2-methoxy-4-propylphenol

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

2-generation study on the source substance, Trans-Isoeugenol (similar to OECD 416, GLP, Rel. 2, K):

- NOAEL fertility ≥ 709 mg/kg bw/day.

- NOAEL development ≥ 233 mg/kg bw/day / LOAEL = 709 mg/kg bw/day, as a worst-case based on decreased male and female F2 pup weights.

- LOAEL parental toxicity ≤ 71 mg/kg bw/day, based on decreased body weight gains at all dose-levels, although probably linked to the bolus effect.

(NOAEL/LOAEL adjusted for MW)

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

709 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

No study was available on Dihydroeugenol. The study on trans-Isoeugenol was selected as the key study. The key study is GLP-compliant and of high quality (Klimisch score = 2)

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

No study was identified on the target substance. However, a study was available on the source substance, trans-Isoeugenol (see Iuclid section 13 for read-across justification).

In this two-generation (NTP, 2003, Rel.2) study conducted similarly to OECD 416 and in compliance with GLP, Trans-Isoeugenol was administered to Crl:CD(SD) rat/s daily via oral gavage at dose levels of 0, 70, 230 or 700 mg/kg bw/day from Study Day (SD) 1 until the day prior to necropsy. The F0 cohabitation began on SD 8. Mating pairs were allowed to produce three litters (F1a, F1b and F1c). Dosing of the F1 generation was initiated on post-natal day (PND) 21 of the F1c animals. On PND 81 ± 10, F1c animals were assigned to mating pairs and allowed to produce three litters (F2a, F2b and F2c).

Throughout the F0 and F1 generation, a dose-related decrease in the mean body weight gain was seen in all adult males compared to control (F0: -8%, -14%* and -34%*; F1: -12%, -25.5%* and -40%* during F1, at 70, 230 and 700 mg/kg bw/day, respectively). Although not dose related, all F0 females had a reduced mean body weight gain compared to control (-23%*, -24%*, -23%*, for 70, 230 and 700 mg/kg bw/day, respectively). Similar reduction was only observed in high-dose adult F1 females (-34%*).

Food consumption values were decreased in the high dose F0 males (-27%*, -7%, -12%*, during Week 1, 12 and 14 respectively). During Week 1, mid- and high-dose F0 females had decreased food consumption (-8%* and -20%*). Combined male and female food consumption was not reduced during Week 6. Food consumption values were decreased in all F1 males during Weeks 12 (-12%*, -13.5* and -15%*, for 70, 230 and 700 mg/kg bw/day, respectively) and Week 14 (-6%, -15% and -23%*, for 70, 230 and 700 mg/kg bw/day, respectively). Combined male and female food consumption was also reduced during Week 3 (-6%, -8%* and -8%*, for 70, 230 and 700 mg/kg bw/day, respectively) and Week 6 (-2%, -5% and --9%*, for 70, 230 and 700 mg/kg bw/day, respectively).

The aggregate number of live male pups born during all litters to the F0 parents was decreased by 21%* in the high-dose group (F1a: -22%, F1b: -13%, F1c: -22%). In an outbreeding study, a 42%* increase in the number of live females per litter and a 34%* increase in the number of implantation sites was observed when naïve females were mated with high-dose males. This finding was not reproduced during all litters to the F1 parents and in the outbreeding study, i.e.naïve males mated with high-dose females. Moreover, it occurred only at concentrations greater than that which caused parental toxicity. Historical control data are not available, however, in the absence of an obvious dose-response relationship and reproducibility, this finding is considered to be of very low toxicological concern.

A decreased body weight was observed in all high-dose litters to the F1 parents compared to control (Combined: -5%, Males: -5.5%, Females: -4%). This effect occurred only at concentrations greater than that which caused parental toxicity.

There were no effects on any other reproductive parameters throughout both generations. Sperm parameters and vaginal cytology were unchanged in the F0 and F1 generations.

At the F0 and F1 necropsies, some decrease in absolute organ weights and increases in organ-to-body weight ratios were seen in the high-dose males and females. These differences may be attributed to decreased terminal body weights. Treatment-related findings included hyperkeratosis and hyperplasia in the non-glandular stomach at all dose levels and in both sexes of the F0 and F1 animals.

It should be pointed out that the appearance of hyperkeratosis and hyperplasia in non-glandular stomachs and decreased body weight may be due to the route of administration whereby the test material is administered by intubation thereby delivering a bolus of a substance that is shown to have clearly irritant properties at high concentrations. (HERA, 2005).

A NOAEL was not reported by the study authors for this study. However, based on expert judgment the following NOAELs/LOAELs are proposed:

NOAEL fertility ≥ 700 mg/kg bw/day.

NOAEL development ≥ 230 mg/kg bw/day / LOAEL = 700 mg/kg bw/day, as a worst-case based on decreased male and female F2 pup weights.

LOAEL parental toxicity ≤ 70 mg/kg bw/day, based on decreased body weight gains at all dose-levels, although probably linked to the bolus effect.

A correction factor based on the ratio between the molecular mass of the target substance (166.22 g/mol) and the source substance ((E)-2-Methoxy-4-prop-1-en-1-ylphenol - 164.21 g/mol) was applied to extrapolate the corrected NOAEL for the target substance:

NOAEL fertility ≥ 709 mg/kg bw/day.

