Registration Dossier

Administrative data

Description of key information

In the key study, a 20-week repeated dose toxicity test in rats, the NOAEL of alpha-Terpinyl Acetate is set to >=400 mg/kg bw/day (10,000 mg/kg.diet. This value can be converted to alpha-Terpineol becoming 314 mg/kg  diet (154/196 x 400 mg/kg bw).

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: oral
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: The reliability is assessed as 2 becasue of its use for read across. In addition: the study is non-GLP and predating current guidelines but is similar to OECD TG 408. It has been published in a peer reviewed journal.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents)
GLP compliance:
no
Limit test:
no
Species:
rat
Strain:
Osborne-Mendel
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Housing: Individually in wire cages
- Diet: Ad libitum
- Water: Ad libitum

Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
7% loss of food flavouring during a 7-day period
Duration of treatment / exposure:
20 weeks
Frequency of treatment:
Fresh diets were made and distributed weekly
Remarks:
Doses / Concentrations:
1000, 2500, 10000 ppm (corresponding to 40, 100 and 400 mg/kg bw)
Basis:
nominal in diet
No. of animals per sex per dose:
10
Control animals:
yes, concurrent no treatment
Observations and examinations performed and frequency:
The rat's weight, food intake and general condition were recorded every week. Haematological examinations were made at termination
Sacrifice and pathology:
At the termination of the experiments the rats were sacrificed and exsanguinated. The tissues of all the rats were examined macroscopically at the time of sacrifice. The viscera were removed and the liver, kidneys, spleen, heart, and testes were weighed. These organs, the remaining abdominal and thoracic viscera, and one hind leg, for bone, bone marrow, and muscle, were preserved in 10 % buffered formalin-saline solution for histopathological
examination. For routine histopathology, sections were embedded in paraffin wax and stained with haematoxylin and eosin. Detailed microscopic examinations in the subacute studies were generally done on 6 or 8 rats, evenly divided by sex, from the high dose group and the control group. If changes attributable to the test compound were found in the high dose group, additional animals on lower dosage levels were examined as indicated.
Details on results:
No effect on growth or haematology, and no macroscopic or microscopic change in the tissues in the 10000 ppm exposure group.
No effect on growth or haematology, and no macroscopic change in the tissues in the 2500 and 1000 ppm exposure groups. No microscopic examination performed.
Dose descriptor:
NOAEL
Effect level:
>= 314 mg/kg bw/day (actual dose received)
Based on:
other: alpha-Terpinyl Acetate converted to alpha-Terpineol
Sex:
male/female
Critical effects observed:
not specified
Conclusions:
For alpha-Terpinyl Acetate no effects were observed in a 20 week repeated dose toxicity study in rats at the tested concentrations (up to 10000 ppm).
Executive summary:

Alpha-Terpinylacetate has been tested in a similar to OECD TG 408 guideline. In a 20 weeks oral exposure study Osborne-Mendel rats (10/dose/sex) were administered alpha-Terpinyl Acetate via diet intake at concentrations of 0 (control), 10000, 2500 and 1000 ppm. Animals were then observed for mortality, weight, food intake and general condition. Haematological examinations were made at termination. At the termination of the experiments the rats were sacrificed and exsanguinated. The tissues of all the rats were examined macroscopically at the time of sacrifice. The viscera were removed and the liver, kidneys, spleen, heart, and testes were weighed. Detailed microscopic examinations in the subacute studies were generally done on 6 or 8 rats, evenly divided by sex, from the high dose group and the control group. No effect on growth or haematology, and no macroscopic or microscopic change in the tissues in the 10000 ppm exposure group were observed. No effect on growth or haematology, and no macroscopic change in the tissues in the 2500 and 1000 ppm exposure groups. No microscopic examination was performed on rats exposed to 2500 and 10000 ppm. For the conversion from ppm to mg/kg bw a factor of 25 was used, resulting in a NOAEL > 400 mg/kg bw. This value can be converted to alpha-Terpineol which results in 314 mg/kg bw (using the molecular weight of both substances: 154/196)

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Study duration:
subchronic
Species:
rat
Quality of whole database:
The information on repeated dose is adequate for assessing to cover this endpoint

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

There is a 20 -week dietary study available for alpha-Terpinyl Acetate similar to OECD TG 408 but predating guidelines and GLP. In this study no effects were seen up to 400 mg/kg bw (10,000 mg/kg diet, the highest dose tested). This data can be used for read across because alpha-Terpinyl Acetate will metabolise into alpha-Terpineol (see adequate documentation in the read across section below) and therefore the dosing to alpha-Terpineol can be calculated as 314 mg/kg bw.

