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Effects on fertility

Description of key information

Fertility NOAEC is >=2230 mg/m3 based on read-across from Terpineol multi which was tested in a 90 -day repeated dose inhalation toxicity study (OECD TG 413, Rel.1). This value can be converted to 1250 mg/kg bw when using 100% inhalation and 50% oral absorption.

Effect on fertility: via inhalation route
Endpoint conclusion:
no adverse effect observed
Study duration:
subchronic
Species:
rat
Quality of whole database:
The study used for read across is considered reliable (Klimisch 1 study).
Additional information

The Terpene hydrocarbon alcohols' fertility and developmental toxicity is derived from Terpineol multi. The executive summaries of the source information are presented below followed by the read-across rationale for both fertility and developmental toxicity.


 


Terpineol multi and fertility toxicity


Terpineol multi data is available from a 90 -day inhalation study according to OECD TG 413 and in compliance with GLP criteria including all reproductive organs. In this study, Terpineol multi was administered by inhalation-aerosol to groups of Crl:CD(SD) rats (10 rats/sex/ group) by snout-only inhalation exposure at target exposure levels of 0.2, 0.6 and 2 mg/L for 6 hours per day, 5 days per week for 13 weeks. Control animals received air only. Recovery animals were similarly treated for 13 weeks followed by a 4 week off dose period. Control and high dose recovery groups were included (10/sex/group). During the study, clinical condition, body weight, food consumption, ophthalmoscopy, haematology (peripheral blood), blood chemistry, organ weight, macropathology and histopathology investigations were undertaken.


The achieved levels were 101, 95 and 112% of the target concentrations of 0.2, 0.6 and 2 mg/L, respectively (achieved concentrations 0.202, 0.572 and 2.23 mg/L). MMAD: <0.52, 0.7 and 1.6 µm for achieved concentrations of 0.202, 0.572 and 2.23 mg/L, respectively. GSD: 2.99 and 1.75 for achieved concentrations of 0.572 and 2.23 mg/L, respectively. MMAD showed a general increase with increasing aerosol concentration. The MMAD for the low dose group could not be calculated, as virtually all the measurable test material was captured on the final filter stage, and the value presented is based on the cut point of the penultimate impactor stage. The mid dose groups particle size distribution values showed a bi-modal distribution with an average of 49% of the captured droplet having a MMAD below 0.52 µm. The MMAD value for the high dose group was within the ideal range (1 to 3 µm), indicating that the aerosol was respirable to the rats. The MMADs for the low and mid dose groups were below the ideal range of 1 to 3 µm. However, since the delivered aerosol was a liquid, it is likely that those inhaled droplets with an aerodynamic diameter below 1 µm would still have impacted on airway surfaces and not been exhaled.


There were no treatment related deaths or effects on food consumption, blood chemistry, ophthalmoscopy, organ weights or macropathology findings. Group mean body weight gains were lower than control for males exposed to 0.202 mg/L and for both sexes exposed to 0.572 and 2.23 mg/L. In both sexes, no relationship between exposure concentration and body weight gain was observed but the decrease in mean body weight gain was statistically significant for males exposed to 2.23 mg/L. Body weights showed full recovery for animals previously exposed to 2.23 mg/L. Clinical pathology measurements following 13 weeks of exposure revealed statistically significantly lower group mean reticulocyte percentages and absolute counts for males exposed to 0.572 or 2.23 mg/L, compared to control (as low as 0.82X control). A similar effect was observed for females exposed to 2.23 mg/L (as low as 0.87X control) but this did not attain statistical significance. During Recovery Week 4, values for both sexes previously exposed to 2.23 mg/L were similar to controls. Histopathological changes related to treatment were observed in the nasal turbinates for the majority of animals given the test substance and nasal pharynx for a limited number of animals given 0.572 or 2.23 mg/L. In the nasal turbinates, minimal to slight hyperplasia of the mucous cells in the respiratory epithelium was present at all exposure levels and did not exhibit a clear dose response in terms of incidence or severity in males, although there were slightly higher incidences in females at 0.572 mg/L or 2.23 mg/L compared with females exposed to 0.202 mg/L. After 4 weeks of recovery, partial recovery was evident, in terms of the severity observed. After 13 weeks of exposures, these changes were generally not associated with an inflammatory cell infiltrate or cellular degeneration; such changes were observed in a minority of animals and were of minimal severity. After 4 weeks of recovery, degeneration and inflammation of the respiratory epithelium showed completed recovery. However, degeneration of the olfactory epithelium showed only partial recovery in terms of the incidence observed. In the nasal pharynx, minimal hyperplasia of the mucous cells was also observed but at a lower incident and severity and was only evident for animals exposed to 0.572 or 2.23 mg/L. Complete recovery from this effect was observed following the 4 week recovery period. The aforementioned changes were typically associated with chronic exposure to an irritant material and are not considered adverse at the incidence and severity seen.


