Tall oil, reaction products with diethylenetriamine

Endpoint summary

Description of key information

This endpoint is addressed based on read across to repeated dose oral toxicity data for the major components (AAI_DETA and Rosin) of the submission substance DTO_DETA.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

sub-chronic toxicity: oral

Type of information:

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

Adequacy of study:

key study

Justification for type of information:

It is considered appropriate to address the data requirements for DTO_DETA by read-across to the available studies on the main components of DTO_DETA: AAI_DETA and Rosin.
DTO_DETA contains comparatively lower levels of imidazolines and higher levels of resin acids than AAI_DETA and therefore consideration of data for resin acids is also considered necessary. The main resin acid in DTO_DETA is abietic acid, but abietic acid derivatives and other acids, such as pimaric acid, are also found in notable quantities, and the resin acids collectively are known as ‘rosin’. DTO_DETA contains up to 25% unreacted rosin, and taking into account the compositional information available for the rosin in DTO_DETA and Rosin (CAS# 8050-09-07, EC# 232-475-7), the latter was considered appropriate for read-across to DTO_DETA.
A recent guideline (OECD 408) 90-day rat study has been conducted with the read across (source) substance AAI_DETA (WIL Research, 2014). In addition, a combined repeated dose oral toxicity study with reproduction/developmental toxicity (OECD 422) conducted with AAI_DETA is available (NOTOX, 2010). Read across to these studies is considered appropriate since AAI_DETA is the main component in the target substance, DTO_DETA. The lowest NOAEL is 10 mg/kg bw/d (90-day) and this value will be used for DNEL derivation. A number of studies conducted with Rosins are available as supporting information; the studies are generally older and predate current guidelines however when taken as a weight of evidence approach they indicate low toxicity following repeated exposure in rats and dogs. The 90-day NOAEL for systemic toxicity following exposure to rosin and its derivatives was found to be 400-500 mg/kg bw/d. Based on these results, the Rosin content is not considered to affect the hazard profile of DTO_DETA following sub-chronic exposure, and therefore read across to AAI_DETA is both justified and conservative.

Reason / purpose for cross-reference:

read-across source

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Males at 30 and 100 mg/kg showed a lower mean body weight and body weight gain from Week 5 of the treatment period onwards, being statistically significant at 100 mg/kg. The lower mean body weight at 100 mg/kg was considered to be primarily due to a lower weight gain of two males. Mean body weight and body weight gain of females at 100 mg/kg also appeared slightly lower than controls during the last weeks of treatment.

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

Males at 30 and 100 mg/kg showed a slightly lower food intake during the larger part of the treatment period. After correction for body weight, food consumption of these males was similar to control levels. Food consumption before or after correction for body weight for females remained similar to control means over the study period.

Food efficiency:

not specified

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

no effects observed

Description (incidence and severity):

Based on subjective appraisal.

Ophthalmological findings:

no effects observed

Haematological findings:

no effects observed

Clinical biochemistry findings:

effects observed, treatment-related

Description (incidence and severity):

The following (statistically significant) changes in clinical biochemistry parameters distinguished treated animals from control animals:
- Higher alanine aminotransferase activity (ALAT) in males and females (most notably for one female) at 100 mg/kg,
- Higher aspartate aminotransferase activity (ASAT) in males (most notably for one male) and females at 100 mg/kg,
- Lower total protein levels in males (most notably for one male) and females at 100 mg/kg,
- Lower albumin levels in males (most notably for one male) and females at 100 mg/kg,
- Higher glucose levels in males at 100 mg/kg (upon excluding one male),
- Lower urea levels in males at 100 mg/kg (a trend towards an increase was also apparent among female dose groups),
- Higher bile acid levels in females at 100 mg/kg,
- Lower calcium levels in females at 100 mg/kg.
One male at 100 mg/kg also showed a lower glucose value and a higher total bilirubin, bile acid and inorganic phosphate level.

Urinalysis findings:

not specified

Behaviour (functional findings):

effects observed, treatment-related

Description (incidence and severity):

Males at 100 mg/kg showed a statistically significantly lower motor activity (based on counts for total movements). Females also showed a trend towards lower motor activity at 30 and 100 mg/kg, but means did not achieve a level of statistical significance.

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

The following (statistically significant) changes in absolute organ weights and relative organ weights (organ to body weight ratio) were considered to be related to treatment:
- Lower liver weights in males at 100 mg/kg (with a decreasing trend for absolute liver weights across other male groups),
- Lower thymus weights in males at 100 mg/kg (with a decreasing trend for absolute thymus weights across other male groups),
- Lower spleen weights in males at 100 mg/kg (with a decreasing trend for absolute spleen weights across other male groups).
- Lower prostate weights at 100 mg/kg.

