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Description of key information

See tables in discussion section

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Dose descriptor:
LOAEL
69 mg/kg bw/day

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Dose descriptor:
LOAEC
152 mg/m³

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Additional information

ORAL

A small number of reliable studies on rats and a single study on mice are available. Rats were clearly more sensitive than mice to the toxic effects of the substance. Effects seen by oral route were body weight reduction, haemolysis, hepatic effects and local irritation effects. Irritation to the forestomach was seen after gavage dosing have also be reported and, to a far lesser extent, after subcutaneous and intraperitoneal injection (not reported in this section - see mechanistic study by Poet in chapter 7.9.3). This difference is most likely due to the higher local concentration after gavage dosing. Overall, a LOAEL of 69 and 82 mg/kg bw/d (in males and females respectively) can be obtained from the data based on a three-month study in rats and based on slight changes observed in hepatocytes at this dose.

NOAEL (mg/kg bw/d)

Effects

Reference

Rats

6 weeks gavage

0, 222, 443 and 885 mg/kg

LOAEL = 222 mg/kg

Haematological effects at all doses and irritant effects on the stomach

Eastman Kodak, 1982

13 weeks in drinking water

69, 129, 281, 367 and 452 mg/kg/day for males and 82, 151, 304, 363 and 470 mg/kg/day for females

LOAEL of 69 and 82 mg/kg bw/day for males and females respectively.

Slight decrease in body weight gain and haematological effects.NOAEL based on liver effects(minimal to mild cytoplasmic changes in hepatocytes).

NTP, 1993

Mice

14 weeks in drinking water

118, 223, 553, 676 and 694 mg/kg/day for males and 185, 370, 676, 861 and 1306 mg/kg/day for females.

NOAEL = >694 and 370 mg/kg bw/d for males and females respectively

LOAEL = 676 mg/kg bw/d for females

Slight decrease in body weight gain

NTP, 1993

 

INHALATION

Numerous studies, including relatively recent ones have been conducted on rats, and mice. Some older studies using dogs, guinea-pigs and non human primates have also been performed. In rats and mice, the common toxicity signs are similar to those observed following acute administration. In general, rats are more sensitive than mice and females are more sensitive than males. The main and critical effect was haemolysis, which was consistently observed and sometimes associated with secondary hepatic effects (Kupffer cells pigmentation and absolute and relative liver weight increases). Other effects observed at similar or higher doses were deemed to be either secondary to the haemolytic effects or not as a result of treatment. In these studies, a NOAEC of 25 ppm in rats in a 90 day study and and a LOAEC of 31 ppm (152mg/m3) rats in a chronic study were established based on haemolysis, as the only significant primary effect. The LOAEC of 31 ppm ( from a six month satellite group in the NTP, 2000 104-week study) is taken into account for the risk characterisation. However, it needs to be borne in mind that the no effect level for haemolysis is not time dependent and likely to be no lower in a chronic study compared to a sub-chronic study and that the LOAEC is likely to be close to the NOAEC, an observation supported by the 25ppm NOAEC.

Summary of the studies on animals performed by inhalation route

NOAEC (ppm)

Effects

Reference

Rats

15 exposures to 0, 20, 50 and 100 ppm.

4 exposures to 250 ppm.

20 ppm (haematological effects).

Haematological effects

Gage, 1970

13 weeks. Doses: 0, 5, 25, 75 ppm

25 ppm (haematological effects only)

Haematological effects only

Bushy Run Research Center, 1981

13 weeks. Doses: 0, 31, 62.5, 125, 250, 500 ppm

LOAEC of 31 ppm

Haematological effects.

Study performed to describe the vascular and bone lesion observed in moribund female.

Nyska, 1999.

Long, 2000

US NTP, 2000

104 weeks. Doses: 0, 31, 62.5, 125ppm

None identified for haematological effects; 31.2 ppm may be considered as an LOAEC.

Haematological effects. Effects on liver (Kupffer cell pigmentation).

NTP, 2000

15 days, 537ppm

None identified

BASF (1970)

90 days, 50ppm

None identified.

Haematological effects

Shell (1970)

Mice

Doses: 0, 100, 200, 400 ppm. Duration: 30, 60 or 90 exposures

100 ppm

Haematological effects at all doses

Mellon Institute of Industrial Research, 1955

14 weeks. Doses: 0, 31, 62.5, 125, 250, 500 ppm

None identified for haematological effects;

LOAECof 31 ppm

Haematological effects. Effect on body weight gain. Irritant effects on the forestomach.

