005

Reliability:

2 (reliable with restrictions)

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, conducted to a valid guideline and was performed under GLP conditions. Since the study was conducted with the read across substance, distillates (pertoleum), oxidized light, it has been assigned a reliability score of 2. Read across from this substance is justified on the basis of its similar physical and chemical properties to those of the registered substance. Furthermore, it has a very similar chemical structure; the registered substance is longer chain material; it is also an esterified form of the read across substance.

Qualifier:

according to guideline

Guideline:

OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Strain: Sprague-Dawley Crl:CD® (SD) IGS BR
- Source: Charles River (UK) Limited, Margate, Kent, UK
- Age at study initiation: approximately 8 weeks
- Weight at study initiation: 201 - 266 g (males); 177 - 238 g (females)
- Housing: Initially in groups of 4, during the mating phase animals were housed in pairs (one of each sex), following mating females where housed individually and males in groups. Cages were polypropylene cages with stainless steel grid floors and tops, suspended over polypropylene trays lined with absorbent paper. Mated females were housed in polypropylene cages with solid floors and stainless steel lids, furnished with softwood flakes (Datesand Ltd. Cheshire, UK)
- Diet: pelleted diet (Rodent PMI 5002 (Certified) diet, BCM IPS Limited, London, UK), ad libitum
- Acclimation period: Up to 16 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 ± 2 °C
- Humidity (%): 55 ± 15 %
- Air changes (per hr): at least 15 air changes per hour
- Photoperiod (hrs dark / hrs light): 12 hours light/ 12 hours dark

Route of administration:

oral: gavage

Vehicle:

polyethylene glycol

Remarks:

400

Details on oral exposure:

PREPARATION OF DOSING SOLUTIONS:
- The appropriate concentrations were prepared in the vehicle weekly and stored at approximately 4 °C in the dark.
- The test material was administered daily by gavage using a plastic catheter attached to a disposable plastic syringe.
- Control animals were treated in an identical manner with 4 mL/kg/day of the vehicle.
- The volume of test and control material administered to each animal was based on the most recent bodyweight and was adjusted at regular intervals.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Samples from each preparation were analysed using gas chromatography to verify the concentration, stability and homogeneity of each formulation.

Method:
- Gas chromatography.
- Samples and standards were prepared in methanol to give a final concentration of 0.1 mg/mL
- Samples were analysed within two days of preparation.
- The method was validated using a range of standard solutions covering the range 0 to 0.1527 mg/mL. The results of which have been considered to be sufficiently accurate for the purpose of this study.

Conditions:
- GC system: Agilent Technologies 5890, incorporating autosampler and workstation
- Column: DB-1 (30 m x 0.32 mm id x 0.25 µm film)
- Oven temperature program: initial 50 °C for 0 mins, rate 5 °C/min, final 200 °C for 0 mins
- Injection temperature: 150 °C
- Flame ionisation detector temperature: 250 °C
- Injection volume: 1 µL
- Retention time: ~14.7 mins

Results:
- The results indicate that the prepared formulations were within ± 9 % of the nominal concentration.
- Analytical verification of the stability and homogeneity of the test preparations was also performed and the formulation was found to be stable for at least fourteen days.

Duration of treatment / exposure:

Up to 54 days (males were sacrificed on Day 43; females were sacrificed on Day 5 post partum)

Frequency of treatment:

daily

Remarks:

Doses / Concentrations:
100, 300 and 1000 mg/kg/day
Basis:
actual ingested

No. of animals per sex per dose:

10 males and 10 females per dose group

Control animals:

yes, concurrent vehicle

Details on study design:

- Rationale for animal assignment: The animals were allocated to dose groups using a randomisation procedure based on stratified bodyweights and the group mean bodyweights were then determined to ensure similarity between the dose groups.

- Dose selection rationale: Dose selection for the definitive study was based on the findings of a preliminary 14 day range finding study.

Preliminary Study:
- Animals were dosed daily for fourteen days and observed for adverse effects resulting from toxicity including; clinical observations, bodyweight and gross pathology.
- Animals were kept under the same conditions as in the definitive study.
- The test material was prepared in the same manner as the definitive study and verified analytically.
- The test material was administered in a limit test daily, for up to 14 consecutive days. Animals were administered 1000 mg/kg/day via oral gavage, a volume of 4mL/kg and a concentration of 250 mg/mL. Control animals were treated in an identical manner with 4 mL/kg/day of polyethylene glycol.