Fertility: No effects were observed on the organ weight of the reproductive organs. In addition, gross macroscopy and histopathology of the reproductive organs did not show any changes due to treatment. The No Observed Adverse Effect Concentration (NOAEC) for general toxicity and fertility is considered to be ≥2.23 mg/L (2230 mg/m3).


 


Terpineol multi and its developmental toxicity


For Terpineol Multi, data is available from a study according to OECD TG 414 and in compliance with GLP criteria. In this study, the test substance diluted in corn oil was administered by gavage to groups of mated female Sprague-Dawley rats (20 mated females/dose) at the dose levels of 0, 60, 200, 600 mg /kg bw/d from Days 6 to 19 after mating. Animals were inspected visually at least twice daily for evidence of ill-health or reaction to treatment. Detailed observations were recorded daily at the following times in relation to dose administration. A detailed physical examination was performed on each animal on Days 0, 5, 12, 18 and 20 after mating to monitor general health. The weight of each adult was recorded on Days 0, 3 and then daily from Days 6 to 20 after mating. The weight of food supplied to each adult, that remaining and an estimate of any spilled was recorded for the periods Days 0-2, 3-5, 6-9, 10-13, 14-17 and 18-19 inclusive after mating. On Day 20 post-coitum, the dams were sacrificed and subjected to macroscopic examination. The gravid uterine weight, number of implantations, live and dead foetuses, early and late resorptions and corpora lutea were recorded. Gross evaluation of the placenta was also performed. Foetuses were sexed, weighed and examined for external, soft tissue and skeletal malformations. With the exception of one female in the 200 mg/kg bw/d group (No. 52) which had a total litter resorption, all females were found to be pregnant with live young at scheduled termination on Day 20 of gestation. No mortality was observed. At scheduled termination on Day 20 of gestation, the adjusted mean liver weight of females receiving 600 mg/kg bw/d was significantly higher than Control (1.10X Control). There were no treatment-related macroscopic abnormalities detected. No relevant clinical signs or signs of reaction to treatment were noted in treated females. Females receiving 60 or 200 mg/kg bw/d showed no treatment-related changes in clinical condition, body weight performance, food intake, liver weight or macropathology. There was no effect of maternal treatment with the test substance at any dose level investigated on litter data. Sex ratio, as assessed by the percentage of males per litter, was generally comparable in all groups and in line with expectations. Embryo-fetal growth was slightly reduced by maternal treatment at 600 mg/kg bw/d. It was considered that there was no adverse effect of maternal treatment on embryo-fetal development; the incidence of major and minor abnormalities and skeletal variants showed no relationship to maternal treatment with the test substance. In the 600 mg/kg bw/d group there was a slightly higher incidence of incompletely ossified or unossified 5th and/or 6th sternebrae compared to concurrent control and the Historical Control Data range. It was considered that this minor finding did not constitute an adverse effect on development. On the basis of the results obtained in this study, the dosage of 600 mg/kg bw/d was considered to be the NOAEL (No Observed Adverse Effect Level) for maternal and developmental toxicity.


 


The reproductive and developmental toxicity of Terpene hydrocarbon alcohols using read across from Terpineol multi (CAS# 8000-41-7).