NTP, 2000

104 weeks. Doses 0, 62.5, 125, 250ppm

none identified

LOAEC of 62.5 ppm

Haematological effects. Effects on liver (Kupffer cell pigmentation).

NTP, 2000

15 days, 537ppm

None identified

BASF (1970)

Guinea pigs

30 days

Dose: 0, 375 and 500 ppm

none identified

Mortality, effects on body weight and on kidneys. No effects on blood parameters.

Mellon Institute of Industrial Research, 1955

15 days, 537ppm

NOAEC=537ppm

BASF (1970)

Rabbits

15 days, 537ppm

None identified

BASF (1970)

Dogs

Duration between 2 and 90 days.

Dose: 0, 100, 200, 385 and 617

None identified

CNS depression, haemolytic anaemia. Effects on lungs, kidneys and liver.

Mellon Institute of Industrial Research, 1955

Cats

15 days, 537ppm

None identified

BASF (1970)

Monkeys

90 days,

Dose: 0, 100, 200 ppm.

-

Haematological effects (haemolysis)

Mellon Institute of industrial research

 

 

In addition to the above, a screening study established that the NOEC for cats, rabbits, rats and mice is well below 537ppm whereas this is a NOEC for guinea pigs. This confirms the observation that guinea pigs are particularly resistance to the toxicological (namely the haematotoxic) effects of this substance.


DERMAL

One sub-chronic study by the dermal route is available. A 13 week subchronic study up to the maximum dose achieved without skin irritancy problems occuring. No adverse effects were observed up to the maximum dose tested of 150 mg/kg bw/d.

Study (rabbits)

NOAEL (mg/kg bw/d)

Effects

Reference

Rabbits

13 weeks. Doses: 10 – 50 – 150 mg/kg bw/d

NOAEL > 150

No effects

Wil Research Lab., 1983

As this is in effect a limit dose study it is not suitable for deriving a DNEL and therefore a quantitative DNEL cannot be derived.

OVERALL SUMMARY

In rats and mice, haemolysis was consistently observed (whichever the route of administration) and was sometimes associated with hepatic effects (Kupffer cell pigmentation and absolute and relative liver weight increases), effects on body weight gain, hyaline degeneration of the olfactive epithelium (by inhalation), effects on the forestomach and effects on the WBC sub-populations (T lymphocyte). In these studies and for the inhalation route, no NOAEC was identified for mice, whereas a NOAEC value of 25 ppm (121 mg/m3) in rats was identified. In a separate study a LOAEC value of 31 ppm (150 mg/m3) can be established inrats, based on haemolysis and Kupffer cell pigmentation. Due to the closeness of the apparent LOAEL and NOAEL, it is considered prudent to take the more conservative LOAEL of 31 ppm forward for risk characterisation. However, the likelihood that this figure is close to the NOAEL will be taken into account in deriving appropriate assessment factors.

As humans are far less sensitive than other species (except Guinea Pig) to the haemolytical properties of 2-butoxyethanol, toxic effects other than haemolytical effects and related secondary effects have been sought which could be induced by 2-butoxyethanol. From all the studies, no specific relevant toxic effects, other that haemotoxicity, can be identified that are clearly related to treatment with 2 -butoxyethanol. For risk characterisation purposes therefore, haemotoxicity will be the end point chosen keeping in mind the interspecies differences (human/rodents) to calculate margin of safety. No other lesion has been identified which can be specifically attributed to treatment with 2-butoxyethanol .



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

Repeated dose toxicity: inhalation - systemic effects (target organ) cardiovascular / hematological: other

Justification for classification or non-classification

The main effects seen following repeated exposure to 2 -butoxyethanol are primary haemolysis and secondary effects as a direct consequence of these primary effects. The extensive data reported in chapter 7.9.3 conclusively establishes that these effects seen in the commonly used test species of rat, rabbit and mouse are not seen in humans. Humans are remarkably resistant to haemolysis. No other significant adverse effects were seen following repeated exposure. In terms of classifying 2 -butoxyethanol for repeat dose effects relevant to humans, no classification is warranted.