Registration Dossier

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

1.2 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

Overall assessment factor (AF):

75

Dose descriptor starting point:

NOAEL

Value:

100 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

88.2 mg/m³

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.3 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

Overall assessment factor (AF):

300

Dose descriptor starting point:

NOAEL

Value:

100 mg/kg bw/day

Modified dose descriptor starting point:

NOAEL

Value:

100 mg/kg bw/day

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

low hazard (no threshold derived)

Hazard assessment conclusion:

low hazard (no threshold derived)

Hazard assessment conclusion:

low hazard (no threshold derived)

Selection of the relevant dose descriptor (starting point):

Two repeated dose toxicity studies in Wistar rats are available, i.e. an oral subacute (28d) toxicity study according to OECD TG 407 and GLP (applied via gavage; BASF 2012, 30C0624/07S043) and an oral subchronic (90d) toxicity study in rats according to OECD TG 408 and GLP (administered via the diet; BASF 2019, 50C0087/18S026).

Application of tetrahydro-4-methyl-2-(2-methylprop-1-enyl)pyran for 28 days via gavage resulted in moderate salivation, possibly induced by a bad taste of the test substance or local affection of the upper digestive tract. A slight anemia was present after 4 weeks of compound administration. In additions, target organs were the epididymides as well as the liver, kidneys and spleen.

- Liver: Liver cell membranes and the liver cell metabolism was affected, as indicated by increased alanine aminotransferase (ALT) activities and higher triglyceride and cholesterol values. Because the mentioned effects were due to functional liver cell alterations, a histopathological correlate could not be detected. Liver weight increases occurred but were without a histopathological correlate (treatment-related but not adverse in nature).

- Spleen: In the spleen slight extramedullary hematopoiesis was observed, correlating with a significant weight increase (considered secondary to the anemia and regarded as an adaptive response).

- Kidney: Kidney weight increases were found without histopathological findings (regarded as treatment-related but not adverse).

- Epididymides: Increases in epididymides weights and adverse histopathological effects were observed (immature ducts in the distal corpus and/or cauda epididymis accompanied by increasing interstitial edema, additional intraductal granulocytic infiltration, apparent sperm stasis).

The LOAEL is 1000 mg/kg bw/d in female and 300 mg/kg bw/d in male Wistar rats, when taking the adverse epididymal and spermatotoxic effects into account. Accordingly, the NOAEL is 300 mg/kg bw/d (females) and 100 mg/kg bw/d (males).

In contrast, a longer application duration of tetrahydro-4-methyl-2-(2-methylprop-1-enyl)pyran for 90 days via feed did not cause any test substance-related, adverse signs of toxicity in male and female animals up to the highest dose tested. The NOAEL is 75000 ppm (12000 ppm a.i.) in male (1547 mg/kg bw/d) and female (1620 mg/kg bw/d) Wistar rats, i.e. the highest dose tested.

In a developmental toxicity study according to OECD 414 and GLP, tetrahydro-4-methyl-2-(2-methylprop-1-enyl)pyran was administered via gavage to time-mated female Wistar rats on gestation days (GD) 6 through 19 (BASF 2019; 30R0624/07R071).

Transient salivation and ploughing nose-first into bedding was observed and considered likely to result from bad taste of the test substance/vehicle preparation or o local irritation of the upper digestive tract. Clinical signs of toxicity consisted of unsteady gait and piloerection. Food consumption, gross and corrected (net) body weight gain (body weight loss GD6-8) was observed in the dams.

Further, clinical chemistry investigations revealed a regenerative hypochromic/ macrocytic anemia and lower inorganic phosphate and calcium levels. A minimal hypertrophy/hyperplasia of the thyroid gland in 2/24 dams and changes in thyroid hormone levels (increased TSH and decreased T3 and T4) were found (but not confirmed in the subchronic 90 day repeated dose toxicity study).

Weights of kidneys, liver (without altered clinical chemical liver markers but consistent with an increased hepatocytic accumulation of presumed glycogen) and spleen (correlating with anemia) were significantly increased.

In the offspring, mean fetal weights were reduced, correlating with mild delays in ossification of a few skeletal elements (skull, sternebrae, sacral arch), with a rather low toxicological relevance.

The LOAEL for maternal and prenatal developmental toxicity is 250 mg/kg bw/d and the NOAEL is 50 mg/kg bw/d under the conditions of this study.