NOAEL development ≥ 233 mg/kg bw/day / LOAEL = 709 mg/kg bw/day,

LOAEL parental toxicity ≤ 71 mg/kg bw/day.

* Statistically significant

Reference:

HERA (2005). Risk assessment of Isoeugenol: 4-Hydroxy-3-methoxy-1-propen-1-yl benzene CAS 97-54-1. Human and Environmental Risk Assessment on ingredients of Household Cleaning Products. February 2005.

Effects on developmental toxicity

Description of key information

Developmental toxicity study on the source substance, Trans-Isoeugenol (similar to OECD 414, GLP, Rel. 1, K):

- LOAEL maternal toxicity = 253 mg/kg bw/day, based on dose-dependent reduced body weight gain.

- NOAEL developmental toxicity = 506 mg/ kg bw/day, based on intra-uterine growth retardations mildly delayed skeletal ossification observed at 1012 mg/kg bw/day. However, this finding is likely secondary to maternal toxicity and not indicative of a teratogenic effect

(NOAEL/LOAEL adjusted for MW)

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

506 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

No study was available on Dihydroeugenol. The study on trans-Isoeugenol was selected as the key study. The key study is GLP-compliant and of high quality (Klimisch score = 1)

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Additional information

No study was identified on the target substance. However, a study was available on the source substance, trans-Isoeugenol (see Iuclid section 13 for read-across justification).

In this key embryo-foetal developmental study (NTP, 1999, Rel.1) with Trans-Isoeugenol, the oral (gavage) administration of 0 (control), 250, 500, or 1,000 mg /kg body weight/day to female CD rats on gestation day (GD) 6 to 19 resulted in a number of test article-related maternal effects at all dose levels (NTP, 1999). These findings included lower maternal body weight (4.6%, 11.6%, and 9.9% lower at dose levels of 250, 500, and 1,000 mg/kg body weight/day, respectively) when measured on GD 20, and statistically significant and dose-dependent lower gestation body weight gain (13.6%, 22.6%, and 30.5% lower at dose levels of 250, 500, and 1,000 mg/kg body weight/day, respectively) when measured over GD 0 to 20 compared to control group.

Other effects in maternal animals included clinical signs of piloerection and sedation at 500 and 1,000 mg/kg body weight/day, and lower gravid uterine weight (statistically significant values of 8.54% and 10.5% at 500 and 1,000 mg/kg body weight/day) and lower maternal relative food intake (statistically significant values of 15.3% at 1,000 mg/kg body weight/day) compared to control group.

There were no treatment-related group mean differences for the following reproductive parameters: number of corpora lutea, number of implantation sites, percent preimplantation loss, percent preimplantation loss, resorptions, late foetal deaths, average litter size, and percentage of male foetuses per litter.

The only developmental effect noted was 7 to 9% lower body weight in high-dose foetuses when compared with Controls. There were non-statistically significant differences among groups for the incidences of foetal malformations (i.e., total, external, or skeletal); however, the incidence of skeletal variations (i.e., unossified sternebrae) was significantly increased in high-dose foetuses. Incidental occurrences of visceral malformations were noted in one mid-dose and one high-dose foetus; however, these did not occur in a dose-related manner and were therefore considered not to be related to the test article; these variations included enlarged lateral ventricle, enlarged nasal sinus, agenesis of the innominate artery, and distended ureter.

The findings of unossified sternebra(e) at the high dose of 1,000 mg Trans-Isoeugenol/kg body weight/day in the embryo-foetal developmental study are likely secondary to maternal toxicity and are not indicative of a teratogenic effect.  It is widely accepted that findings of unossified sternebra(e) are strongly influenced by alterations in maternal factors such as body weight, food consumption, and physiology (Carney and Kimmel, 2007).  In this particular study, the findings of unossified sternebra(e) were only reported at the dose level with maternal toxicity.  Furthermore, even in the absence of maternal toxicity, delayed ossification is considered to be indicative of a foetotoxic effect, but not a teratogenic effect, as ossification usually will complete in the postnatal period and this finding has a relatively high background incidence.

According to the conclusion drawn by NTP, a maternal NOAEL could not be established; however, the lowest-observed-adverse-effect level (LOAEL) was reported to be the low dose level of 250 mg/kg body weight/day. The NOAEL for developmental toxicity was reported to be 500 mg/kg body weight/day, based on findings of growth delay and mildly delayed skeletal ossification in the high-dose foetuses. However, this finding is likely secondary to maternal toxicity and not indicative of a teratogenic effect.

A correction factor based on the ratio between the molecular mass of the target substance (166.22 g/mol) and the source substance ((E)-2-Methoxy-4-prop-1-en-1-ylphenol - 164.21 g/mol) was applied to extrapolate the corrected NOAEL for the target substance:

LOAEL maternal toxicity = 253 mg/kg bw/day,

NOAEL developmental toxicity = 506 mg/ kg bw/day.

Reference:

Carney EW, Kimmel CA (2007). Interpretation of skeletal variations for human risk assessment: delayed ossification and wavy ribs. Birth Defects Res B Dev Reprod Toxicol. 2007 Dec;80(6):473-96.

Justification for classification or non-classification

Harmonized classification:

The substance has no harmonized classification according to the Regulation (EC) No 1272/2008.

Self-classification:

Reproductive toxicity was only reported at concentrations greater than maternal toxicity for Trans-Isoeugenol. As a result, the substance does not meet the criteria for classification according to Regulation (EC) No 1272/2008 and to the GHS.