Also a gavage dose combined repeated dose reproductive toxicity screening study (OECD TG 422, of which only the OECD TG 421 information has been used) is available for Terpineol multi ( (a multi-constituent substance with alpha-Terpineol as its main constituent and gamma-Terpineol as the minor constituent). This study showed adaptive liver effects and testis testicular toxicity at the highest dose tested at 750 mg/kg bw. The liver effects are considered to be of an adaptive nature and have not been used for setting the NOAEL. The testicular effects have been shown to be due to gavage dosing as has been shown in follow up studies, which were performed to characterise these effects. Also in a 20 week dietary dosing with alpha-Terpinyl Acetate, which metabolises fully into alpha-Terpineol, did not show testicular effects supporting the hypothesis that the effect is caused by dosing. The read across adequacy and the reasoning of the effects will be presented at the end of this discussion. First the experimental data of the analogues will be presented.

Alpha-Terpinyl Acetate: key study

In a 20 weeks oral exposure study Osborne-Mendel rats (10/dose/sex) were administered alpha-Terpinyl Acetate via diet at concentrations of 0 (control), 10000, 2500 and 1000 ppm (which relate to 40, 100 and 400 mg/kg bw) (Hagan 1967). Animals were then observed for mortality, weight, food intake and general condition. Haematological examinations were made at termination. At the termination of the experiments the rats were sacrificed and exsanguinated. The tissues of all the rats were examined macroscopically at the time of sacrifice. The viscera were removed and the liver, kidneys, spleen, heart, and testes were weighed. Detailed microscopic examinations were done on the animals from the high dose group and the control group. No effect on growth or haematology, and no macroscopic or microscopic change in the tissues in the 10000 ppm exposure group were observed. No effect on growth or haematology, and no macroscopic change in the tissues in the 2500 and 1000 ppm exposure groups. No microscopic examination was performed on rats exposed to 2500 and 1000 ppm. According to the Guidance on information and chemical safety assessment R8 table R 8 -17, rats eat 40 to 50 mg/kg bw/day. 10000 ppm is equivalent to 1% in the diet. Consequently, rats exposed to 10000 ppm in the diet consumed between 400 and 500 mg alpha-Terpinyl Acetate per kg body weight per day. Therefore, the NOAEL was calculated to be 400 mg/kg bw. This value can be converted into exposure to alpha-Terpineol and results in 314 mg/kg bw (154/195 x 400).

Terpineol multi: supporting study 1A

In the combined repeated dose toxicity study with reproduction/developmental toxicity screening test, conducted following GLP guidelines and OECD guideline 422, three groups, each comprising of ten male and ten female rats for the Main (reproductive) phase and five female rats for the Toxicity phase received Terpineol multi by gavage at doses of 60, 250 or 750 mg/kg bw/day at a dose volume of 5 mL/kg bw/day (Thacker 2010a). Main phase males and Toxicity phase females were dosed daily for a minimum of five consecutive weeks. A similarly constituted Control group received the vehicle, corn oil, at the same volume-dose. An additional ten males and ten females were dosed with the vehicle or at 750 mg/kg/day for five weeks and then given two weeks of recovery before termination. Main phase females were dosed daily for two weeks before pairing, throughout mating, gestation and until Day 6 of lactation.

During the study, data was recorded on clinical condition, performance under detailed physical and arena examination, sensory reactivity, grip strength, motor activity, bodyweight, food consumption, water consumption (visual), haematology, blood chemistry, oestrous cycles, mating performance and fertility and gestation length. Organ weight, macroscopic and microscopic pathology investigations were undertaken in the adults.

