(tris[2-(2-hydroxyethoxy)ethyl] borate )

Repeated dose toxicity: oral

Administrative data

Endpoint:

sub-chronic toxicity: oral

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study

Justification for type of information:

Read across approach adequate to support 7.6.1 according to "Guidance on information requirements and chemical safety assessment Chapter R.6: QSARs and grouping of chemicals" (ECHA 2008) and Read-Across Assessment
Framework (RAAF) (ECHA 2017)

Cross-reference

Reason / purpose for cross-reference:

read-across source

Reference

Endpoint:

sub-chronic toxicity: oral

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Justification for type of information:

Read across approach adequate to support 7.6.1 according to "Guidance on information requirements and chemical safety assessment Chapter R.6: QSARs and grouping of chemicals" (ECHA 2008) and Read-Across Assessment
Framework (RAAF) (ECHA 2017)

Reason / purpose for cross-reference:

read-across source

Qualifier:

according to guideline

Guideline:

OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)

Species:

rat

Strain:

Sprague-Dawley

Sex:

female

Route of administration:

oral: drinking water

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

In a preliminary acute range-finding study conducted as part of this study, single oral (gavage) doses of 700, 2,000, or 8,000 mg/kg DEG were shown to produce dose related changes in renal function, as measured by several urinalysis parameters
A single (gavage) dose of 200 mg/kg DEG produced no changes.

Duration of treatment / exposure:

90 DAYS

Frequency of treatment:

daily

Dose / conc.:

0 mg/kg bw/day (nominal)

Dose / conc.:

200 mg/kg bw/day (nominal)

No. of animals per sex per dose:

8 females

Control animals:

yes

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Dose descriptor:

NOAEL

Effect level:

200 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

female

Basis for effect level:

body weight and weight gain

mortality

organ weights and organ / body weight ratios

Remarks on result:

not determinable due to absence of adverse toxic effects

Critical effects observed:

no

Conclusions:

A single group of eight adult female Sprague-Dawley rats was exposed daily to 0 or 200 mg/kg body weight DEG in drinking water for 90 days. In a preliminary acute range-finding study
conducted as part of this study, single oral (gavage) doses of 700, 2,000, or 8,000 mg/kg DEG were shown to produce dose-related changes in renal function, as measured by several urinalysis parameters. A single (gavage) dose of 200 mg/kg DEG produced no changes. Oral (drinking water) exposure to 200 mg/kg/day DEG for 90 days resulted in no significant effects on body weight or relative kidney weight versus the control groups.

Data source

Reference

Reference Type:

publication

Title:

Toxicity and carcinogenicity studies of Boric Acid

Author:

NTP

Year:

1987

Bibliographic source:

NTP tr 324

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)

Deviations:

not specified

GLP compliance:

not specified

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Reference substance 002

Cas Number:

10043-35-3

Specific details on test material used for the study:

- Name of test material: Technical grade boric acid
- Analytical purity: 99.7 %
- Stability under test conditions: Stable

Test animals

Species:

mouse

Strain:

B6C3F1

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Breeding Laboratories, MI, USA
- Age at study initiation: 7-8 weeks old
- Feed: Ad libitum

Administration / exposure

Route of administration:

oral: feed

Vehicle:

not specified

Details on oral exposure:

PREPARATION OF DOSING SOLUTIONS: In food given ad libitum

Analytical verification of doses or concentrations:

not specified

Details on analytical verification of doses or concentrations:

no data

Duration of treatment / exposure:

13 weeks for control and top dose group, 16 weeks for other dose groups

Frequency of treatment:

5 days per week in diet

Doses / concentrations

Doses / concentrations 1

Remarks:

0, 169 (47), 560 (98), 1120 (196), 2240 (392), 4480 (784) mg boric acid (mg B)/day females

Doses / concentrations 2

Remarks:

0, 194 (34), 405 (71), 811 (142), 1622 (284), 3246 (568) mg boric acid (mg B)/day males

No. of animals per sex per dose:

10 males and 10 females were used in each group.

Control animals:

yes, concurrent no treatment

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: No data


DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Twice per day


BODY WEIGHT: Yes
- Time schedule for examinations: Weekly


FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No data
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No data



OPHTHALMOSCOPIC EXAMINATION: No


HAEMATOLOGY: No


CLINICAL CHEMISTRY: No


URINALYSIS: No


NEUROBEHAVIOURAL EXAMINATION: No:

Sacrifice and pathology:

GROSS PATHOLOGY: Yes, all dose groups; organs: brain, spinal cord (if neurologic signs), pituitary, thyroid, parathyroid, thymus, oesophagus, salivary glands, stomach, small and large intestines, liver, pancreas, kidneys, adrenals, spleen, heart, trachea, lungs, bronchi, gonads, uterus, mammary gland, prostate, urinary bladder, gall bladder, mandibular lymph nodes, skin, eyes (if abnormal),
gross lesions and tissue masses.