 


Introduction and hypothesis for the analogue approach


Terpene hydrocarbon alcohols have the following constituent types of substances: Solely hydrocarbons-terpene type, Alcohol-type, Ketone-type and Ether-type all having a saturated or unsaturated cyclic hydrocarbon backbone. For this substance no reproductive toxicity 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, QSARs, grouping and read-across. For assessing the fertility and developmental toxicity of Terpene hydrocarbon alcohols the analogue approach is selected because for constituents of this substance, Terpineol multi, information is available which can be used for read-across.


Hypothesis: Terpene hydrocarbon alcohols have the same reproductive toxicity as Terpineol multi.


Available information for fertility: For Terpineol multi an OECD TG 422 is available which showed some testicular fertility effects at the 750 mg/kg bw dose, probably due to gavage dosing, which caused overloading of the metabolic pathway. This was supported with dietary studies in which no such effects were seen. In addition a 90-day inhalation study (OECD TG 413, Rel. 1) is available at which no fertility effects were seen in the reproductive organs at >=2230 mg/m3 (1250 mg/kg bw using 50 and 100% oral and inhalation absorption, respectively).


Developmental toxicity: Terpineol Multi, data is teste for developmental toxicity in an OECD TG 414 (Rel. 1) at the dose levels of 0, 60, 200, 600 mg /kg bw from Days 6 to 19 after mating. There were no adverse effect of maternal treatment on embryo-fetal development; the incidence of major and minor abnormalities and skeletal variants showed no relationship to maternal treatment with the test substance. In the 600 mg/kg bw/d group there was a slightly higher incidence of incompletely ossified or non-ossified 5th and/or 6th sternebrae compared to concurrent control and the Historical Control Data range. It was considered that this minor finding did not constitute an adverse effect on development. On the basis of the results obtained in this study, the dosage of 600 mg/kg bw was considered to be the NOAEL for maternal and developmental toxicity.


Target chemical and source chemical(s)


Constituent types of the target substance and chemical structures of the source substances are shown in the data matrix, including physico-chemical properties and toxicological information, thought relevant for reproductive toxicity.


Purity / Impurities


Constituent types of the target substance are covered by the presented constituent types, there are no other constituent that impacts the repeated dose toxicity.


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 a common functional group. 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, which is documented below.


Analogue selection: For Terpineol hydrocarbon alcohols the reproductive toxicity can be covered with Terpineol multi because this latter substance (and constituents) is present for at least 40% in the Terpene hydrocarbon alcohols. The Camphor information considered in the EFSA opinion on Camphor (2008) and on the ECHA dissemination site is not showing other reproductive toxic effects.


Structural similarities and differences: Terpene hydrocarbon alcohols almost all have a similar hydrocarbon backbone with an alcohol as a functional group. The secondary alcohols in this group can be oxidised to a ketone but it is more likely that the ketone is reduced to a secondary alcohol to give handles for further metabolic processing.


Toxico-kinetic: All Terpene hydrocarbon alcohols are absorbed somewhat similar via all routes based on the similarities in molecular weight and physico-chemical properties including the Terpineol multi constituents.


Metabolism: Terpene hydrocarbon alcohols metabolites result in similar metabolites as those from Terpineol Multi. The first metabolic step will result in primary, secondary or tertiary alcohols if these are not already constituents as such. Thereafter these metabolites will be further oxidised into acids and /or are conjugated. In view of the fast absorption of these Terpene hydrocarbon alcohols overloading of the metabolic pathway may occur during bolus dosing as has been seen in the Terpineol multi OECD TG 422 study, which was not seen after dietary dosing in follow up studies.


Toxico-dynamics considering reproductive toxicity: The Terpene hydrocarbon alcohols that can metabolise in primary alcohols, like Terpineol multi at the terpene functional group, can be susceptible to fertility (testicular effects) after bolus dosing, which are not seen after dietary or inhalation dosing and therefore are not considered further.


Uncertainty of the prediction: There are no uncertainties not already addressed above.


Data matrix


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


Conclusions on reproduction and developmental toxicity for hazard and risk assessment


For Terpene hydrocarbon alcohols no reproductive toxicity information is available but for a number of key constituents such information is present. When using read across the result derived should be applicable for C&L and/or risk assessment and be presented with adequate and reliable documentation. This documentation is presented in the current text.