The clinical condition of offspring, litter size and survival, sex ratio and offspring body weight were assessed and macroscopic pathology investigations were undertaken.

In the 60 mg/kg/day dose group, one male was found dead on Day 31 of study and one female was killed because of parturition difficulties. In the absence of any other death in the intermediate and high dose groups these deaths are not attributed to the test material. No significant findings were recorded for clinical signs, detailed physical examination and arena observations. Underactive behaviour and unsteady reactions, in males and females were observed briefly during Week 1 in animals receiving 750 mg/kg/day and dose‑related increases in post‑dosing salivation and chin rubbing were seen. Behavioural testing during Week 5 of dosing, including sensory reactivity findings, grip strength values and motor activity scores showed no differences considered to be associated with exposure to the test material. There were no clear effects on body weight in males or unmated females receiving up to 750 mg/kg/day. Males receiving 750 mg/kg/day showed lower overall weight gain (Week 0-5) compared to Control. Bodyweight during the recovery phase was similar to Controls. Body weight and body weight gain were unaffected during gestation. During lactation females receiving 250 mg/kg/day showed lower weight gain than Controls. There were no adverse effects on food consumption in males, unmated females or females during gestation and lactation but visual assessment of water consumption indicated that males and females receiving 750 mg/kg/day were consuming more water than the Controls during the dosing period.

There were no effects of Terpineol multi on oestrous cycles, precoital interval or mating. Gestation length was within the normal range but there was a small increase in the numbers of animals at 250 mg/kg/day having longer (23 day) gestation periods. At dose levels up to and including 250 mg/kg/day there were no effects of the test material on the number of implantations, post implantation survival index, live birth index, viability index and lactation index. Male and female offspring body weights were not adversely affected by Terpineol multi. At 750 mg/kg/day, relative liver weights were significantly higher than in Controls in males and females and relative kidney weights were significantly higher than in Control males. Testis weight was markedly low in males receiving 750 mg/kg/day and there was also an indication of low epididymal weights at this dose. Liver and kidney weights returned to normal after two weeks when the animals did not receive Terpineol multi but testis and epididymal weights showed no evidence of recovery. Adaptive centrilobular hepatocyte hypertrophy in the liver of females dosed with Terpineol multi at 750 mg/kg/day was not present after 2 weeks recovery and histopathological findings in the kidneys of males receiving 250 and 750 mg/kg/day also resolved after the end of dosing. At 750 mg/kg/day, reduced numbers or complete absence of spermatozoa, accompanied by the presence of degenerate spermatogenic cells in duct(s) were observed in the epididymides and were still present following the 2‑week recovery period. Spermatocele granuloma(ta) that were seen in two males receiving 750 mg/kg/day and one receiving 60 mg/kg/day were not seen at the end of the recovery period. The significance of this change in the single male receiving 60 mg/kg/day is uncertain as spermatocele granuloma(ta) can occur spontaneously in rats of this age and there was no other degenerative change in the testes or epididymides of this animal. Moderate to severe seminiferous tubular atrophy/degeneration was seen in the testes of all animals dosed with Terpineol multi at 750 mg/kg/day, accompanied by minimal to moderate spermatid giant cells and minimal to slight seminiferous tubular vacuolation. Similar findings were still evident following the 2‑week recovery period but at a lower incidence and severity suggesting a degree of recovery. However, gavage is considered to be a worst case for this effect (not confirmed by diet administration).