The subchronic repeated dose toxicity key study represents a suitable study as the basis for the derivation of the systemic DNELs. However, the outcome of this study is in contrast with the subacute repeated dose toxicity study results, since the adverse effects were not confirmed after a longer application duration. A comparative toxicokinetic study is currently planned to elucidate potential differences in the uptake of tetrahydro-4-methyl-2-(2-methylprop-1-enyl)pyran after application via gavage or via feed. Until these data are available to better interpret the observed differences, the NOAEL for males of the subacute repeated dose toxicity study will be used as a worst-case basis for the derivation of the systemic DNELs.

Beginning maternal toxicity during pregnancy was observed in the developmental toxicity study at doses of 250 mg/kg bw/d. By choosing a NOAEL of 100 mg/kg bw/d as a point of departure, the derived DNEL will also cover potential maternal toxicity.

Route to route extrapolation:

No experimental data on absorption of tetrahydro-4-methyl-2-(2-methylprop-1-enyl)pyran are available. Based on its physicochemical properties, tetrahydro-4-methyl-2-(2-methylprop-1-enyl)pyran is considered to become readily bioavailable via the dermal and oral route. On the basis of the low vapour pressure, the exposure with tetrahydro-4-methyl-2-(2-methylprop-1-enyl)pyran via inalation as a vapour is low. According to Chapter R.8 of REACH Guidance on information requirements and chemical safety assessment, it is proposed in the absence of route-specific information to include a default factor of 2 in the case of oral-to-inhalation extrapolation. For dermal absorption, the default ratio of 1 for oral to dermal extrapolation is used for the DNEL derivation.

Workers – Hazard via inhalation route

Long term, systemic inhalation DNEL

For derivation of the long-term systemic inhalative DNEL for tetrahydro-4-methyl-2-(2-methylprop-1-enyl)pyran, the oral NOAEL for males of the subacute repeated dose toxicity study (100 mg/kg bw/d) was taken as a worst case basis and converted into a corrected inhalative NOAEC of 88.2 mg/m3 according to the procedure, recommended in the current guidance document (R8, ECHA 2008). Applying all assessment factors, the inhalative long-term systemic DNEL was set at 1.2 mg/m3 for the worker.

Long-term –inhalation, systemic effects

Description	Value	Remark
Step 1) Relevant dose-descriptor	NOAEL: 100 mg/kg bw/day
Step 2) Modification of starting point	2 0.38 m³/kg bw 6.7 m³/10 m³	Ratio of inhalation to oral absorption (default value, as proposed in the REACH guidance (R.8.4.2) Standard respiratory volume of a rat, corrected for 8 h exposure, as proposed in the REACH Guidance (R.8.4.2) Correction for activity driven differences of respiratory volumes in workers compared to workers in rest (6.7 m³/10 m³).
Modified dose-descriptor	NOAEC corrected inhalative = 100(1/0.38)(50/100)*(6.7/10) = 88.2 mg/m³
Step 3) Assessment factors
Allometric scaling	1	No allometric scaling has to be applied in case of oral to inhalation route to route extrapolation according toR8 ECHA 2008.
Remaining differences	2.5	Default assessment factor according to R8 ECHA 2008 was used as worst case to cover uncertainties due to putative species specific toxicodynamic differences and results from a study type used to address reprotoxic effects; i.e. a 28 day study.
Intraspecies	5	Default assessment factor according to R8 ECHA 2008 was used as worst case.
Exposure duration	6	Subacute to chronic extrapolation
Dose response	1	according to R8 ECHA 2008
Quality of database	1	based on validity of studies performed
DNEL	Value
	88.2 / (1 x 2.5 x 5 x 6 x 1 x 1) = 1.2 mg/m³

When considering the NOAEL for prenatal developmental toxicity (50 mg/kg bw/d) as a point of departure for the derivation of the respective DNEL, a higher value is obtained; i.e. 44.1 mg/m3 (corrected inhalative NOAEC) / 1 (allometric scaling) x 2.5 (remaining differences) x 5 (intraspecies differences) x 1 (exposure duration fully covers development of implanted embryo/fetus) x 1 (dose response) x 1 (data quality) = 3.5 mg/m3. However, the lowest DNEL will be used for further risk characterization.

