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Toxicological information

Repeated dose toxicity: oral

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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:
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:
read-across source
Qualifier:
according to
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity 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:
mortality
body weight and weight gain
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:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents)
Deviations:
not specified
GLP compliance:
not specified
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
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 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 / concentrationsopen allclose all
Remarks:
0, 169 (47), 560 (98), 1120 (196), 2240 (392), 4480 (784) mg boric acid (mg B)/day females
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

open allclose all
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
Dose descriptor:
NOAEL
Effect level:
1 200 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
clinical signs
mortality
body weight and weight gain
food consumption and compound intake
other: testes degeneration and splen extramed hematopoiesis
Dose descriptor:
NOAEL
Effect level:
34 mg/kg bw/day (nominal)
Based on:
element
Sex:
male/female
Basis for effect level:
clinical signs
mortality
body weight and weight gain
food consumption and compound intake
other: testes degeneration and splen extramed hematopoiesis
Dose descriptor:
NOAEL
Effect level:
194 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
clinical signs
mortality
dermal irritation
body weight and weight gain
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

ma

f

m

fa

ma

fa

ma

fa

ma

fa

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