Supporting study 1B: In the follow up study, the toxicity of Terpineol multi to the male reproductive system was examined when administered by dietary or oral gavage routes (Thacker 2010c). This study was done to characterise the effects seen in the supporting study 1 with Terpineol multi. Three groups of Crl:CD(SD) male rats (five/dose) were dosed daily with Terpineol-multi by dietary and/or oral gavage routes at the following doses: group 1: dietary 7500 ppm + supplementary gavage dose 300 mg/kg/day, group 2: dietary 10000 ppm + supplementary gavage dose 150 mg/kg/day, group 3: Terpineol multi at 750 mg/kg/day by gavage only. During the study, data was recorded on mortality, clinical condition, bodyweight and food consumption. Surviving animals were subjected to a detailed sperm analysis. Testes (L&R), epididymis (L&R), prostate and seminal vesicles were weighed at necropsy and tissues of right testes and epididymis were fixed for histopathological examination. During week 1 of the study, Group 1 and 2 animals consumed less diet than expected; From Day 11 Group 1 animals, receiving 7500 ppm, also received two daily doses of 150 mg/kg/b.i.d. four to five hours apart and average intake was boosted to 663 mg/kg/day whilst Group 2 animals, receiving 10000 ppm, also received a single daily dose of 150 mg/kg boosting intake to 678 mg/kg/day. Clinical signs were generally minimal. Dosing signs for Group 3 animals included salivation and chin rubbing. Food consumption for Group 1 and 2 animals receiving the test material in the diet was low throughout the study; this was attributed to the palatability of the test material. Body weight gains of these animals were also low. Food consumption and bodyweight changes of Group 3 animals were considered to be not adversely affected by the test material. Necropsy data indicated that decreases in reproductive organ weights and changes to macroscopic appearance were most marked in the animals receiving Terpineol multi at 750 mg/kg/day. Occasional animals (1/5 and 1/5 in each of the other groups 1 and 2 respectively) also showed changes to testicular and/or epididymal tissue appearances and/or weights. Sperm analysis showed that motile sperm with normal morphology were present in 4/5 males of Group 2 and 1/5 males of Group 1. The outliers in each group were at the extreme of achieved overall exposure for the group suggesting that absolute exposure was important, although the route of exposure and consequently potential to exceed threshold levels was of greater significance. Microscopic examination indicated there were relatively fewer changes in the testes and epididymides in the animals which were given Terpineol-Multi by the dietary route with oral gavage supplementation (Groups 1 and 2), whereas there were significant changes in those which received it solely by oral gavage (Group 3). The results of dietary administration suggest that exposure via the dietary route of administration reduces the testicular and sperm toxicity of the test material compared to dosing by oral gavage. The results of this study, in part, support the hypothesis that a high peak plasma level is necessary to induce the observed toxic effects.

This result can be explained by the combined high oral absorption and high dosing. Gavage-dosing result in high peak exposure and can thus results in overloading, the oxygen requiring, glucuronic pathway in the liver, especially when combined with high absorption potential of substances such as the Terpineols. The parent substance (and/or the toxic metabolite) can then enter the systemic circulation instead of being readily excreted via the urine. All organs have the potential to glucuronate substances including the testis. The testis is, however, vulnerable for depletion of oxygen e.g. during glucuronation, because the blood flow in the testicles is low compared to other organs (Aitken and Roman, 2008). This type of testicular effects, including effects on spermatids is related to oxygen depletion by a variety of substances (Aitkin and Roman, 2008). This hypothesis is confirmed with high dietary dosing similar to gavage with Terpineol multi in which no testicular effects were seen. It is also supported by the repeated dose toxicity data of alpha-Terpinyl Acetate in which the rats were dosed much longer (20-wks) and also no such testicular effects were seen up to a dose of 400 mg/kg bw. This latter dose can be roughly converted to 314 mg/kg bw alpha-Terpineol (154/196 Mol x 400 mg/kg bw).

Overall it can be concluded for alpha-Terpineol for fertility for males and females that up to the limit dose of alpha-Terpinyl Acetate of 400 mg/kg bw, no effects were seen. Alpha-Terpinyl Acetate will be fully metabolised in the liver and the gut to alpha-Terpineol. This 400 mg/kg bw of the acetate can be converted to 314 mg/kg bw for alpha-Terpineol. This value is supported by the two supporting studies of Terpineol multi, which contains mainly alpha-Terpineol, showing no effects via the dietary route up to the highest dose of 750 mg/kg bw. The overall NOAEL is therefore >= 314 mg/kg bw.

Assessing the repeated dose toxicity of alpha-Terpineol using the 20-week study from the alpha-Terpinyl Acetate and the supporting information from Terpineol multi for read across.

