1,4-dioxane

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

Based on a weight of evidence (WoE) approach in accordance with REACH Annex XI Section 1.2 it can be concluded that there are no indications that exposure to 1,4 -dioxane affects reproductive organs or causes impairment of fertility functionality.

Link to relevant study records

Reference

Endpoint:

extended one-generation reproductive toxicity - basic test design (Cohorts 1A, and 1B without extension)

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

other:

Justification for type of information:

According to REACH Annex XI Section 1.2 data from studies other than required according to Annex IX and/or Annex X for a specific endpoint may be used to sufficiently conclude on this endpoint by an weight of evidence (WoE) assessment and taking into account the overall picture of all data sources available.
There are comprehensive data available with the registered substance investigating repeated dose toxicity under sub-chronic as well as chronic exposure conditions via the oral and inhalation route in two different species (rats and mice). None of these studies revealed a test item related impairment of the reproductive organs in either sex or species. Thus, there are no indications that fertility functions could be affected by the test item below maternal toxic concentrations.

Furthermore, a prenatal-developmental toxicity study in the rat is available with the registered substance. Results demonstrate that there is no concern in regards to developmantal toxicity / teratogenicity with the test item.

It should be noted that the registered substance has to be classified for carcinogenicity (cat. 1B) according to CLP and appropriate risk management measures are implemented. This legally binding classification makes further testing for toxicity to reproduction obsolete, also considering animal welfare reasons.

Effect on fertility: via oral route

Endpoint conclusion:

no study available

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

There is no adequate fertility study available with 1,4-dioxane.

However, there is sufficient and reliable data from sub-chronic and chronic toxicity studies available in two different species and via the oral as well as the inhalation route.

Therefore, and in accordance with REACH Annex XI Section 1.2, a weight of evidence (WoE) approach was applied in order to address the endpoint of toxicity to reproduction.

In conclusion it can be stated that there are no indications that exposure to 1,4 -dioxane could affect reproductive organs in either sex based on pathological and histopathological evaluations after repeated dose exposure. Therefore, it is not expected that 1,4 -dioxane could cause any impairment of fertility functions in mammals.

Effects on developmental toxicity

Description of key information

In an oral teratogenicity study with rats the NOAEL for maternal and embryotoxicity can be established at 0.5 mL/kg/bw, equivalent to 517 mg/kg bw/day.

Link to relevant study records

Reference

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

GLP compliance:

not specified

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River, Calco Italy
- Weight at study initiation: 178-182 gram
- Housing: females caged overnight with males.
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 2 weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18-22
- Humidity (%): 60
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

oral: gavage

Vehicle:

water

Details on exposure:

daily administration by gavage at a constant volume (3 mL/kg)

Details on mating procedure:

Females were caged overnight with males. The day on which sperm was found in the vaginal smear was considered day 1 of gestation.

Duration of treatment / exposure:

gestation day 6-15

Frequency of treatment:

daily

Duration of test:

the animals were killed on day 21 of pregnancy

Dose / conc.:

258 mg/kg bw/day (actual dose received)

Remarks:

corresponding to 0.25 mL/kg bw/d

Dose / conc.:

517 mg/kg bw/day (actual dose received)

Remarks:

corresponding to 0.5 mL/kg bw/d

Dose / conc.:

1 034 mg/kg bw/day (actual dose received)

Remarks:

corresponding to 1.0 mL/kg bw/d

No. of animals per sex per dose:

0 mL/kg bw/day (control): 18 (17 pregnant)
0.25 mL/kg bw/day: 18 (17 pregnant)
0.5 mL/kg bw/day: 19 (19 pregnant)
1.0 mL/kg bw/day: 20 (20 pregnant)

Control animals:

yes

Maternal examinations:

Food consumption: daily
Weight determination: every three days

Ovaries and uterine content:

corpora lutea, implantations, resorptions, live fetuses

Fetal examinations:

Examination of the viscera and skelatal obervations

Statistics:

The data were analysed using Student's f-test or analysis of variance, except for pre- and postimplantation loss and frequency of malformations, which were analysed using 2 x 2 contingency tables.