Observations and examinations performed and frequency:

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: immediately before and after dosing, then at 1 and 5 hours after dosing. The 5 hour observation was omitted at weekends, except for females during parturition, where applicable.
- Observations recorded: overt signs of toxicity, ill-health and behavioural changes.

FUNCTIONAL OBSERVATIONS: YES
- Time schedule: prior to the start of treatment and at weekly intervals.
- Observations recorded: signs of functional behavioural toxicity (except for non-pregnant female number 71). Functional performance tests were also performed on five selected males and females per dose level, prior to termination, together with an assessment of sensory reactivity to various stimuli.

BEHAVIOURAL ASSESSMENTS: Yes
- Observations recorded: gait, tremors, twitches, convulsions, bizarre/abnormal/stereotypic behaviour, salivation, pilo-erection, exophthalmia, lachrymation, hyper/hypothermia, skin colour, respiration, palpebral closure, urination, defecation, transfer arousal, tail elevation.

BODY WEIGHT: Yes
- Time schedule for examinations: males were weighed on day 0, then weekly until termination. Females were weighed on day 0 and then weekly until evidence of mating was evident. Bodyweights were recorded on day 0, 7, 14 and 20 post coitum, and on day 1 and 4 post partum.

FOOD AND WATER CONSUMPTION: Yes
- Weekly food consumption was recorded for each caged group of adults, which was continued for males after mating. Food consumption for females showing evidence of mating was recorded for the periods covering days 1-7, 7-14 and 14-21. For females with live litters, consumption was recorded during the lactation period.
- Water consumption was observed daily by visual inspection of water bottles for any overt change.

HAEMATOLOGY: Yes
- Time schedule for collection of blood: on day 14, prior to pairing.
- Anaesthetic used for blood collection: No data
- Animals fasted: No
- How many animals: five males and five females per dosing group.
- Parameters examined on blood collected into tubes containing potassium EDTA anti-coagulant: haemoglobin, erythrocyte count, haematocrit, erythrocyte indices, total leucocyte count, differential leucocyte count, platelet count, prothrombin time and activated thromboplastin time.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: on day 14, prior to pairing.
- Animals fasted: No
- How many animals: five males and five females per dosing group.
- Parameters examined on blood collected into tubes containing lithium heparin anti-coagulant: urea, glucose, total protein, albumin, albumin/globulin ratio (by calculation), sodium, pptassium, chloride, calcium, inorganic phosphorus, aspartate aminotransferase, alanine aminotransferase, Alkaline phosphatise, creatinine, total cholesterol and total bilirubin.

NEUROBEHAVIOURAL EXAMINATION: Yes
- Battery of functions tested: sensory activity, forelimb/hind limb grip strength and motor activity

Sensory reactivity: Each animal was individually assessed for sensory reactivity to auditory, visual and proprioceptive stimuli. The following parameters were observed: grasp response, vocalisation, toe pinch, tail pinch, finger approach, touch escape, pupil reflex, startle reflex and blink reflex.

Grip strength: An automated grip strength 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.

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).

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
All males were killed by intravenous overdose of sodium pentobarbitone followed by exsanguination. The interim death female was killed by carbon dioxide asphyxiation followed by cervical dislocation. The remaining surviving adult females were killed by intravenous overdose of sodium pentobarbitone followed by exsanguination on Day 5 post partum.

All adult animals, including those dying during the study, were subjected to a full external and internal examination, and any macroscopic abnormalities were recorded.

ORGAN WEIGHTS:
The following organs were dissected free from fat and weighed at the end of the study; adrenals, brain, epididymides, heart, kidneys, liver, ovaries, spleen, testes and the thymus.

HISTOPATHOLOGY: Yes
Samples of the following tissues were preserved from five males and five females, from each dose group: adrenals, aorta (thoracic), bone & bone marrow (femur including stifle joint), bone & bone marrow (sternum), brain (including cerebrum, cerebellum and pons), caecum, coagulating gland*, colon, duodenum, epididymides*, eyes, gross lesions, heart, ileum, jejunum, kidneys, liver, lungs (with bronchi), lymph nodes (cervical and mesenteric), mammary gland, muscle (skeletal), ovaries*, pancreas, pituitary*, prostate*, oesophagus, rectum, salivary glands (submaxillary), sciatic nerve, seminal vesicles*, skin (hind limb), spinal cord (cervical), spleen, stomach, thyroidparathyroid, trachea, testes*, thymus, urinary bladder, uterus/cervix* and the vagina.
The tissues from five selected control and 1000 mg/kg/day dose group animals and those animals dying during the study, were prepared as paraffin blocks, sectioned at nominal thickness of 5 µm and stained with haematoxylin and eosin for subsequent microscopic examination. Tissues marked with an asterisk were also processed from the remaining control and 1000 mg/kg/day animals.

