Registration Dossier

Administrative data

Description of key information

A NOAEL for subacute toxicity of 1000 mg/kg bw/day was derived from a 28 day toxicity in rats after oral (gavage) administration.
For evaluation of the subchronic toxicity read across to 3,6,9,12-Tetraoxatetradeca-1,13-diene (CAS 765-12-8) was made. 
A NOAEL of 300 mg/kg bw/day was derived from a 2 generation reproduction toxicity study with rats after oral (gavage) administration.

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:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP; guideline study. For justification of read across see endpoint summary.
Qualifier:
according to guideline
Guideline:
other: OECD 416 (Two-generation reproduction toxicity study)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
male/female
Route of administration:
oral: gavage
Vehicle:
water
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The analyses mentioned were carried out at the Analytical Chemistry Laboratory of Experimental Toxicology and Ecology, BASF Aktiengesellschaft, Germany. Analytical verifications of the stability of the test substance in doubly distilled water for a period of 8 days deep frozen at -20 0C were carried out before the study was initiated.
Duration of treatment / exposure:
F0: 20 weeks
F1: 19 weeks
Frequency of treatment:
once a day
Remarks:
Doses / Concentrations:
0; 100; 300 and 1000 mg/kg body weight/day
Basis:
nominal in water
No. of animals per sex per dose:
25
Control animals:
yes, concurrent vehicle
Observations and examinations performed and frequency:
mortality; littering and lactation behavior; food consumption; body weight data
Details on results:
The clinical examinations of the F0 and F1 parental rats for general signs of toxicity revealed some substance-related effects at the high dose (1,000 mg/kg body weight/day). These were substantiated by unsteady gait and/or abdominal position, which occurred intermittently in several, but not all top dose rats shortly after gavage dosing and persisted only for some minutes. Moreover, all male and nearly all female F0 and F1 parental animals of the high dose group (1,000 mg/kg body weight/day) showed transient salivation during major parts of the treatment period. Salivation persisted in the respective animals only tor some minutes after daily gavage dosing. It is very likely, that the observed salivation was induced by bad taste of the test substance or local affection of the upper digestive tract. Salivation itself is not assessed as an adverse or toxic effect. There occurred no mortalities that could be causally related to the test substance. Food consumption and body weight data of the F0 and F1 parents, collected during premating, gestation, and/or lactation phases, were not influenced by the test substance administration.
Regarding pathology, kidneys, liver and/or thyroid glands proved to be the target organs in both genders of the two parental generations at the top dose (1,000 mg/kg body weight/day), and much less pronounced at the mid dose (300 mg/kg body weight/day). The absolute and relative kidney weights were statistically significantly increased in high dose F0 and F1 males and high dose F1 females. Histopathologically, high dose F0 and F1 males showed a slightly increased incidence of chronic progressive nephropathy with higher graded severity, when compared to controls. The increased kidney weights in high dose F0/F1 males are related to the increase of chronic nephropathy and thus are considered to demonstrate treatment-related, adverse effects. Furthermore, the increased kidney weights in high dose F1 females are also considered as substance-related. This weight increase had, however, no histopathological correlate and was therefore not considered as an adverse effect.
The mean liver weights were statistically significantly increased in high dose F0 males (relative) and in the top dose F1 males and F1 females (absolute and relative). The increased liver weights correlated with a minimal centrolobular hypertrophy of hepatocytes that was noted in seven high dose F1 males (controls: one F1 male). Although there was no histopathological correlate for the increased liver weights in F0 males and F1 females at 1,000 mg/kg, the increased liver weights of these rats are also considered as substance related.
For the increased mean relative liver weight in mid dose F1 males (300 mg/kg body weight/day), a substance-related effect cannot be ruled out with certainty.
However, the observed effects on the parental livers at 300 and 1,000 mg/kg body weight/day are considered to mirror an adaptive process and not an adverse effect.
The mean weights of the thyroid glands were statistically significantly increased in the top dose F0 and F1 males (relative), and in the mid and high dose F0 and F1 females (absolute and relative). For the increased thyroid weights a clear dose-response relationship was not present and there were no histopathological correlates. Therefore, it seems very unlikely, that the weight changes of the thyroid demonstrate an adverse effect.
Dose descriptor:
NOAEL
Effect level:
300 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: see 'Remark'
Critical effects observed:
not specified
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
300 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
GLP and guideline study