Gross pathological findings:

no effects observed

Neuropathological findings:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

The following microscopic findings were considered to be related to treatment:
- Lung (alveolar (mainly foamy) macrophage aggregations):
At 100 mg/kg: increased incidence and severity in females (6/10 females, 4 minimal, 2 slight).
- Small intestines (foamy macrophages in the lamina propria):
At 10 mg/kg: in jejunum in 1/10 males and 3/10 females and in ileum in 3/10 males and 3/9 females (all minimal).
At 30 mg/kg: in duodenum in 1/10 males (slight), in jejunum in 1/10 males (minimal) and 4/10 females (minimal) and in ileum in 8/10 males (6: minimal, 2: slight) and females 10/10 females (5: minimal, 5: slight).
At 100 mg/kg: in duodenum in 8/10 males (7: minimal, 1:slight) and in 5/10 females (4: minimal, 1: slight), in jejunum in 10/10 males (2: minimal, 8: slight) and 8/10 females (6: minimal, 2: slight) and in ileum in 10/10 males (1: minimal, 7: slight, 2: moderate) and in 10/10 females (8: slight, 2: moderate).
- Kidneys (foamy macrophages in the glomeruli):
At 100 mg/kg: in 7/10 males (6: minimal, 1: slight) and in 9/10 females (minimal).
- Mesenteric lymph node (foamy macrophages):
At 10 mg/kg: in 1/10 female (slight),
At 30 mg/kg: in 2/10 males (minimal) and in 3/10 females (minimal)
At 100 mg/kg: in 10/10 males (7: slight, 2: moderate, 1: marked) and in 8/10 females (1: slight, 7: moderate).
- Mesenteric lymph node (pigmented macrophage foci):
At 30 mg/kg: slightly increased incidence and/or severity in 9/10 males (4: minimal, 5: slight) and in 9/10 females (7: minimal, 2: slight).
At 100 mg/kg: slightly increased incidence and/or severity in 10/10 males (5: minimal, 5: slight) and in 7/10 females (3: minimal, 4 slight).

Histopathological findings: neoplastic:

no effects observed

Other effects:

effects observed, non-treatment-related

Description (incidence and severity):

ESTROUS CYCLE DETERMINATION
No treatment related changes in estrous cycle length were noted across the dose groups during the period in which estrous cycle length was determined (Day 72 up to and including Day 92). One control female, and three females at 30 mg/kg showed an irregular estrous cycle length. All other females showed a normal (regular) estrous cycle of 4 days. The incidence of irregular estrous cycle length showed no relationship to the dose, and was therefore considered unrelated to treatment.

SPERM ANALYSIS
The spermatogenic staging profiles were normal for all males of the control group and the 100 mg/kg group, except for one male at 100 mg/kg (all stages missing). The macroscopic and microscopic findings recorded for this male at 100 mg/kg included effects in the reproductive organs (flaccid and reduced size of testes, microscopic correlate: undeveloped testes; reduced size of epididymides, microscopic correlate: reduced sperm; reduced size of prostate gland, microscopic correlate: immature) and liver (reduced size, no microscopic correlate and accentuated lobular pattern, microscopic correlate: difference in cell size periportal-centrilobular). These findings for this single male at 100 mg/kg were considered to be incidental findings and unrelated to treatment.

Key result

Dose descriptor:

NOAEL

Effect level:

ca. 10 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

histopathology: non-neoplastic

Key result

Critical effects observed:

yes

Lowest effective dose / conc.:

30 mg/kg bw/day (nominal)

System:

gastrointestinal tract

Organ:

intestine

mesenteric lymph node

Treatment related:

yes

Dose response relationship:

yes

Relevant for humans:

yes

Conclusions:

The 90-day NOAEL is considered to be 10 mg/kg bw/d. At higher dose levels an increase of the presence of foamy macrophages in the lamina propria of the small intestines and mesenteric lymph nodes is observed, as well as lower mean body weight and body weight gain, especially in the males, with lower food intake, essentially during the second half of the treatment period.

Executive summary:

A guideline (OECD 408) 90-day rat study has been conducted with the read across (source) substance AAI_DETA (WIL Research, 2014). AAI_DETA was administered to rats by daily gavage at dose levels of 0, 10, 30 and 100 mg/kg bw/d for 90 days. The NOAEL was determined to be 10 mg/kg bw/d based on the presence of foamy macrophages in the lamina propria of the small intestines and mesenteric lymph nodes, as well as lower mean body weights and body weight gain with lower food intake at 30 mg/kg bw/d and above. AAI_DETA is a major component of DTO_DETA therefore read across is considered justified. A number of other repeated dose toxicity studies are available for AAI_DETA and Rosins, and are provided as supporting information; the NOAEL obtained in the 90-day rat study with AAI_DETA (WIL Research, 2014) is the lowest available NOAEL and is therefore used for DNEL derivation.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

10 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

Read across to OECD guideline and GLP-compliant study

System:

gastrointestinal tract

Organ:

intestine

mesenteric lymph node

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Repeated dose oral toxicity

No repeated dose oral toxicity data are available for DTO_DETA; this endpoint is addressed based on read across to studies conducted on the main components of DTO_DETA: AAI_DETA and Rosin. Studies available in the rat and dog with Gum Rosin indicate low toxicity with minor effects linked to poor palatability; these studies demonstrate that the rosin component will not significantly impact on the overall toxicity profile of DTO_DETA. A guideline (OECD 408) 90-day rat study is available with AAI_DETA (WIL Research, 2014). The NOAEL was determined to be 10 mg/kg bw/d based on the presence of foamy macrophages in the lamina propria of the small intestines and mesenteric lymph nodes, as well as lower mean body weights and body weight gain with lower food intake at 30 mg/kg bw/d and above. A number of other repeated dose toxicity studies are available for AAI_DETA and are provided as supporting information; the NOAEL obtained in the 90-day rat study with AAI_DETA is the lowest available and is therefore used for DNEL derivation.

Justification for classification or non-classification

Based on the results of the available studies, DTO_DETA does not require classification for repeated exposure (STOT-RE) according to Regulation (EC) No. 1272/2008.