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Toxicity to reproduction: other studies

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Administrative data

Endpoint:
toxicity to reproduction: other studies
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Meets generally accepted scientific standards with acceptable restrictions.
Cross-reference
Reason / purpose:
reference to other study

Data source

Reference
Reference Type:
publication
Title:
Blood boron concentrations in pregnant rats fed boric acid throughout gestation
Author:
Price CJ, Strong PL, Murray FJ and Goldberg MM
Bibliographic source:
Reproductive Toxicology, Vol 11, No 6 pp 833-842

Materials and methods

Test guideline
Qualifier:
no guideline available
Principles of method if other than guideline:
Timed-mated Sprague-Dawley rats were exposed to boric acid in the diet from Gestational day 0 to 20. Dietary concentrations of Boric acid yielded average daily intakes equivalent to 0, 3, 6, 10, 13 and 25 mg/kg/d. At termination on Gestational day 20, maternal whole blood was collected in heparinized vacutainer tubes, stored frozen (-20°C) and subsequently prepared by a high-temperature alkaline ashing procedure for analysis of boron by inductively coupled plasma optical emission spectrometry.
GLP compliance:
yes
Type of method:
in vivo

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): BA (CAS No 10043-35-30
- Analytical purity:
99% by ICP
98% by titration with 0.1 N sodium hydroxide
- Lot/batch No.:872703

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source:Charles River Laboratories Inc. (Raleigh, NC)
- Diet: ad libitum
- Water: ad libitum

Further details are reported in: Price et al, Developmental toxicity NOAEL and postnatal recovery in rats fed boric acid during gestation, Funamental applied toxicology. 1996 32: 179-93

Administration / exposure

Route of administration:
oral: feed
Vehicle:
not specified
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
ICP
LOQ 0.00281%
Duration of treatment / exposure:
Gestation day 0 to 20
Frequency of treatment:
In feed, ad libitum
Duration of test:
20 days
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
0.025%, 0.050%, 0.075%, 0.100%, 0.200%
Basis:
analytical conc.
Remarks:
Doses / Concentrations:
0, 19, 36, 55, 76, 143 mg Boric acid/kg BW/day
Basis:
actual ingested
Remarks:
Doses / Concentrations:
Equivalent to 0, 3, 6, 10, 13, 25 mg Boron/kg BW/day
Basis:
actual ingested
No. of animals per sex per dose:
28 to 32
Control animals:
yes, plain diet
Statistics:
In order to determin the degree to which calculated maternal boron intake predicted maternal blood boron concentration on gestation day 20, a linear regreassion by least square estimation was performed using the regression tool in Excel.

Results and discussion

Effect levels

Dose descriptor:
other:
Effect level:
0.075 - 0.1 other: %
Based on:
test mat.
Sex:
female
Basis for effect level:
other: Concentrations in whole blood from the 0.075% and 0.1% exposure groups (1.27 and 1.53 µg B/g blood) coresponded to the NOAEL and LOAEL (10 and 13 mg B/kg bw/d respectively).

Any other information on results incl. tables

Blood boron concentrations on gestation day 20:

Almost all of the boron concentration in the control group and 2 of 29 in the low dose group fell between the LOD and the LOQ (LOD = 0.105µg B/g blood, LOQ = 0.350µg B/g blood).All remaining samples where above the LOQ. Blood samples had boron concentrations that were clearly related to the concentration of boric acid in the diet.

 

Table 1: Boron concentration (µg boron/g) in whole blood on gestation day 20

Boric acid in feed

(% in feed gestation day 0 to 20)

Control 

0.025% 

0.050% 

0.075% 

0.100% 

0.200% 

Boron intake  

(mg B/kg BW/day)

 -

3.3±0.1 

6.3±0.1 

9.6±0.1 

13.3±0.2 

  25.4±0.4

Blood boron

(µg B/g blood)

 0.229±0.143

(n=24)

0.564±0.211* 

(n=29)    

0.975±0.261* 

(n=27)  

1.27±0.298* 

(n=25)  

1.53±0.546* 

(n=26)  

2.82±0.987* 

(n=24)  

Relative SD (%)

 62.6

37.5 

26.8 

23.4 

35.7 

35.1 

Minimum

(µg B /g blood)

0.122 

0.189 

0.407 

0.705 

0.222 

1.09 

Maximum  

(µg B /g blood)

0.695 

1.34 

1.57

1.75

2.47

5.13 

*Statistically significant (one tailed Studentt-test (P<0.05)

 

Correlation of blood boron concentrations on gestation day 20 with dietary intake and time of blood collection:

Maternal blood boron concentrations at termination showed a robust positive correlation with measured boron intake expressed as either the average daily intake for the entire exposure period (gestation day 0-20) or for the final 24 h (gestation day 19-20).

 

Correlation of selected developmental toxicity endpoints with blood boron concentration on gestation day 20:

Examples of affected and unaffected developmental toxicity endpoints were selected as response variables for regression analysis.

Three related exposure indices were used as the regressors, specifically nominal concentration of boric acid in feed (%), individual maternal daily intake (mg boron/kg body weight/d), and individual maternal blood boron concentrations (µg boron/g) on gestation day 20. The regression analyses for number of live foetuses per litter yielded R2 values close to zero for all three indices of boron exposure. This is consistent with the finding that the number of live foetuses per litter was not affected by ingestion of diets containing 0 to 0.2% boric acid.

Three embryo/foetal endpoints were affected on gestation day 20 following exposure to ≥0.1% boric acid in the diet, specifically decreased foetal body weight and increased incidences of short rib and wavy rib. Data for the rib endpoints were not suitable for regression analysis, due to the large proportion of litters that exhibited no foetuses with either of these findings in most of the dose groups. Therefore, foetal body weight was the only affected embryo/foetal endpoint used for regression analysis. Regression analyses for foetal body weight indicated a significant, though not robust, correlation between average male or female body weight per litter and each of the three exposure indices. Because R2 values were similar for male or female foetuses, the scatter plot for the female foetal body weight per litter versus maternal blood boron are provided to demonstrate the outcome of the regression analyses for foetal body weight. These results are consistent with the finding that average foetal body weight per litter on gestation day 20 (both sexes) was significantly reduced following exposure to 0.1% or 0.2% BA (94% or 88% of control foetal weight, respectively).

 

Table 2: Correlation of individual maternal blood boron (µg boron/g) with developmental toxicity endpoints

Response variable

Toxic effect

Regressor

R2

No live foetuses/litter

No effect

Intake

Blood

Dose

-0.00554

-0.00525

-0.00612

Female foetal body wt (g)/litter

↓*

Intake

Blood

Dose

0.253

0.340

0.290

Male foetal body wt (g)/litter

↓*

Intake

Blood

Dose

0.239

0.343

0.273

*Mean foetal body weights (g/litter) were significantly reduced treatment groups fed 0.100% or 0.200% boric acid in the diet

Applicant's summary and conclusion

Executive summary:

Average concentration of boron in the blood increased with increased dietary exposure.

Concentrations in whole blood from the 0.075% and 0.1% exposure groups (1.27 and 1.53 µg B/g blood) coresponded to the NOAEL and LOAEL (10 and 13 mg B/kg bw/d respectively) reported previously