Clinical signs:

not specified

Dermal irritation (if dermal study):

not examined

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

The females treated with 1 mL/kg bw/d showed a slightly smaller weight gain during treatment, which continued during the second stage of gestation.

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

Food consumption in the females treated with 1mL/kg bw/d was decreased during treatment, especially evident in the first 2 days of treatment.

Food efficiency:

not examined

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

not specified

Ophthalmological findings:

not specified

Haematological findings:

not specified

Clinical biochemistry findings:

not specified

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Immunological findings:

not specified

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

not specified

Neuropathological findings:

not specified

Histopathological findings: non-neoplastic:

not specified

Histopathological findings: neoplastic:

not specified

Other effects:

no effects observed

Number of abortions:

not specified

Pre- and post-implantation loss:

effects observed, non-treatment-related

Description (incidence and severity):

Number of implantations was slightly decreased at 1 mL/kg bw and preimplantation loss was slightly increased at this dose level.

Total litter losses by resorption:

not specified

Early or late resorptions:

not specified

Dead fetuses:

not specified

Changes in pregnancy duration:

not specified

Changes in number of pregnant:

not specified

Other effects:

no effects observed

Key result

Dose descriptor:

NOAEL

Effect level:

517 mg/kg bw/day

Basis for effect level:

body weight and weight gain

food efficiency

Key result

Abnormalities:

no effects observed

Fetal body weight changes:

effects observed, treatment-related

Description (incidence and severity):

The average weight of live foetuses from dams treated with 1 mL/kg bw was significantly less than controls.

Reduction in number of live offspring:

effects observed, non-treatment-related

Description (incidence and severity):

Number of foetuses alive was slightly decreased at 1 mL/kg bw/d.

Changes in sex ratio:

not specified

Changes in litter size and weights:

not specified

Changes in postnatal survival:

not examined

External malformations:

no effects observed

Skeletal malformations:

effects observed, non-treatment-related

Description (incidence and severity):

At the dose level of 1mL/kg bw/d a delay of ossification was found in the area of the sternum. There was no indication for teratogenicity.

Visceral malformations:

no effects observed

Other effects:

no effects observed

Key result

Dose descriptor:

NOAEL

Effect level:

517 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: slightly decreased number of implantations and number of foetuses alive, slightly increased preimplantation loss, delay of ossification in the area of the sternum

Remarks on result:

other: effects seen only at dose levels inducing maternal toxicity, too

Key result

Abnormalities:

no effects observed

Key result

Developmental effects observed:

no

Effect on developmental toxicity: via oral route

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

517 mg/kg bw/day

Study duration:

subacute

Species:

rat

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

An acceptable teratogenicity study is available, in which rats were treated with 0, 0.25, 0.5 or 1.0 mL 1,4-dioxane/kg bw/day by gavage during gestation days 6 -15. At 1 mL/kg bw/day slight maternal toxicity was seen (decreased weight gain and food consumption) together with slight unspecific embryotoxicity (decreased weight of live foetuses, slightly decreased number of implantations and number of foetuses alive, slightly increased preimplantation loss, delay of ossification in the area of the sternum). Embryotoxicity can be atributed to maternal toxicity in this case. No teratogenic effects were observed. The NOAEL for maternal and embryotoxicity was established at 0.5 mL/kg bw/day (equivalent to 517 mg/kg bw/day).

Justification for classification or non-classification

Classification, Labelling, and Packaging Regulation (EC) No 1272/2008
The available experimental test data are reliable and suitable for classification purposes under Regulation (EC) No 1272/2008. The available developmental toxicity study does not trigger classification for developmental toxicity and no apparent effects on reproductive organs or fertility functionality were observed in rats or mice in several subchronic and chronic toxicity studies with 1,4 -dioxane. As a result the substance does not require classification for toxicity to reproduction under Regulation (EC) No 1272/2008, as amended for the twelfth time in Regulation (EU) 2019/521.