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

Oral:

For repeated dose toxicity, only a 28-day subacute toxicity study with the test substance 1,1'-[oxybis(ethyleneoxy)]diethylene is available indicating a NOEL in rats of 1000 mg/kg bw/day. To address longer subchronic exposure time, read across to the structural analogue 3,6,9,12 -Tetraoxatetradeca-1,13 -diene (CAS 765 -12 -8) was made. The NOEL of 300 mg/kg bw/day was derived from a 2 -generation reproduction toxicity study. Both substances behave very similar in acute toxicity tests (oral and dermal LC50 > 2000 mg/kg bw) and also in skin and sensitisation tests. Both substances are not irritating to skin and eye and do not show any signs of skin sensitisation. In addition mutagenicity tests show negative results in both substances. In conclusion, read across is supported by the structural similarity and the available toxicological information. The use of the 2 -generation study instead of a 90d repeated dose toxicity study is scientifically justified, as the animals were treated for a comparable time period (F0: 20 weeks, F1: 19 weeks).

subacute toxicity

The test item was administered to rats by intragastric intubation, daily, for twenty-eight consecutive days at dosage levels of 30, 100, 300 and 1000 mg/kg bw/day (Charles River Laboratories, 2007). Microscopic observations attributed to the test article were limited to minimal to mild epithelial hyperplasia and hyperkeratosis in the non glandular region of the stomach of both males and females treated with 1000 mg/kg/day and one female treated with 300 mg/kg/day. There was no other toxicity observed in the male and female rats as high as 1000 mg/kg/day. The stomach findings were considered of minimal toxicological significance and possibly an indication of local irritation rather than systemic toxicity. Therefore the no-observable-adverse-effect-level (NOAEL) was considered to be 1000 mg/kg/day in both the male and female rats (highest dose tested).

subchronic toxicity (read across)

The structural analogue 3,6,9,12-Tetraoxatetradeca-1,13-diene (CAS 765-12-8) of the test item was orally administered in a 2-generation reproduction toxicity study to groups of 25 male and 25 female Wistar rats at dosages of 0, 100, 300 and 1000 mg/kg bw/d for up to 20 weeks (OECD 416; BASF 73R0162/03041). There were no indications for reproductive or developmental toxicity. The clinical examinations of the F0 and F1 parental rats for general signs of toxicity revealed some substance-related effects at the high dose (1000 mg/kg bw/d). These were substantiated by unsteady gait and/or abdominal position, which occurred intermittently in several, but not all top dose rats shortly after gavage dosing and persisted only for some minutes. Moreover, all male and nearly all female F0 and F1 parental animals of the high dose group (1000 mg/kg bw/d) showed transient salivation during major parts of the treatment period. Salivation persisted in the respective animals only for some minutes after daily gavage dosing. There occurred no mortalities that could be causally related to the test substance. Food consumption and body weight data of the F0 and F1 parents, collected during premating, gestation, and/or lactation phases, were not influenced by the test substance administration. Regarding pathology, kidneys and liver proved to be the target organs in both genders of the two parental generations at the top dose (1,000 mg/kg body weight/day). The absolute and relative kidney weights were statistically significant increased in high dose F0 and F1 males and showed corroborative histopathological findings (i.e. increased incidence of chronic progressive nephropathy). The mean liver weights were statistically significantly increased in high dose F0 males (relative) and in the top dose F1 males and F1 females (absolute and relative). The increased liver weights correlated with a minimal centrolobular hypertrophy of hepatocytes that was noted in seven high dose F1 males (controls: one F1 male). Although there was no histopathological correlate for the F0 males and F1 females at 1000 mg/kg, the increased liver weights of these rats are also considered as substance related. Thus, the NOAEL for overall general toxicity on the parental rats could be fixed at 300 mg/kg body weight/day.

No data are available on the dermal or inhalation route.


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
The Key study with the lowest NOAEL was selected (GLP and Guideline study).

Repeated dose toxicity: via oral route - systemic effects (target organ) digestive: liver; urogenital: kidneys

Justification for classification or non-classification

The criteria for classification according to EU Directive 67/548/EEC and EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No 1272/2008 are not met.