1. Introduction and hypothesis for the analogue approach for repeated dose toxicity

Alpha-Terpineol is a tertiary alcohol attached to an unsaturated cyclohexyl ring, with a methyl group attached to the unsaturated bond at the para-position. For this substance, as such no repeated dose toxicity information is available.

In accordance with Article 13 of REACH, lacking information should be generated whenever possible by means other than vertebrate animal tests, i.e. applying alternative methods such as in vitro tests, QSARs, grouping and read-across. In this case read across will be used for assessing the repeated dose toxicity because alpha-Terpinyl Acetate will quickly metabolise into alpha-Terpineol and therefore test information from the ester can be used to determine the repeated dose toxicity

Hypothesis: Alpha-Terpineol (target) has similar repeated dose toxicity compared to alpha-Terpinyl Acetate (source) resulting in a similar NOAEL because the acetate will be metabolized into the alcohol resulting in a similar repeated dose toxicity potential.

Available information: The repeated dose toxicity of alpha-Terpinyl Acetate has been tested in a 20-week dietary subchronic study, similar to OECD TG 408 but predating guidelines and GLP and has therefore a reliability of 2. In addition, also information on Terpineol multi is considered which has been tested in oral gavage combined repeated dose toxicity study with reproduction / developmental toxicity screening, according to OECD TG 422, with a reliability of 1. From this OECD TG 422 only the information available from an OECD 421 is used.

2. Target chemical and source chemical(s)

Chemical structures of the target and the source are shown in the data matrix (see also the attached document in IUCLID section 7.8).

3. Purity / Impurities

The constituents of the target and the source substance are presented in the toxico-kinetic section. Both substances have a purity > 80%. The constituents are expected to have a similar repeated dose toxicity based on similarities in backbone and the target substance (including its constituents, see toxico-kinetic section). Alpha-Terpineol is the metabolite of the source chemicals alpha-Terpinyl Acetate. The constituents of Terpineol multi are also included. This multi-constituent substance has alpha-Terpineol as its main constituent and gamma-Terpineol as the minor one. Gamma-Terpineol is expected to behave similarly to alpha-Terpineol due to its similarity in structure, and metabolic profile. It can be seen that alpha Terpineol and Terpineol multi have a similarity of > 80%, because both alpha and multi contain significantly gamma-Terpineol.

4. Analogue approach justification

According to Annex XI 1.5 read across can be used to replace testing when the similarity can be based on a common backbone and “common breakdown products via physical and biological processes, which result in structurally similar chemicals”. When using read across the result derived should be applicable for C&L and/or risk assessment and it should be presented with adequate and reliable documentation.

This read across will be based on a common structural backbone and a common breakdown product bases on the fact that alpha-Terpinyl Acetate will be metabolised into alpha-Terpineol.

Structural similarities and differences: The target and the source chemical (the ester) both have an unsaturated cyclohexyl ring, with a methyl group attached to the unsaturated bond. At the opposite side (C4 position) two methyl groups and a tertiary alcohol (target) or ester (source) bond is attached.

Toxico-kinetic: Absorption: The source chemicals and the target chemicals have similar absorption potential based on the similarity in chemical structure and physico-chemical properties. Though the source is an acetic-ester and the target is an alcohol resulting in slight differences, the physic chemical values are still expected to result in readily absorption via the oral, dermal and inhalation route. Both substances are liquids. Their vapour pressures are between 1 and 10 Pa. It can be seen that the water solubility of the alcohol is higher and the log Kow lower compared to the acetic ester. The metabolisation of alpha-Terpinyl Acetate by carboxylesterases in the gut and liver will result in alpha-Terpineol and acetic acid, while passing. No alpha-Terpinyl Acetate will remain as has been indicated in general terms by WHO (2000) for terpinyl-esters, Yamada et al. (2013) for allyl-esters and by Wu et al. (2010) for Terpinyl Propionate. After this ester cleavage the route of metabolisation will be the same as for alpha-Terpineol. The metabolisation is shown in the toxico-kinetic section. The repeated dose toxicity of alpha-Terpinyl Acetate will therefore be the same as for alpha-Terpineol.

