Reaction mass of 5,8,11,14-Tetraoxaoctadecane and 5,8,11,14,17-Pentaoxaheneicosane

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

750 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

One key study on the registration substance and two supporting studies on the read-across supporting substance; database sufficient for a reliable assessment

Additional information

Short description of key information:
The registration substance induced no significant effects up to dose of 750 mg/kg bw in the combined repeated dose toxicity study with the reproduction/developmental toxicity screening test (OECD 422). Based on the read-across consideration, the introduced study is representative for reproduction toxicity after prolonged exposure over multi-generation. No significant reproduction toxicity can be predicted for the registration substance.

Justification for selection of Effect on fertility via oral route:
Scienficially well-performed; Guideline study; GLP study

Effects on developmental toxicity

Description of key information

The database of five studies, comprising three applicaiton routes (oral/dermal /respiratory) and two species (rat and rabbit), are used for the assessments of developmental toxicity of the registration substance. One study is on the registration substance itself and four studies on the read-across supporting substances.  The results of these studies are consistent. The primary maternal toxicity is the hemolysis causing developmental toxic effect of secondary nature.  No developmental toxicity was found in absence of maternal toxicity for all group members. No significant developmental toxicity can be reliably derived for the registration substance. 

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Species:

rat

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no adverse effect observed

Species:

other: rat and rabbit

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no adverse effect observed

Species:

rabbit

Additional information

The category approach is used to asses the developmental toxicity of DEGDBE. Following aspects will be discussed:

a)     Category approach justification

b)     Developmental toxicity of DEGDBE based on category building

a) Category approach justification:

The developmental toxicity of DEGDBE is to be assessed by read-across consideration. Three structurally related glycol ethers are identified as suitable surrogates. Together with DEGDBE, a category building is proposed to increase the robustness of the read-across consideration.

a1) Category members and chemical structures: the similarity in their structure is given by presence of butoxylated ethylene glycol at terminal position (Butyl-O-CH₂-O-).

Ethylene glycol butyl ether (EGBE)* CAS 111-76-2	Butyl-O-CH2-OH
Diethylene glycol butyl ether (DEGBE)* CAS 112-34-5	Butyl-O-CH2-O-CH2-OH
Diethylene glycol dibutyl ether (DEGDBE)** CAS 112-73-2	Butyl-O- CH2-O-CH2-O-Butyl
Polyethylene glycol dibutyl ether (PolyEGDBE)*** CAS 31885-97-9	Butyl-O- CH2-O-CH2-O-CH2-O-Butyl

* EGBE and DEGBE are extensively investigated substances and reviews on their toxicity profiles are available in public domain (i.e. EU Risk Assessment Report, 2-Butoxyethanol (EGBE), CAS 111 -76 -2, 2008; Opinion on Diethylene Glycol Monobutyl Ether (DEGBE), SCCP/1043/06, 2006). **target chemical. ***Clariant own data, details provides in corresponding endpoint study record.

a2) The proposed grouping is justified by the common mode of action, namely systemic exposure to 2-butoxyacetic acid (2-BAA) and/or butoxyethoxyacetic acid (BEAA):

- EGBE: 2-BAA is the major urinary metabolite (summarized in EU risk assessment, 2008)

- DEGBE: BEAA is the major urinary metabolite (Deisinger et al. 1989)

- DEGDBE: in 28-day study (Clariant own data) the urinary 2-BAA determination was incorporated; 750 mg/kg bw external dose level corresponded to 1400 mg/L 2-BAA in urine.

- PolyEGDBE: no experimental data is available; BEAA and/or 2-BAA as metabolite can be reasonably assumed due to the observed RBC reduction and indication of compensatory increased hematopoietic activity.

a3) The proposed grouping is justified by the comparable toxicity profiles, which reflects the toxicity action of 2-BAA and/or BEAA. Both metabolites are known to induce hemolysis (Udden 2002; Udden 2005).

- EGBE: hemolytic action demonstrated in acute and repeated dose toxicity studies (summarized in EU risk assessment, 2008)

- DEGBE: i.e. in 2 and 13 week oral toxicity studies (Johnson et al. 2005)

- DEGDBE: in 28-day study (Clariant own data) RBC reduction and hematuria was evident.

- PolyEGDBE: in dose-range finding study for OECD 422 (Clariant own data), RBC reduction was evident together with compensatory increased hematopoietic activity.

 

b) Findings obtained in studies with registration substance, DEGDBE, DEGBE and EGBE

In all studies presented in this dossier, no developmental toxicity occurred in absence of maternal toxicity. At doses above NOAELs the maternal toxicity was comparable for all group members in that hemolysis occurred. The developmental effect found for DEGDBE and EGBE are almost identical and should be considered as secondary to the hemolysis in dams.

The NOAELs obtained for the groups members are indicative of the potency order of EGBE > DEGDBE > DEGBE ≈ the registration substance, which is the same order of the systemic toxicity obtained from the repeated dose toxicity studies (summarized as endpoint summary of repeated dose toxicity in this dossier)

 

Table: Overview of the developmental toxicity studies of the grouped chemicals
Group member	Study type	NOAEL	Effects found above NOAEL
Registration substance PolyEGDBE	OECD 414^a;  rat; oral	750 mg/kg bw	^b
DEGBE	OECD 414 rabbit; dermal	1000 mg/kg bw	^b
DEGDBE	OECD 414^a ; rat; oral	250 mg/kg bw	increased pre- and post-implantation loss, reduced live fetuses, reduced litter mean weight and increase in skeletal abnormalities.
EGBE	OECD 414 equivalent; rabbit; respiratory	140 mg/kg bw^c	increased pre-implantation loss, reduced number of live fetuses and increased incidence of skeletal variations
	OECD 414 equivalent; rat; respiratory	70 mg /kg bw^d

^aAlthough no significant developmental toxicity was found, the study as stand-alone data not sufficient due to the deviation of using limited number of animals (Eight instead of twenty)

^bThe NOAEL equals the highest dose

^cThe NOAEL of 100 ppm (483 mg/m3) was obtained in the study; the value of 140 mg/kg bw is obtained by using the conversion factor of 0.29 m³/kg bw (Table R.8-2 of ECHA Guidance)

^dThe NOAEL of 50 ppm (242 mg/m3) was obtained in the study; the value of 70 mg/kg bw is obtained by using the conversion factor of 0.29 m³/kg bw (Table R.8-2 of ECHA Guidance)

 

Not only the study on the registration substance is indicative of no concern for the developmental toxicity, but also for other group members no significant developmental toxicities are demonstrated. The latter aspect is important to cover the weakness of the provided study on the registration substance. The assessment is considered to be reliable and robust. No concern is derived with respect to the developmental toxicity for the registration substance.

Justification for selection of Effect on developmental toxicity: via oral route:
Weight of evidence approach is used. All provided data are considered to be equally valid for the assessment.

Justification for selection of Effect on developmental toxicity: via inhalation route:
Weight of evidence approach is used. All provided data are considered to be equally valid for the assessment.

Justification for classification or non-classification

Based on the data on the registration substance and on the read-across approach no significant reproduction toxicity could be derived for the registration substance.

No classification is warranted.