Other examinations:

Observations were also performed during mating and pregnancy and parturition, as part of reproduction screening. Litter data were also recorded and reproductive indices calculated.

Statistics:

Data were processed to give group mean values and standard deviations where appropriate. Haematological, blood chemical, organ weight (absolute and relative to terminal bodyweight), weekly bodyweight gain and quantitative functional performance data were assessed for dose response relationships by linear regression analysis, followed by one way analysis of variance (ANOVA) incorporating Levene’s test for homogeneity of variance. Where variances were shown to be homogenous, pairwise comparisons were conducted using Dunnett’s test. Where Levene’s test showed unequal variances the data were analysed using non-parametric methods: Kruskal-Wallis ANOVA and Mann-Whitney ‘U’ test.

The haematology variable basophils was not analysed since consistently greater than 30% of the data were recorded as the same value.

Probability values (p) are presented as follows:
p < 0.001 ***
p < 0.01 **
p < 0.05 *
p 20.05 (not significant)

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Description (incidence and severity):

only consumption was monitored.

Food efficiency:

no effects observed

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

no effects observed

Description (incidence and severity):

only consumption was monitored.

Ophthalmological findings:

not examined

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

not examined

Behaviour (functional findings):

no effects observed

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Histopathological findings: neoplastic:

not specified

Details on results:

MORTALITY:
No treatment related deaths were observed during the course of the study. One female treated with 1000 mg/kg/day was killed in extremis during parturition. This was attributed to dystocia and of no toxicological significance.

CLINICAL OBSERVATIONS:
Increased salivation was detected prior to dosing and up to one hour after dosing fix animals of either sex treated with 1000 mg/kg/day from Day 3 onwards. An isolated incident of increased salivation was also detected up to one hour after dosing for one female treated with 300 mg/kg/day on Day 17 only. This observation is often recorded following the oral administration of an unpalatable or irritant test material. Isolated incidents of noisy respiration were also observed at 1000 mg/kg/day.
No such effects were detected at 100 mg/kg/day. Incidents of scab formation, generalised fur loss and staining of the external body surface were observed throughout the treatment and control groups. These are occasionally seen in laboratory maintained rodents and are considered to be incidental and not indicative of toxicity.
Isolated incidents of noisy respiration were detected for one male and one female treated with 1000 mg/kg/day during the Week 1 assessments. One 1000 mg/kg/day male also showed noisy respiration during Week 6.

BODYWEIGHT:
There were no adverse effects on bodyweights for males throughout the study. Bodyweight gains for treated females throughout the maturation, gestation and lactation phases of the study were comparable to controls.

FOOD COMSUMPTION:
No adverse effects were observed on dietary intake and food efficiency during the course of the study.
The statistically significant reductions in dietary intake detected for all male treatment groups during the final week of treatment were minimal (p<0.05) and attributable to a slightly higher dietary intake for the controls and considered unrelated to treatment.

HAEMATOLOGY:
No treatment-related effects were detected.
The statistically significant reduction (p<0.05) in haemoglobin levels detected for females treated with 1000 mg/kg/day was minimal. In the absence of any other changes to suggest a haemolytic or haematological effect, and in the absence of histopathological correlates, this was considered to have arisen fortuitously.

CLINICAL CHEMISTY:
No toxicologically significant effects of treatment were demonstrated.
The statistically significant increases in plasma albumin, total protein and creatinine and the reduced chloride levels detected for females treated with 1000 mg/kg/day, in the absence of supporting data to suggest test material toxicity, were considered unrelated to treatment.
The elevated creatinine levels detected for females treated with 300 mg/kg/day was minimal (p<0.05) and the absence of any other biochemical or histopathological effects detected at this dose level, this finding was considered to have arisen incidentally.

NEUROBEHAVIOUR:
There were no treatment-related changes in any of the functionality tests; sensory reactivity, grip strength and motor activity.
- 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 the ages used and were of no toxicological importance.