Acute/short term, systemic and acute/short term and long term, local inhalation DNEL

The substance tetrahydro-4-methyl-2-(2-methylprop-1-enyl)pyran is not classified and labelled for acute systemic toxicity, according to Regulation (EC) No 1272/2008 (CLP), based on the test data for acute oral and dermal toxicity. Thus, no DNEL for systemic effects after acute inhalation exposure is required. Furthermore, the DNEL derived for systemic effects after long term inhalation exposure is considered sufficiently conservative to cover potential acute systemic and general local inhalation effects.

Workers - Hazard via dermal route

Long term, systemic dermal DNEL

For derivation of the long-term systemic dermal DNEL of tetrahydro-4-methyl-2-(2-methylprop-1-enyl)pyran, the oral NOAEL for males of the subacute repeated dose toxicity study (100 mg/kg bw/d) was taken as a worst case basis and was converted into a corrected dermal NOAEL of 100 mg/kg bw/d according to the procedure, recommended in the current guidance document (R8, ECHA 2008). Applying all assessment factors, the dermal long-term systemic DNEL derived was 0.3 mg/kg bw/d for the worker.

Long-term – dermal, systemic effects

Description	Value	Remark
Step 1) Relevant dose-descriptor	NOAEL: 100 mg/kg bw/day
Step 2) Modification of starting point	1	On the assumption that, in general, dermal absorption will not be higher than oral absorption, no default factor should be introduced when performing oral to dermal extrapolation.
Modified dose-descriptor	NOAEL corrected dermal = 100*(100/100) = 100 mg/kg bw/d
Step 3) Assessment factors
Allometric scaling	4	Assessment factor for allometric scaling according to R8 ECHA 2008
Remaining differences	2.5	Default assessment factor according to R8 ECHA 2008 was used as worst case to cover uncertainties due to putative species specific toxicodynamic differences and results from a study type used to address reprotoxic effects; i.e. a 28 day study.
Intraspecies	5	Default assessment factor according to R8 ECHA 2008 was used as worst case.
Exposure duration	6	Subacute to chronic extrapolation
Dose response	1	according to R8 ECHA 2008
Quality of database	1	based on validity of studies performed
DNEL	Value
	100 / (4 x 2.5 x 5 x 6 x 1 x 1) = 0.3 mg/kg bw/day

When considering the NOAEL for prenatal developmental toxicity (50 mg/kg bw/d) as a point of departure for the derivation of the respective DNEL, a higher value is obtained; i.e. 50 mg/kg bw/d (corrected dermal NOAEL) / 4 (allometric scaling) x 2.5 (remaining differences) x 5 (intraspecies differences) x 1 (exposure duration fully covers development of implanted embryo/fetus) x 1 (dose response) x 1 (data quality) = 1.0 mg/kg bw/d. However, the lowest DNEL will be used for further risk characterization.

Acute/short-term systemic dermal DNEL

The substance tetrahydro-4-methyl-2-(2-methylprop-1-enyl)pyran is not classified and labelled for acute systemic toxicity, according to Regulation (EC) No 1272/2008 (CLP), based on the test data for acute oral and dermal toxicity. Thus, no DNEL for systemic effects after acute dermal exposure is required. Furthermore, the DNEL derived for systemic effects after long term dermal exposure is considered sufficiently conservative to cover potential acute systemic dermal effects.

Acute/short-term and Long term local dermal DNEL

Tetrahydro-4-methyl-2-(2-methylprop-1-enyl)pyran is to be classified as skin irritant (category 2) according to 1272/2008/EEC. Since no quantitative data addressing the hazard of skin irritation are available, a respective no effect concentration cannot be derived and included in the derivation of the short term/long term local dermal DNEL. However, a qualitative risk characterization including the implementation of suitable risk management measures is performed in the CSR.

Worker - Hazard for the eyes

Tetrahydro-4-methyl-2-(2-methylprop-1-enyl)pyran is to be classified as eye irritant (category 2) according to 1272/2008/EEC. Since no quantitative data addressing the hazard of eye irritation are available, a respective no effect concentration cannot be derived and included in the derivation of a no effect level for eye irritation. However, a qualitative risk characterization including the implementation of suitable risk management measures is performed in the CSR.

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.3 mg/m³

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

Overall assessment factor (AF):

150

Dose descriptor starting point:

NOAEL

Value:

100 mg/kg bw/day

Modified dose descriptor starting point:

NOAEC

Value:

43.5 mg/m³

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

no hazard identified

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

0.2 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

Route of original study:

Oral

Overall assessment factor (AF):

600