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EC number: 204-001-9 | CAS number: 112-73-2
The reproduction toxicity of DEGDBE was investigated according to OECD 421. In order to compensate the potentially reduced statistical power due to the reduced number of pregnant animals in all groups in the main study, the results obtained in the dose-range finding study were combined for the robust evaluation.
The male wistar rats after being treated with diethyleneglycoldibutyether in corn oil for the period of 28 days at the dosage of 250, 500 and 750 mg/ kg body weight revealed treatment related changes for body weight development and food consumption at and above 500 mg/kg bw when compared to the corresponding controls. Due to the minor degree of the observed effect no toxicological meaning was attributed.
The female rats were dose administered for approximately 54 days at the same dosage. There was changes observed for body weight development and food consumption at and above 500 mg/kg bw; mortality of one female at 750 mg/kg body weight (due to assumed complication during parturition) and Reddish urine or bedding (LD 1/13, MD 4/13 and HD 8/13 females, observed only on dose application day 2) at and above 250 mg/kg bw. The reddish urine observed in LD group was considered minor due to its finding in an individual isolated female.
There was changes observed for the number of still births, % implantation loss, litter weight data, number of live male, female and total pups and viability index (%) at or above 250 mg/kg body weight. The changes observed at 250 mg/kg body weight were of minor degree and considered of no toxicological meaning.
Based on the result the NOAEL for adult males toxicity is believed to be at 750 mg/kg body weight and for females and fetal toxicity is believed to be at 250 mg/ kg body weight. .
See the discussion given for the developmental toxicity.
DEGDBE induced developmental toxicity at dose levels associated with clear maternal toxicity. Further, the mode of action is the systemic exposure to 2-butoxyacetic acid, which is known to be of limited relevance for humans. No concern is derived for humans with respect to the developmental toxicity.
The category approach is used to asses the developmental toxicity of DEGDBE. Following aspects will be discussed:
a) Category definition and 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)*
Diethylene glycol butyl ether (DEGBE)*
Diethylene glycol dibutyl ether (DEGDBE)**
Polyethylene glycol dibutyl ether (PolyEGDBE)***
* 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) Developmental toxicity of DEGDBE based on category building
Data availability on DEGDBE is limited to one dose-range finding for developmental toxicity study (DRF for OECD 414) in rat and one NTP screening study (Schuler et al. 1984; Hardin et al., 1987) in mouse. The DRF for OECD 414 is performed with reduced number of animals so that the result alone cannot be evaluated to be sufficiently robust to consider DEGDBE as a non-developmental toxicant. The same consideration applies to NTP screening study since the observation parameters were limited.
However, these data are in line with the knowledge gained in the studies with EGBE and DEGDBE. Following aspects are to be discussed:
b1) comparative findings in studies with DEGDBE and in studies with EGBE of Tyl et al. (1984);
b2) assessment of DEGDBE comparative to DEGBE and EGBE based on the NTP screening study;
b3) relevance of findings in studies with PolyEGDBE;
b4) assessment of DEGDBE based on the EU assessment on EGBE and DEGBE
Relevant data are provided as endpoint study records.
b1) Comparative findings in studies with DEGDBE and in studies with EGBE of Tyl et al. (1984)
The developmental toxicity of DEGDBE was investigated according to OECD 414 with deviations of using limited number of animals. Each eight pregnant rats were treated with DEGDBE per gavage at doses of 0. 250, 500, 750 mg/kg bw.DEGDBE at 500 and 750 mg/kg bw induced transient body weight loss (gestation day 5 -8, ), reduced body weight gain, increased pre- and post-implantation loss, reduced live fetuses, reduced litter mean weight and increased incidences of findings upon skeletal examinations. No maternal and fetal toxicity was found at 250 mg/kg bw.
Rats and rabbits were exposed to EGBE at doses of 0, 25, 50, 100 and 200 ppm from GD 6 to 16. In rats, maternal toxicity together with developmental toicity was evident at 100 and 200 ppm; body weight decrease in the early phase of treatment, hematuria, hematology alteration, increased pre-implantation loss, reduced number of live fetuses and increased incidence of skeletal variations. No teratogenic effect was found.
It should be pointed out that the mode of action for the alteration of hematology are known for EGBE, namely systemic exposure to 2 -butoxyacetic acid, and is known to be of limited relavance to human (Udden, 2002; also mentioned in EU Risk Assessment). In the 28 -day oral toxicity study, the systemic exposure to 2 -butoxyacetic acid could be demonstrated and thereby confirming the identical mode of action for DEGDBE.
For both DEGDBE and EGBE, the developmental toxicity occurred only with maternal toxicity and the maternal as well as the developmental toxic effects observed in rats/rabbits are of limited relevance for human. No concern can be derived for both substances with respect to developmental toxicity.
b2) Assessment of DEGDBE comparative to DEGBE and EGBE based on the NTP screening study
The NTP screening study (Schuler et al. 1984; Hardin et al., 1987) included EGBE and DEGBE as well as the target chemical DEGDBE, so that the comparative toxicity assessment can be performed. Various chemicals were to be screened for the developmental toxicity. One parameter was the percent of viable litters to pregnant survivors. EGBE induced effect whereas DEGBE and DEGDBE induced nearly no effect at dose level corresponding to LD10. No influence on other parameters were found for all three chemicals. It is reasonable to derive the developmental toxicity of DEGBE and DEGDBE to be lower than that of EGBE.
b3) Relevance of findings in studies with PolyEGDBE
The PolyEGDBE was investigated for its developmental toxicity using the identical study design (OECD 414 with reduced number of animals) as for DEGDBE. The findings were similar to those found for DEGDBE. No conclusive assessment was possible on the potency difference. The findings for prenatal data are indicative of comparable potency, while for PolyEGDBE there is no finding upon fetal skeletal examination up to the highest dose applied.
b4) Assessment of DEGDBE based on the EU assessment on EGBE and DEGBE
According to the official EU opinion (EU Risk Assessment 2 -Butoxyethanol Cas 111 -76 -2, ECB, 2008; Opinion on Diethylene Glycol Monobutyl Ether (DEGBE) SCCP/1043/06, 2006) both EGBE and DEGBE are non-developmental toxicant and no developmental toxicity in humans can be expected without maternal toxicity. Also other official assessments of competent authorities are of similar opinion (i.e. EPA, OECD SIDS and BAuA in Germany).
DEGDBE induced no reproduction effect in absence of maternal toxicity in the reproduction toxicity screening test and in the developmental toxicity study. Also for read-across substances no concern is derived according to the EU official opinions.
No classification is warranted.
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