ORGAN WEIGHTS:
No toxicologically significant effects of treatment were detected.
Elevated liver weights, relative to terminal bodyweights were detected for animals (of either sex treated with 1000 mg/kg/day, with statistical significance achieved for males (p<0.01). Elevated adrenal weights, both absolute and relative to terminal bodyweight was detected for females treated with 1000 mg/kg/day. In the absence of histopathological correlates, these effects were most probably attributed to xenobiotic induction and of no toxicological importance.
The statistically significant reduction in absolute adrenal and heart weights detected for males treated with 1000 mg/kg/day were not reflected in the relative weights and therefore considered unrelated to treatment.
The statistically significant increase in relative liver weight detected for 100 mg/kg/day males was minimal (p<0.05) and in the absence of a convincing dose related response, was considered incidental and unrelated to treatment.

NECROPSY/GROSS PATHOLOGY:
No treatment-related macroscopic abnormalities were detected for adult animals at terminal kill.
One male showed dorsal scab formation at termination but this isolated incident was unrelated to treatment.

HISTOPATHOLOGY
The following treatment-related changes were observed:
- Kidneys: Globular accumulations of eosinophilic material were observed in the tubular epithelium of males treated at all treatment levels. One control male was similarly affected. There was no indication of associated degenerative tubular changes and no dose relationship. This finding is consistent with the presence of hydrocarbon nephropathy following treatment with petroleum based test materials. This results from the excessive accumulation of alpha2-microglobulin in renal proximal tubular epithelial cells, found only in the proximal tubular epithelium of adult male rats.
- Thyroids: A marginal effect was observed in respect of the prevalence and severity of follicular cell hypertrophy in relation to treatment for animals of either sex treated with 1000 mg/kg/day. A similar effect was also seen for males treated with 300 mg/kg/day, extending into the 100 mg/kg/day dose group. Although not convincing due to similar findings in the controls, the possibility that treatment with the test material has affected the thyroid follicular epithelium cannot be entirely excluded; this can, however, be generally regarded as an adaptive change.
- Stomach: Minimal acanthosis, occasionally with associated hyperkeratosis, was observed in relation to treatment for two male rats and for three females treated with 1000 mg/kg/day, but not at any other treatment level. These are adaptive responses, secondary to oral gavage administration of a highly concentrated epithelial irritant.

All remaining morphological changes were those commonly observed in laboratory maintained rats of the age and strain employed and, since there were no differences in incidence or severity between control and treatment groups, all were considered to be without toxicological significance.

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Critical effects observed:

not specified

Results of Preliminary toxicity Study:

- Increased salivation was detected up to ten minutes after dosing for animals of either sex treated with 1000 mg/kg/day from Day 2 onwards. This observation is often recorded following the oral administration of an unpleasant tasting and/or locally irritant test material formulation and in isolation, is not considered to be indicative of systemic toxicity.

- No mortalities were observed or systemic signs of toxicity.

Conclusions:

Under the conditions of the study the maximum dose level of 1000 mg/kg/day resulted in treatment-related microscopic changes in the kidneys, thyroid glands, and fore stomach at all treatment levels. The renal changes observed were considered to be a consequence of protein accumulation exclusive to the male rat. Changes in thyroid glands and fore stomach were considered to be minimal and adaptive in nature. The ‘No Observed Adverse Effect Level’ (NOAEL) for systemic toxicity was therefore considered to be 1000 mg/kg/day.

Executive summary:

In a GLP compliant study the repated dose toxicity of the test material was determined in accordance with the standardised guideline OECD 422. During the study male and female Sprague-Dawley rats were administered test material daily, at dose levels of 100, 300 or 1000 mg/kg, over a period of up to 54 days. The maximum dose level of 1000 mg/kg/day resulted in treatment-related microscopic changes in the kidneys, thyroid glands, and forestomach at all treatment levels. Changes in thyroid glands and forestomach were considered to be minimal and adaptive in nature. No mortalities or other systemic signs of toxicity were observed as a direct result of dosing. Under the conditions of the test the ‘No Observed Adverse Effect Level’ (NOAEL) for systemic toxicity was therefore considered to be 1000 mg/kg bw/day to both male and female rats.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

The study was performed in line with GLP and an accepted standardised guideline with a high standard of reporting. The study was performed with a structural analogue and so was assigned a reliability score of 2 in accordance with the criteria for assessing data quality as outlined in Klimisch (1997) and considered suitable for assessment as an accurate reflection of the test material. The oral route was considered the most appropriate route of exposure.