Fertility: For Terpineol multi no adverse fertility effects are seen in a 90-day inhalation study according to OECD TG 413, Rel. 1, up to 2230 mg/m3 (1250 mg/kg bw using 50 and 100% oral and inhalation absorption, respectively).


Developmental toxicity: No adverse effects were seen in an oral developmental toxicity study according to OECD TG 414 (Rel. 1) up to 600 mg/kg bw.


Final conclusionFor Terpene hydrocarbon alcohols there are no adverse effect for Fertility up to the highest concentration of 2230 mg/m3 (or 1250 mg/kg bw using 50 and 100% oral and inhalation absorption, respectively). The NOAEL is therefore >=2230 mg/m3 (or >=1250 mg/kg bw). For developmental toxicity a NOAEL of 600 mg/kg bw is derived.


Data matrix supporting the Terpene hydrocarbon alcohol reproductive toxicity assessment by using read across from Terpineol multi.


















































































































































Terpene hydrocarbon alcohols



Terpineol hydrocarbon alcohols



Terpineol multi



 



Target



Source



Structure



Not applicable



 


(α-Terpineol)


 


(γ-Terpineol)



CAS



Not applicable



8000-41-7 (generic CAS no)



EC No.



945-149-0



232-268-1



Reach registration



2018



Registered



Molecular weight



136-154



154



Phys-chem properties



 



 



Appearance



Liquid



Liquid



Vp (Pa)



51.9


(10-52, exp)



6.48


(exp. α-Terpineol, IFF)



Log Kow



3.3-5.5; IFF



2.6


(α-Terpineol, IFF)



Identity, Constituent type (%)



100%



Multi constituent



Solely hydrocarbons



 



 



Limonene type



0-15



 



Alcohol type



 



>80



Tertiary alcohols



40-90



 



Secondary alcohols



7-40



 



Ketone type



-



 



Camphor-Type



0-17%



 



Ether type



 



 



Cineol type



<10%-



 



Aromatic ether type



<10%



 



Human health



 



 



Repeated dose, oral, sub-acute: NOAEL mg/kg bw



103*


(Read across from Camphor)



 



Repeated dose, inhalation, 90-day (sub-chronic) NOAEC in mg/m3)



>=2230


(Read across for other than Camphor constituents)



≥2230


(OECD TG 413)


(corresponding to 1250 mg/kg bw, using 50 and 100% oral and inhalation, respectively)


(OECD TG 413)



Reproductive toxicity



 



 



Fertility NOAEL


90-day sub-chronic inhalation



>=2230 mg/m3 (corresponding to 1250 mg/kg bw, using 100% absorption via inhalation and oral route)



≥2230


(OECD TG 413)


(corresponding to 1250 mg/kg bw, using 50 and 100% oral and inhalation, respectively)


(OECD TG 413)



Developmental toxicity mg/kg bw



600


(Read across)



600


(OECD TG 414)



 


References:


Camphor in flavourings and other food ingredients with flavouring properties, 2008,Scientific opinion of the Panel on Food Additives, Flavourings, Processing Aids and Materials in contact with Food (AFC) on a request from the Commission on Camphor in flavourings and other food ingredients with flavouring properties. The EFSAJournal 729, 1-15,http://www.efsa.europa.eu/sites/default/files/scientific_output/files/main_documents/729.pdf.

Effects on developmental toxicity

Description of key information

Terpene hydrocarbon alcohols developmental toxicity is 600 mg/kg bw based on read-across from Terpineol multi which was tested in an oral study according to OECD TG 414.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
600 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
The study used for read across is considered reliable (Klimisch 1 study).
Additional information

The reproduction and development toxicity is assessed based on read-across from Terpineol multi to Terpene hydrocarbon alcohols. For the executive summaries of the source information, and the read-across rationale, see 'Effects on fertility - Additional information'.

Justification for classification or non-classification

Based on absence of adverse effects for fertility and developmental toxicity the substance does not need to be classified and labelled according to EU CLP (EC No. 1272/2008 and its amendments)

Additional information

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