Experimental data: The source chemical alpha-Terpinyl Acetate has been tested in 20-week dietary chronic study, similar to OECD TG 408 but predating this guideline and without GLP. The highest dose tested was 400 mg/kg bw (recalculated from a diet of 10000 ppm). Terpineol multi has been tested in a combined repeated dose reproductive toxicity screening test according to OECD TG 422. In this test at the highest dose of 750 mg/kg bw dosed via gavage liver and testicular effects were seen. Further 14-day dietary testing has been done to show that the testicular effects were probably due to ‘an overloading the metabolic pathway’ effect because testicular effects were not seen in the dietary study. Also the liver effects in this latter study were not seen in the dietary alpha-Terpinyl Acetate study. 

Similarities in results for toxicological endpoints between the target and the source chemical: In the data matrix is shown that the target and the source substances have limited acute toxicity and both are negative in the Ames test.

Uncertainty of the prediction: For the alpha-Terpinyl Acetate no effects were seen at 400 mg/kg bw in a sub-chronic study of 20-weeks, which would lead to the conclusion: “No hazard identified”, because at the highest dose tested no effects were seen. During dietary dosing the substance is dosed regularly and peak exposures do not occur. This enables the liver to metabolise the substance and conjugate it with glucuronic acid in a regulated and balanced way. This conjugate will be excreted via urine (WHO, 2000) and Madyastha and Srivatsan (1988). High dosing during gavage will present peak concentrations because alpha-Terpinyl Acetate and even more so alpha-Terpineol are expected to be readily absorbed in view of their chemical structure and physico-chemical properties. During peak exposures via gavage it is likely that the glucuronic pathway will be overwhelmed and that alpha-Terpineol will enter the system because for tertiary alcohols the glucuronation is the main metabolic pathway (WHO, 2000). It has been shown for Terpineol multi that the liver and testicular effects seen during gavage are not seen during dietary dosing, which contributes to the reasoning above. In summary, this means that the systemic effects seen on liver and testis seen for Terpineol multi are considered to be due to an overloading of the glucuronic pathway and the absence of effects during the 20-week dietary chronic study will be taken forward to the risk assessment. 

Another uncertainty may be the metabolisation of esters into alcohols. This metabolisation of esters into alcohols is one of the better known and described metabolic pathways (WHO, 2000 on specifically tertiary esters, Yamada et al., 2013 on allylic esters and Wu et al, 2010 presenting the read across from Terpinyl Propionate to alpha-Terpineol). The likelihood that alpha-Terpinyl Acetate is metabolised into its alcohol is without doubts. Therefore for alpha-Terpineol the conclusion for repeated dose toxicity is that there is “no hazard identified”.

5. Data matrix

The relevant information on physico-chemical properties and toxicological characteristics are presented in the Data matrix in Table 1.

6. Conclusions per endpoint for C&L, PBT/vPvB and dose descriptor

When using read across the results derived should be applicable for C&L and/or risk assessment, cover an exposure period duration comparable or longer than the corresponding method and be presented with adequate and reliable documentation.

For assessing the repeated dose toxicity of alpha-Terpineol the repeated dose toxicity results of alpha-Terpinyl Acetate are the most appropriate to use. The liver and thetesticular effects of Terpineol multi do not need to be considered for repeated dose C&L, specific target organ toxicity because it has been convincingly shown that the effects are considered secondary to the overloading of the glucuronic pathway likely resulting in oxidative stress.

Final conclusion on hazard, C&L, DNEL and risk characterization

For alpha-Terpinyl Acetate it can be concluded that there the NOAEL is >= 400 mg/kg bw, resulting in a NOAEL for alpha-Terpineol of >= 314 mg/kg bw when converted. Alpha-Terpinyl Acetate does not need to be classified for repeated dose exposure and therefore alpha-Terpineol does not need to be classified according to EU Directive 67/548/EEC (DSD) and CLP Regulation (EC) No. 1272/2008.