HISTOPATHOLOGY: Yes

Results and discussion

Results of examinations

Clinical signs:

effects observed, treatment-related

Mortality:

mortality observed, treatment-related

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

not specified

Histopathological findings: neoplastic:

not specified

Details on results:

CLINICAL SIGNS AND MORTALITY
Eight out of the ten males and six out of the ten females from the 20000 ppm group died and one of the ten males from the 10000 ppm group died before end of study. Symptoms included nervousness, haunched appearance, dehydration, foot lesions and scaly tails. Incidences of extra medullary heamatopoiesis of spleen observed of varying severity in all dose groups for both males and females and hyperkeratosis and/or acanthosis of the stomach observed at the highest dose only in both males and females. At doses > 5,000 ppm (142 mg B/kg bw for the male), degeneration or atrophy of the seminiferous tubules was observed.


BODY WEIGHT AND WEIGHT GAIN
The mean bodyweights in the 5000, 10000 and 20000 ppm groups were 10 %, 17 % and 23 % lower than controls in males, and 8 %, 10 % and 18 % lower in females.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
food consumption increased by about 40 % by the 12th week in the 3 lower dose groups. Because of excessive scattering at the two highest dose levels intakes were unreliable.


GROSS PATHOLOGY AND HISTOPATHOLOGY: Incidences of extra medullary heamatopoiesis of spleen observed of varying severity in all dose groups for both males and females and hyperkeratosis and/or acanthosis of the stomach observed at the highest
dose only in both males and females. At doses of 5,000 ppm (142 mg B/kg bw for the male) and above, degeneration or atrophy of the seminiferous tubules was observed.

Effect levels

1

Dose descriptor:

LOAEL

Effect level:

> 811 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Critical effect in males was testis atrophy at doses (> 142mg B/kg bw) per day. In females deaths were observed at 4480 mg boric acid/kg bw (784mg B/kg bw)per day

2

Dose descriptor:

NOAEL

Effect level:

1 200 ppm

Based on:

test mat.

Sex:

male/female

Basis for effect level:

body weight and weight gain

clinical signs

food consumption and compound intake

mortality

other: testes degeneration and splen extramed hematopoiesis

3

Dose descriptor:

NOAEL

Effect level:

34 mg/kg bw/day (nominal)

Based on:

element

Sex:

male/female

Basis for effect level:

body weight and weight gain

clinical signs

food consumption and compound intake

mortality

other: testes degeneration and splen extramed hematopoiesis

4

Dose descriptor:

NOAEL

Effect level:

194 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

body weight and weight gain

clinical signs

dermal irritation

mortality

other: testes degeneration and splen extramed hematopoiesis

Target system / organ toxicity

Critical effects observed:

no

Any other information on results incl. tables

Results Mouse 90 day of repeated dose toxicity study

Parameter	Control		1200 ppm		2500 ppm		5000 ppm		10000 ppm		20000 ppm
	m^a	f	m	f^a	m^a	f^a	m^a	f^a	m^a	f^a	m	f
number of animals  examined	10	10	10	10	10	10	10	10	10	10	10	10
Mortality	0	0	0	0	0	0	0	0	1	0	8	6
clinical signs	0	0	+/-	+/-	+/-	+/-	+	+	+	+	++	++
body weight gain (g)	11.7	9.4	10.2	8.4	10.5	8.3	7.3	7.2	5.2	6.6	2.7	4.1
food consumption g/kg bw (wk 12)	140	190	165	229	164	219	199	271	456*	431*	753*	1138*
testes degeneration	0/10		0/10		0/10		2/10		8/10		8/10
spleen extramed. hematopoiesis	1	0	3	2	5	4	5	6	10	10	1	2

*unreliable because of food scatter

Applicant's summary and conclusion

Conclusions:

Eight out of the ten males and six out of the ten females from the 20000 ppm group died and one of the ten males from the 10000 ppm group died before end of study. Symptoms included nervousness, haunched appearance, dehydration, foot lesions and scaly tails. Incidences of extra medullary heamatopoiesis of spleen observed of varying severity in all dose groups for both males and females and hyperkeratosis and/or acanthosis of the stomach observed at the highest dose only in both males and females. At doses > 5,000 ppm (142 mg B/kg bw for the male), degeneration or atrophy of the seminiferous tubules was observed