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

Oral

The toxicity of the test material, following repeated oral exposure, was determined under GLP conditions and in accordance with the standardised guideline OECD 422. During the study 10 rats of each sex were given 100, 300 or 1000 mg/kg test material, daily, for a period of up to 54 days. Male animals were sacrificed on Day 43 while female animals were sacrificed on Day 5 post partum. The maximum dose level of 1000 mg/kg/day resulted in treatment-related microscopic changes in the kidneys, thyroid glands, and forestomach at all treatment levels. The renal changes observed were considered to be a consequence of protein accumulation exclusive to the male rat. Changes in thyroid glands and forestomach were considered to be minimal and adaptive in nature. The ‘No Observed Adverse Effect Level’ (NOAEL) for systemic toxicity was therefore considered to be 1000 mg/kg bw/day.

Since the study was performed with a structural analogue it was assigned a reliability score of 2 in accordance with the criteria for assessing data quality as outlined in Klimisch (1997). The results of this read-across study can be considered to represent a worst case since the test material (Distillates (petroleum), oxidized light) is a shorter chain material and therefore has a greater potential for absorption within the body. The read-across substance can therefore be considered to be potentially more bioavailable than the registered substance, which, due to its very high log Pow value, is anticipated to have only very limited potential for bioavailability.

In accordance with Column 2 (adaptation statement) of Annex IX of Regulation (EC) 1907/2006 (REACH), it is considered justified to omit the sub-chronic toxicity study (90 day) required under information point 8.6.2 if the substance is unreactive, insoluble and not inhalable and if there is no evidence of absorption and no evidence of toxicity in a 28-day 'limit test'. Since no systemic toxicity was observed in the OECD 422 Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test, further testing is omitted.

 

Inhalation

In accordance with Column 1 of Annex VIII of Regulation (EC) 1907/2006 (REACH), the repeated dose toxicity study required under information point 8.6. should be conducted using the most appropriate route of administration. It is considered justified to omit the repeated dose inhalation toxicity study on the basis of exposure considerations. 

Integrated testing strategies state that determination of the most likely route of exposure needs to take into account not only how the substance is manufactured and handled, including engineering controls and risk management measures, but also the physicochemical properties of the substance.

The nature of the registered substance means that it is not potentially inhalable; the substance has low vapour pressure and therefore is unlikely to be available for inhalation as a vapour. The low water solubility, high molecular weight and high log Pow value, all suggest a limited absorption after inhalation.

If any amount of the substance reaches the alveoli, this will be likely phagocytised by macrophages, located into the immune surveillance tissues and broken down in lysosomes and peroxisomes.

Data are available in the form of an oral study conducted to OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test); this data sufficiently addresses the repeat dose toxicity data requirements.

 

Dermal

In accordance with Column 1 of Annex VIII of Regulation (EC) 1907/2006 (REACH), the repeated dose toxicity study required under information point 8.6. should be conducted using the most appropriate route of administration. It is considered justified to omit the repeated dose dermal toxicity study on the basis of exposure considerations. 

Integrated testing strategies state that determination of the most likely route of exposure needs to take into account not only how the substance is manufactured and handled, including engineering controls and risk management measures, but also the physicochemical properties of the substance.

The physical state, high molecular weight and high log Pow value, together with the low water solubility, indicate very low potential for dermal absorption. Similarly to mineral oils, deposition in the stratum corneum is expected to occur slowly; however, the substance is not sufficiently water soluble to partition from the stratum corneum into the epidermis.

As dermal absorption cannot be greater than oral absorption, the data that are already available from testing via the oral route can be regarded as representing the worst-case scenario. Furthermore, no dermal absorption of the registered substance is expected to occur.

The available data, from an oral study conducted to OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test), are considered to sufficiently address the repeat dose toxicity data requirements.

 

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
Only one study is available.

Justification for classification or non-classification

In accordance with the criteria for classification as defined in Annex I, Regulation 1272/2008 (CLP) and Directive 67/548/EEC (DSD)

, the test material does not require classification for specific organ toxicity, repeated dose. The effects observed in the main study are not considered to be toxicologically significant and do not indicate any signs of organ dysfunction.