For alpha-Terpinyl Acetate the starting point for the risk characterization would be ‘no hazard identified, because of the NOAEL of > =400 mg/kg bw, being the highest dose tested and no adverse effects were seen at this dose. Therefore for alpha-Terpineol the conclusion is also ‘no hazard identified’ , with a NOAEL if >=314 mg/kg bw.

WHO, 2000, Evaluation of certain additives,http://whqlibdoc.who.int/trs/WHO_TRS_891.pdf, page 51 and onwards.

Wu, S., Blackburn, K., Amburgery, J., Jaworska, J., and Federle, T.,framework for using structural, reactivity, metabolic and physico-chemical similarity to evaluate the suitability of analogs for SAR-based toxicological assessments, Regul. Toxicol. Pharmacol., 56, 67-81.

Yamada, T., Tanaka, Y., Hasegawa, R., Sakuratani, Y., Yamada, J., Kamata, E., Ono, A., Hirose., A., Yamazoe, Y., Mekenyan, O., Hayashi, M., 2013, A category approach to predicting the repeated-dose hepatotoxicity of allyl esters, Reg. Toxicol. Pharmacol, 65, 189-195.

Data matrix for the read across to alpha-Terpineol from alpha-Terpinyl Acetate including information from Terpineol multi

Common names

Alpha-Terpineol

Alpha-Terpinyl Acetate

Terpineol multi

Chemical structures*,

Main constituent is alpha-Terpineol

CAS no

98-55-5

80-26-2

8000-41-7

 

Target

Source (key)

Source (Supporting)

Molecular weight

154

196

154

Appearance

Liquid

Liquid

Liquid

Physico-chemical data

 

 

 

Melting point,oC

-20

-20

-36

Vapour pressure, Pa

6.5

3.5

300#

Water solubility, mg/l

2870

23

2540

Log Kow

2.6

4.4

2.6

Human health

 

 

 

Acute oral tox in mg/kg bw

Read acrossfrom Terpineol multi

(Similar to OECD TG 401)

5075

(Similar to OECD TG 401)

4300 mg/kg bw

(Similar to OECD TG 401)

Genotoxicity – Ames test

Negative

(OECD TG 471)

Negative

(OECD TG 471)

Negative

(OECD TG 471)

Repeated dose toxicity mg/kg bw

Read acrossfrom Alpha-Terpinyl Acetate

NOAEL: > =400

(similar to OECD TG 408)

NOAEL >=750 mg/kg bw

(OECD TG 421/retreived from OECD TG 422))

Reproductive toxicity

Fertility in mg/kg bw

 

 

Developmental toxicity

Read across from alpha-Terpinyl Acetate

 

 

 

Read across from Terpineol multi and expert judgment

 

.>=400 mg/kg bw

 

 

 

 

Read across from Terpineol multi and expert judgment

 

NOAEL >= 750

Testicular effects seen at 750 but considered to be due to overload phenomena

 

NOAEL >=250 because at 750 mg/kg bw dams are not pregnant due to male infertility.

*Chemical structures are presented in the read across document attached; # Vapour pressure is thought to be incorrect due to information on alpha-Terpineol and QSAR calculation from EpiSuite using the MPVPBP, which present the value of 2.62 Pa.


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
The repeated dose toxicity results of alpha-Terpinyl Acetate is the most appropriate to use, because the dosing regime is more reflecting human health exposure (dietary versus gavage) and this test covers an exposure period duration longer than the OECD TG 421: 20 weeks exposure versus circa 6-weeks. This study is sufficiently reliable.

Justification for classification or non-classification

For assessing the repeated dose toxicity of alpha-Terpineol the repeated dose toxicity results of alpha-Terpinyl Acetate are used instead of those of Terpineol multi. The liver and the testicular effects of Terpineol multi do not need to be considered for repeated dose C&L, specific target organ toxicity because it has been convincingly shown that the effects are considered secondary to the overloading of the metabolic pathway. In addition, the effects seen are far above the guidance value in CLP (>=314 mg/kg bw (converted from the acetate) versus 100 mg/kg bw. Therefore, classification of alpha-Terpineol is not warranted according to Directive 67/548/EEC (DSD) and EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008.