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Toxicological information

Repeated dose toxicity: inhalation

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Administrative data

Endpoint:
sub-chronic toxicity: inhalation
Type of information:
migrated information: read-across based on grouping of substances (category approach)
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Rationale for reliability of 2: scienfically well performed study; well documented report, assessed in official review (i.e.European Comission and OECD SIDS) Rationale for grouping; the structural similarity is given by presence of butoxy ethylen glycol units; systemic exposure to 2-butoxyacetic acid and/or to butoxyethoxyacetic acid as common mode of action for all members; comparable findings in repeated-dose toxicity for all members

Data source

Referenceopen allclose all

Reference Type:
publication
Title:
Unnamed
Year:
2000
Reference Type:
review article or handbook
Title:
Unnamed
Year:
2008

Materials and methods

Principles of method if other than guideline:
Rats were treated with EGBE vapour at concentrations of 0, 31, 62.5 and 125 ppm for 6h/day, 5d/week, 14 weeks. The observation parameters were similar to those required for OECD 413.
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent

Test animals

Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals and environmental conditions:
Rats were held in the testing laboratory for 11 - 12 days and were 6 weeks old when the study began. They were housed individually, water was available ad libitum and feed was available ad libitum except during the exposure periods.

Administration / exposure

Route of administration:
inhalation: vapour
Type of inhalation exposure:
whole body
Vehicle:
clean air
Duration of treatment / exposure:
14 weeks
Frequency of treatment:
6h/d, 5d/week,
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 31, 62.5, 125, 250, 500 ppm (0, 150, 302, 604, 1208, 2416 mg/m3)
Basis:
nominal conc.
No. of animals per sex per dose:
10
Control animals:
yes

Results and discussion

Effect levels

open allclose all
Dose descriptor:
NOAEC
Effect level:
62.5 ppm
Based on:
test mat.
Sex:
male
Basis for effect level:
other: Based on the hematotoxic effect at 125 ppm
Dose descriptor:
LOAEC
Effect level:
31 ppm
Based on:
test mat.
Sex:
female
Basis for effect level:
other: hematological effects seen at all doses tested

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

Summary of result (cited from EU Risk Assessment):

Six female rats were found moribund and killed during the study: five in the 500 ppm group (four in week 1, one in week 5) and one in the 250 ppm group (in week 8). By the end of the study, body weight gains were significantly reduced in females of the 500 ppm group, but were unaffected in all other groups. Clinical findings were most prevalent in rats of both sexes exposed to 125, 250 or 500 ppm and included abnormal breathing, pallor, red urine stains, nasal and eye discharge, lethargy and either increased salivation or lacrimation. All females of the 500 ppm group, particularly during the first two weeks, developed alternating blue and white bands on their tails that caused them to self-mutilate and loose the distal portion of their tails.

Haematological examination showed that inhalation of EGBE resulted in the development of a persistent and exposure-related macrocytic, normochromic, responsive anaemia, as indicated by decreased haematocrit values, haemoglobin concentrations and erythrocyte counts in the 125 ppm or greater group males and in all groups of exposed females. The effects were dose related. This evidence of a sex difference in the severity of the anaemia was also seen in the 500 ppm group, in which the indicators were slightly more severe in the females than in the males. Evidence of an erythropoietic response was shown by increases in reticulocyte and nucleated erythrocyte counts in males of the 125 ppm or greater groups and females of the 62.5 ppm or greater groups. Other haematological changes were decreases in lymphocyte and monocyte counts in males of the 125 ppm or greater groups and increased platelet counts in females of the 125 or 500 ppm groups. Some organ weight changes were observed. These were: increases of the kidney of males in the 500 ppm group and females in the 125 ppm or greater groups; increases of the liver of males in the 250 or 500 ppm and females in the 125 ppm or greater groups; and decreases of the thymus of females in the 500 ppm group. Thrombosis was observed in the tail vertebrae, femur, incisors, nasal cavity, lung, heart and liver of most females in the 500 ppm group, but not at all in the 250 ppm group. Additionally, in the 500 ppm group females, there was degeneration of the hepatic centrilobular areas and renal tubules (4/5 in each case) and atrophy of the thymus (4/5) and spleen (1/5). Haematopoietic cell proliferation was observed in the spleen of 2/5 group same group. Bone marrow hyperplasia was recorded in males of the 250 and 500 ppm groups and females in all groups from 62.5 ppm. The severity of this response was dose related. In the forestomach of females in the 500 ppm group, but not in lower dose groups, observations made were of inflammation (3/5), necrosis (2/5), ulcers (2/5) and hyperplasia (1/5). Effects also observed in the 250 ppm group females were hepatic necrosis, pigmentation of Kupffer cells and renal tubule cells and bone marrow hyperplasia.

No NOAEC was found for female rats. LOAEL was 31 ppm based on haematological effects seen at all doses tested. A NOAEL of 62.5 ppm was found for male rats, based onhaematotoxic effects seen at 125 ppm.

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.

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

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.

 

-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 on metabolism is available; BEAA and/or 2-BAA as metabolite can be reasonably assumed due to the observed RBC reduction in toxicity studies.

 

- 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.

Applicant's summary and conclusion

Conclusions:
Inhalation of EGBE for rats for 14 weeks resulted in the development of hemolytic anemia down to the dose level of 31 ppm (= 150 mg/m3). The LOAEL of 31 ppm was obtained.
Executive summary:

The repeated dose toxicity of DEGDBE was assessed based on the use of read-across. EGBE is considered to be one of the appropriate source chemical.

Rats were treated with EGBE vapour at concentrations of 0, 31, 62.5, 125, 250 and 500 ppm for 6h/day, 5d/week, 14 weeks. Haemolysis, as indicated by decreased hematocrit values, haemoglobin concentrations and erythrocyte, was observed at all doses tested for females and at 125 mg/kg bw and higher for males. At concentrations of 125 ppm and higher the organ weight changes together with histopathological changes were observed liver, spleen and thymus.

No NOAEC was found for female rats. LOAEL was 31 ppm (= 150 mg/m3) based on haematological effects seen at all doses tested. A NOAEL of 62.5 ppm was found for male rats.